Mitral Valve Disease and the
Cavalier King Charles Spaniel
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December 2017: Ohio State cardiologists find systolic function of right ventricles in MVD-affected dogs is affected by the stage of MVD. In a December 2017 article, a team of Ohio State University cardiologists (E.H. Chapel, B.A. Scansen, K.E. Schober, J.D. Bonagura [photo below]) studied 36 MVD-affected dogs divided into three groups -- Stages B1, B2, and C -- to determine whether the heart's right ventricle (RV) systolic function varies as MVD progresses from Stage B1 to Stage C. The breeds were not identified. None of the dogs were being treated with MVD medications. They report finding that right ventricular systolic function differed between stages of MVD, increasing in Stage B2, and declining in Stage C. These conclusions differ from previous reports, where no difference in RV systolic function was measured between the stages of MVD. They stated that the reason might be because of the administration of MVD medications in some dogs in the previous studies.
EDITOR’S NOTE: In this study, the dogs allegedly were separated into three categories: Stage B1 (those with MVD but no heart enlargement); Stage B2 (those with heart enlargement); and Stage C (those in heart failure). In other recent studies of this nature, the investigators have opted to forego carefully determining whether the MVD-affected dogs had enlarged hearts or not. In those studies, the investigators concocted totally unsubstantiated, arbitrary measurements of the vertebral heart score (VHS) value, the left atrium dimension (LA/Ao), and the left ventricle dimension (LVIDDN) and applied them to every dog of numerous breeds. We discuss these bogus measurements at some length in our Blog article, “Why are cardiology researchers inventing bogus definitions of species-wide heart enlargement to test risky drugs?”
That said, we initially were optimistic that, maybe at least in this study, these investigators would behave in a professionally responsible manner and determine for each dog whether it really did have an enlargement of its heart, rather than “defining” enlargement by picking a set of arbitrary numbers and plugging in the dogs’ results. After all, they were only dealing with 36 dogs. How time consuming would it be to determine the ACVIM stage of each dog in an accurate manner? No such luck! Apparently, these investigators, like the others, lacked the patience to analyze the dogs’ MVD stages in a professional way.
They have picked out three arbitrary sets of measurements which they inexplicably somehow divined from the backsides of their minds (since they give no justification for any of these numbers), and they have applied them to all dogs in their study, regardless of breed. Here is what they wrote about that:
“Dogs were divided into 3 groups based on the ACVIM classification of valvular heart disease. The ACVIM staging does not specify a specific method for determining remodeling, and both radiographic and echocardiographic criteria were used in this study. Specifically, asymptomatic dogs with a VHS ≤ 10.5, LVIDDN ≤ 1.6, and absence of left atrial dilatation (long-axis LA:Ao ≤ 2.4)c were classified as stage/group B1 (MR without remodeling); asymptomatic dogs with a VHS > 10.5, LVIDDN > 1.6, and LA:Ao > 2.4 were classified as stage/group B2; and dogs with VHS > 10.5, LVIDDN > 1.6, and LA:Ao > 2.4 and with radiographic and clinical evidence of left-sided CHF were classified as stage/group C.” (Emphasis added.)
Here is a comparison of this study’s species-wide, arbitrary definition of Stage B2 (MVD with enlargement) to the EPIC Study’s species-wide, arbitrary definition:
● VHS value: EPIC Study: >10.5; this study: > 10.5
● LA/Ao ratio: EPIC Study: ≥ 1.6; this study: > 2.4
● LVIDDN: EPIC Study: ≥ 1.7; this study: > 1.6
So, which ones are the correct ones? Let’s face it. These measurements are total nonsense. They do not measure how much the heart has enlarged over time; they just measure the current dimensions of parts of the heart. There are no published, peer-reviewed veterinary studies which justify any such measurements defining heart enlargement for every dog of every breed in their studies. If any such documented support existed, surely the investigators would have cited it in their articles. By arbitrarily picking numbers like these and declaring that they define whether the dogs have enlarged hearts or not necessarily results in a failed study. They have made this research a complete waste of their time and somebody else’s money.
Amazingly, these investigators blame the 2009 ACVIM Consensus Statement for their self-imposed dilemma. They write:
“The ACVIM staging does not specify a specific method for determining remodeling, ... .”
That is a flat prevarication (lie)! Here is what the ACVIM Consensus Statement tells them about how to professionally determine whether a given dog has an enlarged heart or not:
“Thoracic radiography is recommended in all patients to assess the hemodynamic significance of the murmur and also to obtain baseline thoracic radiographs at a time when the patient is asymptomatic for CVHD.
“Stage B2: Hemodynamically significant MR with cardiac remodeling (defined as clearly enlarged LA, LV, or both); normotensive.”
Somehow they missed that paragraph, which is under the uncomplicated heading: “Diagnosis for Stage B.” And note that one of the authors of the 2009 Consensus Statement also is one of the authors of this study. If any of them have no excuse, Dr. Bonagura (right) does not. But even if they had to dream up from scratch their own way to measure enlargement, the worst way is the one they chose -- to pick a bunch of arbitrary numbers and pretend that these numbers define Stage B2 for all breeds of dogs.
December 2017: Cardiologists strike out in search for the genetic cause of MVD in cavaliers. In a December 2017 article, a team of veterinary cardiologists (K.M. Meurs (right) S.G. Friedenberg, B. Williams, B.W. Keene, C.E. Atkins, D. Adin, B. Aona, T. DeFrancesco, S. Tou, T. Mackay) examined the DNA in ten cavalier King Charles spaniels and ten Dachshunds affected with mitral valve disease (MVD), searching for varients of genes known to be analogous to genetic mutations associated with MVD in humans. They report finding no such variants in any of the canine genes evaluated, and that they did not identify any genetic cause responsible for human MVD in the dogs studied. They concluded that MVD in the CKCS and Dachshund may not share an identical genetic cause with the human MVD.
December 2017: EPIC Study's longitudinal analysis has significant surprises for the investigators. In a December 2017 article by the team of cardiologists who conducted the EPIC Study (published in September 2016), they reported the following results:
● Of the 354 dogs in the study, only 135 (38%) reached heart failure (CHF).
● At day 35, heart size (LA/Ao) had reduced in both the pimobendan group and the placebo group.
● Quality of life was perceived by owners to be improved after 1 month of treatment for both the placebo and pimobendan groups.
● At the onset of CHF, dogs receiving pimobendan were indistinguishable from those receiving placebo, and both groups had larger hearts and worse quality of life compared to baseline.
● A greater number of dogs in the pimobendan group experienced deterioration in exercise tolerance at the onset of CHF.
They found that there were no consistent differences observed between treatment groups in quality of life scores, change in heart murmur intensity, change in heart disease stage, and change in body condition scoring when examined over the first two years. They concluded that "Pimobendan treatment reduces heart size."
EDITOR'S NOTE: Despite the EPIC Study authors' claim that all dogs in the study had enlarged hearts at the start of the trial, we already know (by lead investigator Dr. Adrian Boswood's own admissions in an on-line interview) that the inclusion criteria were for many dogs with normal-sized hearts and not enlarged ones. Also, all that the inclusion criteria did was measure heart size and not whether the hearts actually were enlarged. Since no determination was made to identify which of the 354 dogs really had enlarged hearts at the start, they did not have adequate information in order to assign an equal number of dogs with enlarged hearts to the two groups -- the pimo group and the placebo group. Therefore, all comparisons of results are totally unreliable.
When you consider that nearly half of all of the dogs in this study were cavalier King Charles spaniels, the investigators' use of inclusion criteria which all 36 of them had to know did not come close to defining cardiomegaly (enlargement) in the CKCS, is nothing less than professionally irresponsible, thereby intentionally putting our breed at high risk by administering pimobendan for several years to cavaliers with no heart enlargement at all.
Nevertheless, these results suggest that as many as 62% of the dogs in the study did not need pimobendan because they never reached CHF. This is consistent with a previous estimate that as many as 70% of all MVD-affected dogs with mild heart enlargement will never reach CHF and therefore do not need any medication to delay the onset of heart failure.
Also, this article shows that left atrium of dogs in both groups -- pimo and placebo -- had reduced in size when measured on the 35th day. This finding apparently was so disappointing to the authors (and especially to the study's 100+% financial sponsor, the manufacturer of Vetmedin) that they spent a very lengthy paragraph of their article wildly speculating on how it could have been possible for the hearts of the placebo group to significantly reduce in size, using such terms as "One possible explanation for this would be ...".
They admit that more of the pimodendan group dogs experienced deterioration in exercise tolerance at the onset of CHF than the placebo group dogs. And, finally, there was no significant difference in the quality-of-life measurements for dogs in either group as of the 35th day. But, as with these investigators' first EPIC Study article, it is what they do not report or explain which is most disappointing, albeit totally expected. For example, they fail to explain whether pimobendan was at all needed for the 62% of the dogs which never reached heart failure. After all, delaying the onset of CHF was what the EPIC Study was supposed to be all about. All in all, this has been an EPIC FAIL!
December 2017: An ACE gene polymorphism may explain why ACE-inhibitors are less effective in MVD-affected cavaliers. In a December 2017 article, a team of veterinary cardiologists (Meurs KM, Olsen LH, Reimann MJ, Keene BW, Atkins CE, Adin D, Aona B, Condit J, DeFrancesco T, Reina-Doreste Y, Stern JA, Tou S, Ward J, Woodruff K) studied 73 cavalier King Charles spaniels and report finding that:
"The CKCS appears to have a high prevalence of the ACE variant. Dogs with the ACE variant had lower levels of ACE activity even in more advanced mitral valve disease than dogs without the variant."
They conclude with the hedge comment that the impact of their finding "on the need for ACE-I in dogs with the polymorphism and heart disease deserves further study."
EDITOR'S NOTE: This is one of four reports by members of this team of researchers regarding the reasons for ACE-inhibitors not being necessary to reduce angiotensin converting enzyme (ACE) activity in treating cavaliers with MVD. We report on two of the others here: this November 2017 article and this June 2016 article. In 2002, the SVEP Study of 229 cavaliers concluded that ACE-inhibitors were ineffective in delaying the onset of heart failure in MVD-affected CKCSs which were in either Stage B1 or B2. These more recent studies help to explain the reasoning behind the SVEP Study findings, which is that ACE-inhibitors do not benefit cavaliers because the breed has reduced ACE activity to begin with.
At some point we would hope that the estimated 70% of veterinary cardiologists who have been ignoring the SVEP Study for the past 15 years and still insist upon prescribing unnecessary ACE-inhibitors to cavaliers might bother to read this body of research and stop treating cavaliers as if they are no different from other breeds with MVD. What is there about the SVEP Study -- the largest veterinary cardiology trial of CKCSs in history -- that these cardiologists cannot understand? When it comes to MVD, the cavalier is a very unique breed, and it is time for all cardiologists to realize that fact and start treating cavaliers accordingly.
December 2017: Japanese surgeons report successful, complicated mitral valve repair of a mixed-breed Chihuahua using Gore-Tex e-PTFE sutures. In a November 2017 article by a team led by Japanese heart surgeons (Satoko Yokoyama, Isamu Kanemoto, Kippei Mihara, Takanori Ando, Koudai Kawase, Yasuaki Sahashi, Kazuhito Iguchi), they report the successful complicated repair of the deformed mitral valve of a Chihuahua mixed breed using Gore-Tex e-PTFE sutures. The valve's two leaflets had multiple lesions causing deep gaps and several elongated or ruptured chordae. The surgeons used three mitral valve plasty techniques: artificial chordal reconstruction for the ruptured or elongated chordae tendineae, semicircular suture annuloplasty for a dilated mitral annulus, and valvuloplasty for the deformed valve leaflets. Gore-Tex e-PTFE sutures were used to make the repairs. (The diagram shows where suture repairs were made to the valve leaflets.) The dog lived nearly five years following the heart surgery and endured two major non-heart surgeries in the interim. This report was first presented to a veterinary cardiology conference in 2010.
December 2017: Bulgarian cardiologist finds echo marker of LA/Ao ratio and x-ray VHS values cannot be used to initiate MVD therapy. In an October 2017 article, Bulgarian cardiologist Atanas Pankov (right) studied the usefulness of the echocardiographic ratio of the left atrium to the aorta (LA/Ao) in MVD-affected dogs as a marker for Stage B2 heart enlargement and the timing to initiate medical treatment. He used two groups of multi-breed MVD-affected dogs, one group with pulmonary edema (including a cavalier King Charles spaniel) and the other group without edema. He found that:
"LA/AO can be used as an important indicator in the interpretation of data in group studies, but it cannot conclusively demonstrate the need for a medical intervention in the individual."
He also found that VHS values were not useful as a marker for starting treatment. He concluded:
"The ratios LA/AO; LC/AO and the values of VHS, despite the statistically significant differences between the two treatment groups, cannot be used as a marker to initiate therapy in patients with MVD, due to the overlapping values obtained in this study."
EDITOR'S NOTE: This study completely discredits the EPIC Study's inclusion criteria and final recommendations. The EPIC Study "defined" Stage B2 heart enlargement as any dog having at least a certain LA/Ao ratio, a certain VHS value, and one other specified echo measurement, for all 360 of its dogs, regardless of breed. Considering the EPIC Study investigators' abject failure to perform any independent analysis to determine whether any of its 360 dogs actually had any heart enlargement at the start of their testing (and how the non-heart-enlarged dogs were assigned among the two study groups), this Bulgarian study demonstrates the total lack of usefulness of both the EPIC Study's inclusion criteria and its clinical recommendations for starting pimobendan therapy. This study finds that no such minimum markers can be used to start treatment, because they do not accurately indicate heart enlargement on a species-wide basis.
November 2017: USA cardiologists study 247 records of MVD-affected dogs to determine what VHS values also equated to EPIC Study echo criteria. In a September 2017 abstract presentation to the European Society of Veterinary Internal Medicine’s 27th ECVIM-CA Congress in Malta, a group of USA cardiologists (J.P. Vitt, S. Gordon, R.C. Fries, J.D. Rhinehart, S.E. Achen, I. Sosa, A.H. Estrada, J.A. Carlson, R.L. Winter, S. Kadotani, K.E. Lamb) examined the radiographic and echocardiographic records of 247 MVD-affected dogs at 8 locations to attempt to identify a minimum vertebral heart score (VHS) value that would also predict EPIC’s echocardiography inclusion criteria without having to perform echocardiographic examinations. They report that of the 247 dogs which met EPIC’s minimum VHS value of 10.5, only 126 (51%) met EPIC’s two minimum echo parameters (LVIDDN ≥1.7 and LA:Ao ≥1.6). They found that MVD-affected dogs with a VHS > 11.7 had an 85% likelihood of also meeting the echo parameters, and that roughly 34% of dogs with VHS values between 10.6 and 11.7 may meet those two echo measurements. They conclude:
“These results may help veterinarians apply the results of the EPIC Trial to dogs with preclinical MMVD when an echocardiogram is not readily available.”
EDITOR’S NOTE: This study unintentionally highlights the fact that the EPIC Study’s inclusion criteria -- vertebral heart size (VHS) >10.5, echocardiographically derived normalized left ventricular internal dimension in diastole (LVIDDN) ≥1.7, and left atrial to aortic ratio (LA:Ao) ≥1.6 -- do not in reality define enlargement and necessarily include dogs with normal-sized hearts. This fact alone proves that the EPIC Study is fatally flawed and puts some MVD-affected dogs, particularly cavaliers, at greater risk of suffering the harmful effects which pimobendan has been shown to cause in some instances of its premature administration.
If we assume (an assumption which already has been disproven) that EPIC’s two echo parameters will always predict heart enlargement regardless of breed, then this study tells us that if the clinician relies only upon an x-ray showing a VHS value of >11.7, then 15% of the dogs still will not have enlarged hearts. It also proves that there can be no such thing as a species-wide minimum measurement for heart enlargement, without forcing dogs with normally smaller hearts to have to reach enlargement measurements so big that they would guarantee that the dogs reach heart failure before being treated.
We already know that even the EPIC Study’s chief lead investigator, Dr. Adrian Boswood, began ridiculing the VHS >10.5 and LVIDDN ≥1.7 and LA/Ao ≥1.6 criteria within a month of the EPIC Study report’s publication last year when he stated in an audio-recorded interview:
“A vertebral heart score of 10.5 is in the normal range for some dogs, particularly cavaliers actually.”
“Now interestingly, if you look in the literature, the normalized left ventricular diameter [LVIDDN] of 1.7 is in the normal range. The abnormal is above about 1.85, [1.]9, 1.9 depending upon how you read it, so that's nudging the top of the normal range but still normal.”
“Everyone knows you can get an inaccurate single measurement of left atrium to aortic ratio -- over-estimated. The dog goes on to treatment it didn't need.”
So, now we have another of the EPIC Study three lead investigators -- Dr. Sonya Gordon -- and a few other cardiologists trying to salvage the study’s parameters from the trash heap. What they are telling us is that MVD-affected dogs with an VHS value above 11.7 have a better than average chance of also having echo measurements within the range of the EPIC Study’s echo parameters. And, they report that dogs with VHS values from 10.6 to 11.7 have a much worse than average likelihood of meeting those echo minimums.
Interestingly, the same Dr. Gordon published an article in June 2017 in which she confidently advised clinicians:
“Use of a VHS of ≥11.5 will improve the specificity (positive predictive value) of significant heart enlargement and guard against overtreatment of possible stage B1 dogs.”
Yet now we find that she reports that an even higher minimum VHS threshold value of >11.7 will unconfidently give clinicians maybe an 85% chance of predicting enlargement. But what she still does not admit is the fact that EPIC’s two echo parameters are no more accurate guides to species-wide heart enlargement than is EPIC’s VHS parameter. So just because a VHS value above 11.7 might coincide with the two echo parameters, that dog still may have no heart enlargement at all.
What is certain is that the EPIC Study parameters do not equate to heart enlargement and were never intended to. Furthermore no effort was made in the EPIC Study trial, and no effort has been made in this reported retrospective file review, to determine if any of the 360 dogs in the EPIC Study and/or any of the 247 dogs in this file review actually had enlarged hearts. All that these cardiologists are doing is measuring distances within the dogs’ hearts. Those measurements do not mean the dogs’ hearts are enlarged. Enlargement means that the size of the heart has gotten bigger over time. One set of measurements on a single day does not tell the clinician that the dog’s heart is enlarged, because the clinician does not know whether or not the heart ever was smaller than it is on the single day it was measured.
There are -- as there have been, for decades in the field of veterinary cardiology -- professional ways to accurately determine if an MVD-affected dog’s heart is enlarged or not. Examples include (a) careful examination of x-rays showing the shape of the dog's heart, with emphasis upon the left atrium and left ventricle, looking for bulges and roundness; (b) comparison of current x-rays with earlier baseline x-rays. That professionalism is one of the reasons board certified veterinary cardiologists are board certified and earn the big bucks. For some inexplicable reason, the EPIC Study investigators and the authors of this report do not want have to bother to perform that professional veterinary service. They prefer to urge primary care veterinarians to rely upon arbitrary measurements which this report proves are not reliable, and end up putting our cavaliers at risk by prematurely prescribing pimobendan, a drug which as been shown to rapidly accelerate the progression of MVD in dogs which do not yet need it.
We can only imagine how much pressure some hidden force must be putting upon these cardiologists for them to contort their brains and come up with a way to enable more primary care veterinarians to prescribe more Vetmedin pills to dogs which may, but more likely would not, need those pills.
October 2017: USA cardiologists find cavaliers with variant of the angiotensin-converting enzyme (ACE) gene have lower ACE activity reaction to mitral valve disease. In an October 2017 article, a team of mostly USA cardiologists (Kathryn M. Meurs [right], Joshua A. Stern, Clarke E. Atkins, Darcy Adin, Brent Aona, Julia Condit, Teresa DeFrancesco, Yamir Reina-Doreste, Bruce W. Keene, Sandy Tou, Jessica Ward, Kathleen Woodruff) report the results of a study of angiotensin-converting enzyme (ACE) activity in dogs with mitral valve disease. Of 31 MVD-affected dogs, including 10 cavalier King Charles spaniels, 11 dogs (6 CKCSs) were found to have a variant (single nucleotide polymorphism) of the intron 16 gene, which is associated with ACE activity in MVD-affected dogs. The ACE polymorphism was most common in the cavalier. They found that, before any ACE-inhibitor treatment, median ACE activity was significantly lower for ACE polymorphism dogs than in the control group. However, following treatment with enalapril, ACE activity was significantly reduced in both groups. They conclude:
"An ACE polymorphism is associated with lower levels of ACE activity. Dogs with the polymorphism still experience suppression of ACE activity in response to an ACE inhibitor. It is possible that the genetic status and ACE activity of dogs may impact the response of dogs with this variant to an ACE inhibitor."
EDITOR'S NOTE: We already know from the SVEP study of 229 CKCSs and the VETPROOF trial that ACE-inhibitors are ineffective in treating MVD-affected cavaliers prior to heart failure. This study suggests a reason for those previous findings. Perhaps cavaliers tend to have a lower level of ACE activity in reaction to their mitral valve disease, and so treating with ACE-inhibitors is not as necessary to keep the angiotensin-converting enzyme activity under control.
Now, we also notice that the researchers state that:
"All dogs were required to have a grade 4/6 left apical systolic murmur and radiographically evident cardiac enlargement (defined as a vertebral heart scale (VHS) ≥11)."
While they cite two footnoted publications at the end of that sentence, presumably to justify their selection of a minimum VHS parameter of 11.0 for heart enlargement, neither of those cited articles support the selection of that VHS value. In fact, the cited articles do not support the selection of any vertebral heart scale values, at all.
Interestingly, the first of the two cited articles, which is the SVEP Study report, stated that the study's means of determining if the dogs had enlarged hearts was to carefully examine x-rays of the dogs' hearts. The authors stated:
"Thoracic radiographs in left lateral and ventrodorsal projections were made for all dogs. All radiographs were evaluated for signs of cardiomegaly [heart enlargement]... . The radiographic examinations were reviewed at annual evaluation meetings to ensure uniform film readings."
The second of the two articles cited in this October 2017 report as justification for the VHS value of ≥ 11 is the ACVIM's 2007 Consensus Statement on hypertension in dogs and cats, "Guidelines for the identification, evaluation and management of systemic hypertension in dogs and cats". That article likewise does not support the VHS value of ≥ 11 or, indeed, any other VHS value as a parameter for heart enlargement. It does not even discuss that topic.
So, in this October 2017 article, we have several board certified veterinary cardiologists intentionally failing to determine if the dogs' hearts actually are enlarged and instead artificially defining heart enlargement by an arbitrary minimum VHS value. If they had peer-reviewed, published evidence that a VHS value of 11.0 is conclusive proof that all dogs of all species with at least that VHS value had enlarged hearts, surely they would have cited those publications.* They have cited nothing of the sort. As a result, the researchers in this article were flying blind when it came to whether the dogs' hearts were enlarged or not. They ended up studying the VHS measurement instead of heart enlargement. So, to the extent that heart enlargment was an important factor in this study, the researchers failed to make that determination.
* We know of
peer-reviewed publications which expressly contradict the notion that
all cavaliers with a VHS value of 11.0 must have heart enlargement. Here
are two of them, below. In the first one, the researchers found cavaliers with
normal sized (meaning, unenlarged) hearts having a VHS value as high as
11.7. In the second article, the VHS range for cavaliers was as high as
11.4. Other breeds reportedly have normal sizes as high as >14.0.
(1) Lamb CR, Wikeley H, Boswood A, Pfeiffer DU. Use of breed-specific ranges for the vertebral heart scale as an aid to the radiographic diagnosis of cardiac disease in dogs. Vet Rec. June 2001;148(23):707-11. ("There were significant differences between the mean values of the scale for the different breeds; the normal boxer dogs had a significantly higher mean value than the normal dogs of all the other breeds, and the labrador retrievers had a significantly higher mean value than all the other breeds except the boxer and the cavalier King Charles spaniel. ... Cavalier King Charles spaniel: Normal: 10-6 (0-5); Cardiac: 10-6 (0-7) 12.4 (1-5); Normal ranges: 9.9-11-7.")
(2) Hansson K, Häggström J, Kvart C, Lord P. Interobserver Variability of Vertebral Heart Size Measurements in Dogs with Normal and Enlarged Hearts. Vet. Rad. & Ultrasound. March 2005;46(2):122. ("The mean VHS for normal cavalier King Charles spaniels was 10.8 ± 0.49 v (10.0–11.4) ... The use of breed-specific VHS values is needed for the VHS method to have a high specificity for normal heart size. ... Individual variations in actual heart size and vertebral length between dogs need to be considered as well as narrowed disc spaces.")
October 2017: Cardiologist Jeremy Orr advocates prescribing pimobendan to MVD-affected dogs even without heart enlargement. In a September 2017 presentation to the Colorado Veterinary Medical Association, board certified veterinary cardiologist Dr. Jeremy Orr (right) advocated prescribing pimobendan to MVD-affected dogs based upon a minimum vertebral heart score (VHS) value alone, without regard to whether the dogs' hearts are actually enlarged. He purportedly was explaining the findings and conclusions of the EPIC Study to the attendees, but contrary to Dr. Orr's comments, the EPIC Study requires that the left side of the dog's heart be enlarged, based upon two echocardiographic measurements as well as a VHS value. To the contrary, Dr. Orr stated on slide #4 of his presentation (at right below):
"HOW TO APPLY THESE [EPIC STUDY] RESULTS?
"Not all dogs with murmurs should be treated with pimobendan.
"Considerations to the following patients: ...
"If echo is not possible, initiate therapy when VHS exceeds 11.5" ...
The reference to "VHS exceeds 11.5" means that if the dog's x-ray shows that the size of its heart is larger than an x-ray VHS value of 11.5, pimobendan should be started. This appears to be Dr. Orr's recommendation of a species-wide minimum heart size for administering pimobendan to MVD-affected dogs.
EDITOR'S NOTE: Apparently, Dr. Orr is assuming that any MVD-affected dog of any breed with a VHS value over 11.5 must have an enlarged left side of its heart. By making this assumption, he advocated to the attendees at the veterinary conference to not bother to perform a full clinical examination (known as a "subjective" exam, which would call for the clinician to use his professional judgment) of the dog to determine whether or not the left side of the dog's heart is, in fact, enlarged. He cannot cite any evidentiary basis for assuming that all dogs of all breeds with that VHS value must have enlarged hearts and for prescribing pimobendan, because there is no such evidence.
Published research studies have shown that dogs of some breeds, including the cavalier King Charles spaniel, may have hearts larger than 11.5 without any enlargement at all. Dr. Orr therefore is advocating prescribing pimobendan to dogs regardless of whether their hearts are enlarged or not. In at least one study, a CKCS had a normal, unenlarged heart with a VHS value of 11.7. In that same study, a boxer had a normal sized heart with a VHS value of 12.6, and a Labrador retriever had a normal sized heart with a value of 11.7. In another study, a pug had a normal sized heart with a VHS value of 14.1, a bulldog with a normal sized heart had 14.4, and a Boston terrier with a normal sized heart had 13.1. All of these normal heart sizes were substantially higher than Dr. Orr's species-wide recommendation of >11.5 for starting pimobendan.
The "results" Dr. Orr refers to on his slide #4 are not actually in the EPIC Study report at all, or in any other published research. He is just making that up. The EPIC Study conclusion requires that the left side of the patient's heart actually be enlarged. There is absolutely nothing in the EPIC Study report which supports using only an x-ray VHS value of >11.5 for prescribing pimobendan. To the contrary, the EPIC Study article expressly concludes:“Chronic oral administration of pimobendan to dogs with echocardiographic and radiographic evidence of cardiomegaly secondary to MMVD, in the absence of concurrent cardiovascular medication, results in the prolongation of the preclinical period, and is safe and well tolerated.” (Emphasis addded.)In effect, Dr. Orr is recommending treating a mathematical measurement instead of treating the disease. How many Colorado veterinarians went away misinformed but prepared to start prescribing this expensive drug, pimobendan, to dogs without enlarged hearts, remains to be determined.
October 2017: Korean study of echo measurements and biomarkers lists the most reliable parameters for detecting MVD and heart failure. In a September 2017 article, a team of Korean researchers (Hyun-Seok Kim, Sang-Il Suh, Changbaig Hyun [right]) compared the current echocardiographic parameters and cardiac biomarkers for detecting mitral valve disease and heart failure in a study of 51 small breed MVD-affected dogs (none were cavalier King Charles spaniels) and 18 healthy control dogs.
They report that, among the markers, the most reliable markers for detecting heart disease were:
● Indexed left atrial diameter (iLA)
● Left atrial to aorta ratio (LA/Ao)
● Transmitral E-peak (E-peak)
● N-terminal probrain natriuretic peptide (NT-proBNP)
The most reliable markers for detecting heart failure were:
● Left atrial to aorta ratio (LA/Ao)
● Transmitral E-peak (E-peak)
● Septal E/Ea ratio (sE/Ea)
● N-terminal probrain natriuretic peptide (NT-proBNP)
They state that their study "is the first canine study to comprehensively evaluate known echocardiographic markers and cardiac biomarkers in a single study population."
EDITOR'S NOTE: The old fashioned way to determine if a dog has mitral valve disease is to hear a murmur over the valve, using a stethoscope. It certainly is a much cheaper -- and less invasive -- procedure than either echocardiography or biomarkers. Granted, an echo can detect regurgitation backflowing through the mitral valve even before the sound of a murmur can be detected. But since soundless regurgitation is meaningless in terms of treatment -- and even in terms of whether the dog should be bred, under the MVD Breeding Protocol -- we wonder what the point is for a dog to undergo an expensive procedure such as an echo or biomarker to diagnose the onset of heart disease.
In addition, if these echo measurements -- indexed left atrial diameter (iLA), left atrial to aorta ratio (LA/Ao), and transmitral E-peak (E-peak) -- are "the most reliable markers for detecting heart disease", then what about observing regurgitation using color Doppler? These markers measure a deteriorating heart, whereas MVD starts out as totally symptomless backflowing of blood through the valve.
We have understood that the most accurate way of detecting the approach of heart failure is an increasing respiratory rate, while the dog is asleep, which approaches or exceeds 30 breaths per minute. The dog's owner can calculate this rate in her home using a timeclock or watch with a second hand, at no cost whatsoever. Also, x-rays which include an interstitial pattern in the lungs would indicate pulmonary edema, which is a hallmark of heart failure. So, the echo markers and biomarkers discussed here are in addition to those two more direct, conventional, and cheaper parameters. The fact remains that neither echo markers nor any biomarkers can provide a definitive diagnosis of heart failure. They cannot visualize lung congestion. Echocardiography and cardiac biomarkers are discussed at length on our main MVD page.
We wonder if, had cavaliers been included in this study, the findings and conclusions would have been any different. The researchers state that they intentionally focused on breeds whch are more popular in Korea and other Asian countries: Maltese, Shih Tzu, Yorkshire terrier, toy Poodle, Pekingese, miniature Schnauzer, Pomeranian, Chihuahua, and mixed breeds. We are not fans of relying upon dog-group-wide or breed-wide heart-size parameters for determining whether a particular patient has MVD or is approaching heart failure. Average or median heart size and pressure measurements for a species or even a single breed alone do not accurately confirm heart failure for the dog on the examining table.
So, while using these echocardiograph markers and biomarkers as a crib sheet may give comfort that the uncertain or inexperienced clinician's stethoscopic and x-ray diagnoses are on the right track, they should not be used as substitutes for the tried-and-true methods of detecting MVD and heart failure, performed by knowledgeable and confident veterinary specialists.
October 2017: The TEST Study finds torasemide is more effective than furosemide in treating MVD-affected dogs in heart failure over a short term. In an October 2017 article, a team of French researchers (V. Chetboul, J.-L. Pouchelon, J. Menard, J. Blanc, L. Desquilbet, A. Petit, S. Rougier, L. Lucats, F. Woehrle) compared the effectiveness and safety of torasemide with furosemide. Both are loop diuretics, but torasemide is significantly more potent than furosemide and is usually prescribed to dogs diagnosed with heart failure (CHF) due to mitral valve disease beginning at only one tenth of the dosage of furosemide.
The study (called the TEST Study, which was sponsored by Vetoquinol, the manufacturer of UpCard, a torasemide brand name, and included Vetoquinol employees among the researchers) involved 366 dogs in CHF, of which 46 (12.6%) were cavalier King Charles spaniels. They found that over a short-term of 84 to 91 days, torasemide resulted in a two-fold reduction over furosemide in the risk of reaching the cardiac endpoint (either a cardiac-associated death or worsening of the degree of CHF). They concluded by warning:
"However, given its potent diuretic effects, the lowest effective dosage should always be determined and, as recommended by the ACVIM consensus guidelines, dogs under such diuretic treatment should be closely monitored for renal and electrolyte abnormalities. Further studies are now required to explore the potential beneficial antifibrotic effect of torasemide on dogs with CHF, and its potential benefit over furosemide on long-term survival."
September 2017: US and Dutch cardiologists measure mitral valve regurgitation using real-time three-dimensional transthoracic echocardiography (RT3DE). In a September 2017 article, Virginia-Maryland Veterinary School cardiologists (Giulio Menciotti, Michele Borgarelli) and Utrecht University cardiologist (Sandra Müller [right]), utilized measurements of the size of the regurgitant gap in the mitral valve -- called the "anatomic regurgitant orifice area" (AROA) -- to determine if that measurement compares to the severity of mitral regurgitation (MR) assessed by an echocardiographic scoring system (MRSS). They devised four classes of the MRSS -- normal, mild, moderate, and severe. They used "real-time three-dimensional transthoracic echocardiography" (RT3DE) to arrive at the AROA dimensions. Eleven cavalier King Charles spaniels were included in the 60 dog, 25 breed, study.
They found that The AROA was significantly greater in dogs with a severe MRSS compared with dogs with mild MRSS, and that there was no difference between the AROA of dogs in different ACVIM clinical stages (i.e., Stages B1, B2, C). They concluded that it is feasible to obtain the AROA in dogs with MVD using RT3DE, and that the AROA of dogs with severe MR is greater than the AROA of dogs with mild MR.
September 2017: Cardiologists Borgarelli and Menciotti caution against generalizing the narrow EPIC Study results. In a September 2017 article, Virginia-Maryland College of Veteriinary Medicine cardiologists Giulio Menciotti (right) and Michele Borgarelli reviewed the current diagnostic and treatment options for dogs with mitral valve disease.
Regarding the EPIC Study trial, which included 360 MVD-affected dogs in ACVIM Stage B2, they noted that Stage B2 includes various degrees of heart enlargement -- e.g., slight, moderate, and severe. However, the specific echocardiograph and x-ray parameters for selecting those dogs in the EPIC Study were narrower than the full range of Stage B2 and required that the minimum extent of their heart enlargement be "significant". The authors warn that the benefit observed in the EPIC Study -- delaying the onset of heart failure by approximately 15 months, compared to the placebo group -- must be limited to the narrow inclusion criteria of the study. Specifically, they state:
"It is very important to remark, however, that ACVIM Stage B2 dogs represent a heterogeneous group of patients. Therefore, the benefit observed in the EPIC study can be inferred only for dogs that respect inclusion criteria of this study. In fact, for being enrolled in the aforementioned trial, dogs had to have evidence of significant left cardiac enlargement both at echocardiographic examination (LA/Ao ≥ 1.6, LVIDd divided by allometric scaled BW ≥ 1.7) and on thoracic radiographs (Vertebral Heart Score > 10.5)." (Emphasis added.)
EDITOR'S NOTE: What Drs. Menciotti and Borgarelli state here -- about cautiously interpreting the results of the EPIC Study -- is completely consistent with a statement in the EPIC report itself. There, the investigators warned:
"... it should be borne in mind when interpreting these results that all dogs included in the analyses also met the echocardiographic inclusion criteria and these results therefore might not be generalizable to all dogs with a VHS > 10.5 in the absence of concurrent echocardiographic measurements and a confirmed diagnosis of MMVD." (Emphasis added.)
In other words, pimobendan is not for ALL Stage B2 dogs. Essentially, EPIC's conclusion should be confined to its inclusion criteria, as should all scientific research. Unfortunately, these words of caution have been lost in the irresponsible efforts by Vetmedin's manufacturer and some cardiologists (including one of the EPIC Study's lead authors) to market pimobendan to any and all MVD-affected dogs with only the slightest degree of heart enlargement. Even worse, some cardiologists (including another of the EPIC Study's lead authors) are hyping pimobendan treatment for dogs without any enlargement at all (as long as their VHS score is 11.5 or higher). See our July 2017 article, below.
September 2017: Polish cardiologists suggest that echocardiography should be used to detect MVD regurgitation which does not produce murmurs. In a September 2017 study of 107 Dachshunds, a team of Polish researchers (Magdalena Garncarz [right], Marta Parzeniecka-Jaworska, Magdalena Hulanicka, Michał Jank, Olga Szaluś-Jordanow, Anna Kurek) observed mitral valve regurgitation in 68 of the dogs (63.7%) which could not be detected by murmurs heard with stethoscopes (auscultation). In most of the dogs, they found that mitral valve prolapse and leaflet thickening were "mild" and that the regurgitant area was "inextensive". Nonetheless, they conclude that "the prevalence of mitral valve regurgitation is underestimated when looking solely at dogs with heart murmurs." They recommend that:
"Although most dogs with CMVD do not progress to more advanced stages of congestive heart failure, it is beneficial to know that the disease is present, especially for scientific studies. ... Echocardiographic studies in dog breeds predisposed to chronic mitral valve disease without heart murmurs are warranted first of all as a preventative diagnostic method for heart disease if we are to eliminate suspicion of subclinical chronic mitral valve disease, and secondly to enable a better global picture of the prevalence of the disease since studies of dogs with heart murmurs underestimate the number of affected animals." (Emphasis added.)
EDITOR'S NOTE: Sigh... Here is but another example of the march towards over-diagnosis -- detecting an insignificant imperfection which does not cause the dog any health issues at all -- certainly not any needing to be treated. Whether it be to help pay for an expensive ultrasound device or to provide practice for inexperienced clinicians, echocardiograph examinations to find mitral valve regurgitation in dogs without heart murmurs, are a waste of the dogs' time and of the owners' money.
Of course, we have no problem with researchers wanting to test murmurless dogs to determine if they have regurgitation through their mitral valves, for research purposes. But the dogs' owners should not be expected to pay for such research under the guise of "eliminating suspicion of subclinical chronic mitral valve disease."
August 2017: Texas A&M's veterinary cardiology dept. needs young CKCSs for free echo study of healthy mitral valves. The cardiology department at the Texas A&M University's veterinary school is seeking cavalier King Charles spaniels between the ages of 10 and 24 months, with no history of heart murmurs or other illnesses for a free echocardiograph examination and a blood sample at its teaching hospital. If interested, please contact Dr. Sonya Wesselowski (email@example.com) (right) or TAMU Cardiology (firstname.lastname@example.org) to find out about availability and scheduling. See also this link.
July 2017: Spironlactone study of MVD-affected dogs in Stage B2 proves nothing new. In a July 2017 article by a team of UK investigators (M.J. Hezzell, A. Boswood, J. López-Alvarez, N. Lötter, J. Elliott), they report the inconclusive results of a pilot study of 25 dogs (13 treated with spironolactone and 12 with placebo). All of the dogs were MVD-affected and in ACVIM Stage B2 (with heart enlargement). None of them were being treated with any other drugs. Just about the only thing the study results confirm is their statement that the drug's "efficacy in preclinical MMVD is unknown." They call for another study of at least 76 dogs, but now that the EPIC Study calls for treating dogs in Stage B2 with pimobendan, it appears doubtful they will find enough untreated Stage B2 dogs for such a larger study.
EDITOR'S NOTE: While this study breaks no new ground, it does remind everyone that there still is no peer-reviewed evidence warranting the administration of spironolactone to cavaliers not yet in heart failure. Why so many cardiologists nonetheless insist upon prescribing this drug to symptomless MVD-affected cavaliers remains a mystery. See our Blog posts, "All that cavalier owners need to know about spironolactone" and "Why do any veterinarians prescribe useless drugs to MVD-affected cavaliers before heart failure?".
July 2017: Sildenafil (Viagra) beats out enalapril in improving heart rate variability in Stage B MVD-affected dogs. In a July 2017 article, Thai researchers (Prapawadee Pirintr, Nakkawee Saengklub, Vudhiporn Limprasutr, Suwanakiet Sawangkoon, Anusak Kijtawornrat) compared sildenafil (Viagra) to enalapril (an ACE-inhibitor) in their effectiveness in increasing heart rate variability (HRV) in MVD-affected dogs in ACVIM Stage B (pre-heart failure). Thirty-four MVD-affected dogs and thirteen healthy dogs participated, divided into groups of control, sildenafil, and enalapril. At the outset, they noted that MVD degeneration causes an imbalance of "sympathovagal" activity (see Editor's Note below), which results in poor cardiac outcomes. The results showed that MVD-affected dogs had significant higher heart rates (HR), systemic blood pressures, and significant decreased HRV than the healthy control dogs. After treatment with sildenafil for 90 days, both time- and frequency-domain parameters were significantly increased when compared with control and enalapril groups. This study demonstrated that sildenafil improves HRV in Stage B dogs, and that enalapril did not. They concluded that this result suggests that sildenafil should be used in MVD-affected dogs to restore the sympathovagal balance.
EDITOR'S NOTE: Changes in the dog's heart rate are tied to changes in cardiac output. Heart rate variability (HRV) reflects variations in the time periods between heart beats. Generally, a low HRV indicates that the dog is under stress, which may be due to exercise, psychological events, or other internal or external events. A higher HRV usually means that the dog has a strong ability to tolerate stress or is strongly recovering from prior accumulated stress. A reduction in HRV in MVD-affected dogs reflects a "sympathovagal imbalance", which has been identified as a risk factor for sudden cardiac death. "Sympathovagal" refers to an interaction between the dog's sympathetic nervous system and its vagus nerve. HRVs reflect the output of the heart as regulated by the sympathetic nervous system. This study also demonstrates that there is no peer-reviewed reason why Stage B cavaliers should be prescribed enalpril or any other ACE-inhibitor.
July 2017: Tufts researchers locate microRNA associated with heart failure in MVD-affected dogs, including cavaliers. In a July 2017 article, a team of Tufts University investigators (Vicky K. Yang [right], Kerry A. Loughran, Dawn M. Meola, Christine M. Juhr, Kristen E. Thane, Airiel M. Davis, Andrew M. Hoffman) report they have located microRNA* (cfa-miR-9, cfa-miR-181c, cfa-miR-495 and cfa-miR-599) expressions which change with the progression of mitral valve disease and development of heart failure. The study consisted of 47 dogs, including 17 cavalier King Charles spaniels, which were divided into three groups based upon their heart conditions. All of the cavaliers in the study were MVD-affected and were in either the ACVIM Stage B (asymptomatic) or Stage C (heart failure) categories. The found:
"The present observations suggest that dysregulation of miR-9 and miR-599 chronologically precedes CHF, suggesting that these miRNA warrant further investigation as putative initiating factors for CHF, while others were found only at the time of CHF (miR-181c and miR-495), which denotes a role in initiation, progression or consequence of CHF. ... The data analysis shows that relative to young normal dogs, dogs with MMVD or dogs with MMVD-CHF, the expression level of cfa-miR-9 is low in older normal dogs. MiR-9 has been shown to have anti-fibrotic effects, and overexpression of miR-9 in neonatal rats inhibits the proliferation of cardiac fibroblasts and collagen production. ... Both of these effects would suggest that miR-9 has protective effects for cardiac remodelling."
"In contrast, cfa-miR-9 expression once again increases with the development of MMVD, which would suggest that MR [mitral regurgitation], volume-overload, cardiac remodelling or haemodynamic effects on other organs (lungs and kidneys) may initiate or propagate higher expression of circulating cfa-miR-9. However, it is not known if the anti-fibrotic effects of miR-9 are sufficient to counter pro-fibrotic stimuli exerted by volume overload and chronic heart failure."
"The data showed that there is high expression of exosomal cfa-miR-181c in dogs with CHF. MiR-181c is encoded in the nucleus and assembled in the cytoplasm of the cardiomyocytes and is then translocated into mitochondria to regulate mitochondrial gene expression. ... [G]iven the significant increase in cfa-miR-181c expression in MMVD-CHF, miR-181c may serve as an important biomarker or therapeutic target in patients at risk for developing CHF."
"Plasma exosomal miR-495, which is repressed with age, increases with MMVD-CHF. This ex-miRNA was upregulated with heart disease, particularly in advanced disease with CHF in defiance of its age-related trend downward. ... Although speculative, cfa-miR-495 may also serve as a potential biomarker to help monitor progression to active CHF in addition to cfa-miR-181c."
"Exosomal miR-599 declines in MMVD compared to age-matched controls. ... An increase in cfa-miR-599 associated with ageing was observed. Studies have shown that this miRNA can inhibit vascular smooth-muscle cell proliferation and production of collagen I, collagen V and proteoglycan by direct targeting of TGFβ2. Interestingly, there is a downregulation of cfa-miR-599 in dogs with MMVD when compared to normal older dogs."
"Based on the present disease model, two miRNA were found, specifically miR-495 and miR-181c, whose rise in expression level coincides with the observation of CHF. The authors acknowledge that dysregulation of these ex-miRNA may not be unique to CHF secondary to MMVD, but rather may be a signature of canine heart failure which is a consequence of other aetiologies."
*MicroRNA (miRNA) is a non-coding RNA molecule that functions in RNA silencing and regulation of gene expression. Some miRNAs, commonly known as extracellular miRNAs (ex-miRNA), have also been found in circulating exsomes (a small structure excreted from a cell).
July 2017: Fortekor Plus (benazepril and pimobendan) passes its marketer's sponsored efficacy test in Stage C MVD-affected dogs. In a July 2017 article, a team of investigators employed by Elanco Animal Health, which markets Fortekor (benazepril) and Fortekor Plus (benazepril + pimobendan), conducted a study of 67 dogs (including 9 cavalier King Charles spaniels) at a clinic in Japan. All of the dogs were in congestive heart failure (Stage C) due to mitral valve disease (MVD). The dogs were divided into three groups. The test group received the Fortekor Plus, while two control groups received separate doses of benazepril and pimobendan. The researchers found no significant differences between groups. They reported that the frequency of vomiting (emesis) was significantly lower in the Fortekor Plus group. They concluded that:
"Fortekor Plus had non-inferior efficacy and was associated with significantly less emesis compared to administration of Fortekor and Vetmedin in dogs with CHF caused by MMVD."
EDITOR’S NOTE: In this July 2015 entry, we reported that Fortekor Plus was approved in Europe for use on MVD-affected dogs in congestive heart failure.
July 2017: Dr. Sonya Gordon recommends pimobendan for Stage B dogs even without echocardiograms. In a June 2017 article, EPIC Study report lead investigator Dr. Sonya G. Gordon (right), along with Drs. Ashley B. Saunders and Sonya R. Wesselowski, makes a variety of recommendations for treatment of MVD-affected dogs, some of which have not appeared in print elsewhere as yet.
Specifically regarding dogs in ACVIM Stage B2 of mitral valve disease (MVD), they provide parameters for prescribing pimobendan even when no echocardiograms have been performed to determine if the dogs' hearts are enlarged. (The EPIC Study report did not recommend starting pimobendan unless two minimum echo measurements were present, in addition to a Vertebral Heart Score [VHS] greater than [>] 10.5.) They state:
“The EPIC inclusion criteria required both radiographic and echocardiographic evidence of cardiomegaly. The requirement for an echocardiogram may in some cases exclude the recommendation for initiation of pimobendan. However, given the potential low accuracy of depending solely on a radiographic VHS greater than 10.5, ... and that there are known breed-related differences in normal VHS reference ranges with much higher normal VHS ranges reported in some breeds, including the CKCS, it is prudent to use a higher VHS size if recommendations for treatment are based solely on history, physical examination, and thoracic radiographs. Selection of a VHS for this indication is warranted based on the results of previous studies that have demonstrated that dogs with asymptomatic DVD and a VHS of 11.5 to 12.50 have a significant increase in risk of developing left-sided CHF in the near (6–12 months) future. In addition, the median VHS of dogs in the EPIC study was approximately 11.5 ... . An additional factor to consider is rate of progression of heart enlargement. Relatively large increases in heart size, even if the VHS is <11.5, are known to be associated with an increased risk of CHF in dogs with DVD [degenerative valve disease]. Therefore, another criterion to consider is an increase in VHS from one recheck to the next. The Cardiac Education Group (CEG) recommends that, in the absence of an echocardiogram, asymptomatic dogs with an MR murmur (>3/6) and a VHS ≥11.5 or an increase in VHS of ≥0.5 or more in 6 months can be used to recommend pimobendan treatment. Use of a VHS of ≥11.5 will improve the specificity (positive predictive value) of significant heart enlargement and guard against overtreatment of possible stage B1 dogs.” (Emphasis added.)
The authors are not keen on starting an ACE-inhibitor along with the pimobendan for Stage B2 dogs. They state:
“The CEG also addressed the use of concurrent ACE inhibitors in this population in light of the EPIC study results. Their recommendation is to continue ACE inhibitors in dogs already receiving them when the indication for pimobendan is met, but that initiation of an ACE inhibitor in stage B2 DVD should be reserved until the onset of clinical signs or symptoms [meaning, once heart failure is detected and the dog reaches Stage C]. Additionally, the addition of an ACE inhibitor also can be considered if or when reevaluation demonstrates an increase in VHS of 0.5 or more in 6 months in dogs with stage B2 DVD already receiving pimobendan.”
The article does not reference the SVEP study of 229 cavaliers, which found that ACE-inhibitors do not delay the onset of heart failure in CKCSs in Stage B of MVD.
EDITOR’S NOTE: Well, this is interesting. The EPIC Study specifically recommends not using only x-rays to determine enlargement of the heart. It states:
“The conclusions of this study are only relevant to dogs with cardiac enlargement secondary to preclinical MMVD (stage B2) as all dogs entering the study met or exceeded 3 different heart size criteria (LA/Ao ≥ 1.6, LVIDDN ≥ 1.7, and VHS > 10.5) ... .” (Note that LA/Ao and LVIDDN parameters can only measured by echocardiogram.)
Why would Dr. Sonya Gordon, one of the three lead investigators/authors of the EPIC Study report, want to encourage veterinarians to cut corners and not perform echocardiograph examinations in order to determine if an MVD-affected dog’s heart is enlarged? We can think of two possible reasons:
● One is that primary care, general practice (GP) veterinarians, either not having ultrasound devices or not being sufficiently trained to use them for echocardiography, might have complained that the EPIC Study’s requirement of having echocardiograms was discriminatory against them and in favor of the cardiologists. Since GP vets have been prescribing pimobendan to dogs in heart failure (Stage C) for the past ten years without even having an ultrasound device in their clinics, it should come as no surprise that they would be inclined to ignore the EPIC Study report's admonition that minimum echocardiograph measurements are necessary, and issue scripts for this very expensive drug (and sell it from their own inventories) for Stage B2 dogs, based only upon x-rays.
● The other is that Boehringer Ingelheim, the manufacturer of Vetmedin, which fully funded the EPIC Study, might have complained that by requiring that echo exams be conducted before pimobendan can be prescribed prior to heart failure, fewer, rather than more, prescriptions for Vetmedin will be issued, resulting in less profit to that benevolent sponsor. Two of the authors admit a conflict of interest. They state in the article:
“Disclosure Statement: Drs S.G. Gordon and A.B. Saunders have received funding from Boehringer Ingelheim Animal Health GmbH within the past 5 years for some or all of the following activities: research, travel, speaking fees, consultancy fees, and preparation of educational materials. Drs S.G. Gordon and A.B. Saunders are authors of the EPIC Study; Dr S.G. Gordon is a member of the Cardiac Education Group.”You see, Boehringer Ingelheim’s tenacles are insidious. Frankly, this entire article reeks of an excuse to tout prescribing Vetmedin to many dogs which very likely will never need it.
Whatever the reason (they both focus on making more money for somebody), such corner-cutting certainly is of no net benefit to the MVD-affected dogs, particularly cavalier King Charles spaniels. Instead of warning veterinarians to not prescribe pimobendan to Stage B2 dogs without first performing any echocardiograms, Dr. Gordon is ditching the mandatory echo parameters altogether and is recommending a new, dumbed-down, all-breed x-ray-only parameter for them to follow.
Dr. Gordon points out some interesting information about the EPIC Study patients, such as that “the median VHS of dogs in the EPIC study was approximately 11.5”. Of course, that would include all 360 dogs of several breeds. From that figure, she sets a minimum species-wide VHS parameter of ≥11.5 for starting pimobendan if no echos are performed. She also gives her okay to starting the drug if the size of the heart increases by a VHS value of ≥0.5 within a six month period.
So, based upon Dr. Gordon’s advice, any GP veterinarian with only an x-ray machine will be able to calculate VHS values and, once the minimum value of 11.5 is met in any dog of any breed, then go ahead and prescribe the pimobendan. But since there is no research* to back up this deletion of echos as part of the diagnostic process, any veterinarian who chooses to follow her advice and opt out of using echocardiography is essentially “flying blind” in determining if the dog’s heart really is enlarged.
* In a December 2016 publication, the Cardiac Education Group (CEG), of which Dr. Gordon is a member, first proposed this x-ray-only parameter for prescribing pimobendan to Stage B2 dogs. In that publication, the CEG openly admitted that “The EPIC trial did not investigate a cutoff for cardiac enlargement by VHS alone at which to start pimobendan therapy.” (Emphasis added.) And, the CEG also admitted therein that its x-ray-only parameters are “not based on evidence.” (Emphasis added.) See our December 2016 comments about this item. The CEG publication states that it, too, is sponsored by the manufacturer of Vetmedin, so commonality of conflict-of-interest reigns here. Plus, the current article has a strong whiff of a citation-stacking effort.
Clearly, Dr. Gordon’s co-lead investigator in the EPIC Study, Dr. Adrian Boswood, does not agree with her skewed interpretation of the EPIC Study findings. In his May 2017 article on how the EPIC Study trial was designed, he wrote:
“... [I]n order to ensure that the patients recruited to the EPIC study definitely had primary mitral valve disease and enlargement of their heart they underwent both echocardiography and radiography before study entry. If I am now asked by a practitioner – ‘should I treat this dog, which I believe has preclinical mitral valve disease, with pimobendan?’ – my response will typically be ‘to be certain that therapy is indicated the dog will need to undergo echocardiography and ideally also radiography.’” (Emphasis added.)
So, while Dr. Gordon is willing to forego measuring the two echo exam parameters, Dr. Boswood grudgingly would do the opposite – that is, skip the x-ray measurement, but that would not be “ideal”.
What Dr. Gordon ignores is that, for some breeds, especially the cavalier, a VHS value of 11.5 may mean that the heart is not enlarged at all. While she describes using the species-wide 11.5 VHS value for prescribing pimobendan as “prudent” and to “guard against overtreatment of possible stage B1 dogs”, we disagree. We regard it as arbitrary, risky, and unsupported by any research. In fact, the published research contradicts her selection. In at least one study, a VHS value of 11.7 was found normal for one of the CKCSs. So, why does she insist upon using a “one size fits all” set of parameters, which means that the cavalier is put at greater risk? At the very least, she should pay attention to the advice given in the article she cites in her footnote 15, which expressly states:
“The use of breed-specific VHS values is needed for the VHS method to have a high specificity for normal heart size.” (Emphasis added.)
We would prefer using a patient-specific VHS value, rather than just breed-specific, but either one is better than a reckless, species-wide “median” VHS value. In this era of more “individualized medicine”, there is no justification whatsoever for creating a species-wide parameter, especially when it flatly (and admittedly) contradicts the only peer-reviewed research on the topic. She and her cohorts violate the ethical tenet of veterinary medicine to treat the disease and not the arbitrary measurement.
What is even more disturbing is that Dr. Gordon does not acknowledge the dirty little secret about GP vets: many of them cannot determine whether a dog’s heart is enlarged or not, simply by looking at one set of x-rays.*As a result, they often tend to find enlargement when there really is none at all. When that leads to prematurely prescribing pimobendan, severe heart damage can occur, based upon prior peer-reviewed studies. To remedy this hazard, all she had to do was also recommend that the GP vets make baseline x-rays of their MVD patients before any enlargement takes place, so that the GP vet will be able to compare the normal size of the patient’s heart in the baseline x-ray to the later x-ray which may (or may not) show enlargement. This is what we mean by using a patient-specific VHS value.
* Even experienced board certified cardiologists will argue over whether a single set of x-rays (they call them “chest rads”) shows left atrium enlargement or not, and if so, its degree. This usually is due to poor positioning of the dog during the x-rays, which is not uncommon. See e.g., Why Is Cardiac Radiology So Difficult? Christopher R. Lamb. WSAVA Congress 2004. (“In a recent study two experienced observers examined the radiographs of 57 dogs with common congenital cardiac anomalies without access to any clinical information in order to avoid biasing their interpretations. Under these conditions, the observers reached the correct diagnosis in less than 40% cases. This poor result reflects the difficulty observers had identifying shape changes that can occur in radiographs of dogs with enlarged cardiac chambers. Radiographic signs of specific cardiac chamber enlargement (or pulmonary vascular abnormalities) were recognised by both observers in only 20% instances in which they might be expected.”) (Emphasis added.)
Why Dr. Gordon ignored this advice is perplexing. Surely she is aware that the 2009 ACVIM Consensus Statement, of which she was one of the authors, specifically emphasized the importance of obtaining baseline x-rays. Here is what they (she) wrote back in 2009:
“Diagnosis for Stage B: Consensus recommendations: Thoracic radiography is recommended in all patients to assess the hemodynamic significance of the murmur and also to obtain baseline thoracic radiographs at a time when the patient is asymptomatic for CVHD [chronic valvular heart disease].” (Emphasis added.)
Now, Dr. Gordon and her cohorts may reply by saying that, in many instances, no baseline x-rays have been taken, and it is too late now. Apart from the fact that they never mention the baseline option at all, our response to that situation is for the authors to recommend not relying solely upon a current x-ray, and to require that the dog undergo an echocardiographic examination. To advise vets to waive echo exams for cavaliers, when there is no baseline x-ray for confirming if any enlargement has occurred, is, frankly, encouraging malpractice.
Even with baseline x-rays for comparison purposes, relying upon the x-rays alone and their VHS values only tell the clinician that the heart as a whole is enlarged, and not whether the left atrium (LA) and/or the left ventricle (LV) are enlarged. Maybe a board certified cardiologist can tell from x-rays (rads) alone that the LA or LV is enlarged, but as we noted above, even they will disagree from time to time, and especially if the positioning of the dog (even flexing the neck can cause misleading shadowing) and quality of the films are less than perfect, or the dog was inhaling in one view and exhaling in another or sedated in one and not in the other. This list could go on and on.
The EPIC trial report emphasizes the importance that both the left atrium and left ventricle be enlarged by specified minimum dimensions, which is important information that the echocardiogram can provide and even an expertly produced x-ray can not.
Clearly, one of the other two lead investigators/authors of the EPIC Study report flatly disagrees with Dr. Gordon’s short-cut diagnostic trick. Dr. Adrian Boswood, in a Q&A article published in The Veterinary Record in February 2017 was asked how primary care vets can reliably identify MVD-affected dogs which would benefit from pimobendan treatment at Stage B2. He answered:
“At the moment we can only be confident that a dog will benefit from therapy if it undergoes diagnostic imaging; ideally echocardiography. It is probably unrealistic to expect that every dog in primary care practice with a moderately loud heart murmur will undergo echocardiography – so is there another way we can find these dogs? The answer to that question is currently – we don’t know.
“What I would like to develop is a simple tool or algorithm that may combine factors from a dog’s history, clinical examination and perhaps biomarker concentrations to generate a patient risk score. It is possible that such a score could be used to either select those patients in which diagnostic imaging is strongly recommended or, even better, a high score could be used as a basis on which to initiate therapy. We are a long way from having such a validated clinical scoring system, but 10 years ago we were a long way from knowing that pimobendan was effective in the treatment of dogs with preclinical mitral valve disease – and now we do! Difficult questions sometimes take a long time to answer.” (Emphasis added.)
At least Dr. Boswood recognizes that the condition of the individual dog needs to be taken into account, instead of using an arbitrary, species-wide x-ray measurement which has been proven in previous peer-reviewed studies to erroneously indicate actual heart enlargement in several breeds of dogs, including the CKCS.
This is but one more example of why we repeatedly warn cavalier
owners two essential things: (1) they should NEVER
allow any veterinarian to prescribe their dogs any MVD medications except
for a board certified cardiologist (if at all possible) who follows
peer-reviewed research; and (2)
they need to be their dogs’ advocates, because
they cannot always count on veterinarians (even some cardiologists) to put the dogs’ best
interests first. It never hurts to ask the veterinarians treating your
“What, exactly, is the clinical evidence supporting the drugs you want me to buy and give to my dog?”
June 2017: ReGena-Vet Laboratories plans stem cell experiments on MVD-affected dogs. Dr. Philip Richard Vulliet (left), veterinary medical director at ReGena-Vet Laboratories and professor at UC Davis, is investigating the potential of injecting adult bone marrow stem cells in MVD-affected dogs with the goal of slowing the progression of MVD. The lab currently is experimenting with Doberman Pinschers affected with dilated cardiomyopathy. His contact information is: ReGena-Vet Laboratories, LLC, 2079 Anderson Rd., Suite B, Davis, CA, 95616, Tel: 530-902-9006, Fax: 530-756-0459, email email@example.com or firstname.lastname@example.org, website regenavet.com
June 2017: ACE-inhibitor ramipril fails to extend survival times of MVD-affected dogs when combined with pimobendan and diuretic. In a June 2017 poster presented by German veterinary cardiologist Gerhard Wess (right) to the 2017 ACVIM forum, he reported on the results of a study (the VALVE Study) of 156 MVD-affected dogs in congestive heart failure (CHF). The dogs were divided into two groups: 77 being treated only with pimobendan and furosemide ("dual therapy"), and 79 also treated with the ACE-inhibitor ramipril (Vasotop) ("triple therapy").
Dr. Wess noted:
"The ACVIM guidelines [the ACVIM's 2009 Consensus Statement] currently recommend the use of triple therapy including Pimobendan, ACEi and furosemide for the treatment of dogs in congestive heart failure, as there might be an additional beneficial effect of adding ACEI to Pimobendan. However, there is currently no solid proof besides expert opinion that the triple therapy is superior compared to Pimobendan plus furosimide alone. ... The ACVIM guideline is a data item that belongs to the experts' consensus (Level C scientific evidence*). It has not been scientifically proven that ACEi has a substantially better clinical improvement in combination with pimobendan / furosemide. Recalling that pimobendan was not included in clinical trials of ACEi in the past, the VALVE study is a study where the results of triple therapy applying pimobendan, furosemide, and ACEi can be prepared."
* Actually, "expert opinion" is graded as Level D, defined as "Very Low Quality of Evidence". See, "Grading of Recommendations Assessment, Development and Evaluation (GRADE)", below.
The results were troubling: The non-ramipril, dual therapy dogs survived a median time of 223 days, and the ramipril, triple therapy dogs survived only 179 days, a 40% difference between the groups.
EDITOR’S NOTE: This result, of course, must have been disappointing to the VALVE Study's chief sponsor, the producer of Vasotop (ramipril). It is one thing for a study to show that the drug had no benefit, but it is much more of an unwelcome surprise to find that the drug was a hindrance and actually reduced the survival times for the dogs.
Ramipril has not had a good scientific track record in treating MVD-affected dogs. In a 2013 study by Thai graduate students, of twenty dogs (none CKCS) in Stage B2, they found that ramipril had no beneficial effect upon cardiac chamber size, mitral regurgitation severity and systolic function assessed by echocardiography in 91-day period of treatment.
In a January 2007 article, UK cardiologists compared the affect of pimobendan versus ramipril on the vertebral heart score of 42 MVD-dogs in congestive heart failure, including 24 cavaliers. They found that for the first few months of the 21 dogs treated with pimobendan, their VHS heart size decreased, meaning a reduction in the heart enlargement, while during the same period, the 21 dogs treated with rampilril experienced a continued increase in their VHS heart size.
However, until fairly recently, there appeared to be another reason for adding ACE-inhibitors to the treatment cocktail -- to offset the damage that diuretics do by encouraging activation of the kidneys' renin-angiotensin aldosterone system (RAAS), a cause of renal dysfunction. When the RAAS is activated, it causes the kidneys to over-work by retaining more water and sodium and excreting more potassium. As a result of this process, the overall volume of blood increases, meaning that more blood is pumped through narrowed arteries, which also increases the blood pressure.
Other studies have suggested that diuretics such as furosemide should be used only combined with ACE-inhibitors -- which also prevent fluid retention -- so that the diuretic dosage may be sharply reduced to avoid the worst of its negative side effects, such as activation of the renin-angiotensin aldosterone system (RAAS), a cause of renal dysfunction.
In a 2009 study report which did not include CKCSs, veterinary cardiologists observed a three-fold increase in RAAS activity using furosemide. Their conclusion was that "furosemide is not recommended for chronic use in the absence of concurrent therapy to blunt RAAS activity, such as ACE-I, aldosterone receptor blockers, or angiotensin II type I receptor blockers." A subsequent similar study in 2011 concluded:
"These results in clinically normal dogs suggested that furosemide, administered with or without pimobendan, should be accompanied by RAAS-suppressive treatment."However, in a September 2014 study of ten healthy hounds, researchers found that benazepril (another ACE-inhibitor) did not prevent the activation of the RAAS. This is called “aldosterone break-through” (ABT). In a similar study in September 2015, researchers found that enalapril (still another ACE-I) also did not prevent activation the RAAS. In a November 2015 study, researchers found that high doses of benazepril or enalapril were not any more effective than standard doses of those drugs in suppressing the RAAS.
These studies demonstrate that, despite what Dr. Wess describes as "expert opinion" (literally: hunches and anecdotes) -- that ACE-inhibitors play such an important role in treating MVD-affected dogs that the drug should be included in all treatment levels (ACVIM Stages B2, C, and D) -- there is no clinical evidence to support such "expert opinion" but there is a lot of clinical evidence cautioning against using the drug.
The scientific value of "expert opinion" is so insignificant that the Centre for Evidence-Based Medicine, at Oxford University, ranks it at Level 5 (the lowest rank out of five levels); the University of Michigan Practice Guideline gives it a "D" (the lowest grade out of four levels); and as noted in the footnote above the Grading of Recommendations Assessment, Development and Evaluation (GRADE) gives "expert opinion" the quality grade of Level D, defined as "Very Low Quality of Evidence". And keep in mind, that unlike most instances of uncontested "expert opinion", in the case of the value of ACE-inhibitors to MVD-affected dogs, this "expert opinion" is directly contradicted by published, peer-reviewed clinical evidence showing how worthless the ACE-I therapy actually has been.
This whole story demonstrates that, even among board certified veterinary cardiologists, hunches and anecdotes can be converted into counter-factual "expert opinion" that ends up in treatment protocols for our MVD-affected cavaliers. So, it never hurts to ask the veterinarians treating your dog:
“What, exactly, is the clinical evidence supporting the drugs you want me to buy and give to my dog?”
You need to be your dog's advocate!
June 2017: Dr. Borgarelli reports successful replacement of mitral valve chords using the Harpoon TSD-5 device. In a May 2017 article, a team of Virginia-Maryland veterinary college surgeons, led by Dr. Michele Borgarelli (M. Borgarelli, O. Lanz, N. Pavlisko, J.A. Abbott, G. Menciotti, M. Aherne, S.M. Lahmers, K.K. Lahmers, J.S. Gammie), report the successful implantation of synthetic expanded polytetra-fluoroethylene (ePTFE) replacement mitral valve chords in four of six healthy Beagles, using minimally-invasive surgical techniques in beating hearts (without cardio-pulmonary bypass or cardiac arrest). The investigators used a biomedical device called the Harpoon Medical TSD-5. The body cavity was opened to reveal the beating heart. Then a "valved introducer" was inserted into the left ventricle, and the thin metal shaft of the Harpoon TSD-5 was inserted through the introducer, leading to the mitral valve. When the shaft was in proper position, the trigger of the Harpoon TSD-5 (see image below) was pressed, and its needle pierced the mitral valve leaflet, forming a bulky knot of the ePTFE chord through the leaflet. The other end of the chord ultimately is extended and attached to the heart muscle through the intial insertion location. This video shows how the procedure is designed to operate. The study authors concluded:
"This pilot study has demonstrated feasibility of using the Harpoon TSD-5 device to place and anchor ePTFE artificial chords to the MV of small dogs and that endothelialization of the synthetic cord and knots can start within 30 days."
June 2017: EPIC Study authors plan to announce "longitudinal analysis" of the participating dogs' data. At a September 15, 2017 meeting of the ECVIM-CA (European College of Veterinary Internal Medicine - Companion Animals) in Malta, the EPIC Study's three lead invesigators (Jens Häggström, Adrian Boswood, Sonya Gordon) are scheduled to report on a "Longitudinal analysis of data from dogs with pre-clinical mitral valve disease receiving pimobendan or placebo: the EPIC study". This is expected to be a review of the long term results of the treatment of the nearly 360 dogs in the EPIC trial after they reached heart failure (Stage C). The focus likely will be on a comparison of the lifespans of the two sets of dogs while in Stages C and D.
EDITOR’S NOTE: Previously, some observant veterinary cardiologists have suggested that the EPIC trial's longitudinal data showed that once dogs in the pimobendan group reached Stage C, they did not survive as long in the heart failure stage as did the dogs from the placebo group. Whether this anomaly was due to toxicity of the pimobendan or to the dogs having developed a tolerance to the drug -- making it less effective as time went on -- remains to be seen. Hopefully, this upcoming longitudinal study will provide these details which were inexplicably excluded from the original EPIC Study publication.
June 2017: Virginia-Maryland veterinary college creates a database of MVD-affected dogs. Dr. Michele Borgarelli of the Virginia-Maryland Regional College of Veterinary Medicine is spearheading a longitudinal outcome database to serve as a reference library about dogs with mitral valve disease. He said:
“Despite being the most common cardiovascular disease in dogs, we don’t have much data to better understand the natural history of mitral valve disease or assess what happens to the dogs once a veterinarian makes a diagnosis,” he explained. “Through this database, we are collecting a large amount of data from as many patients as possible and then following them for the next five years.”
The database will allow researchers to pose questions about which metrics predict outcomes and which interventions affect prognosis. No such database currently exists for mitral valve disease, but according to Dr. Borgarelli, disease registries have proven effective in other veterinary and human diseases. He added, “The preliminary phase of the study started in October, and we are already tracking data on more than 500 dogs in just a few months.”
Patients with a new diagnosis at the Veterinary Teaching Hospital in Blacksburg are entered into the database. The cardiology clinicans also are partnering with cardiologists at Chesapeake Veterinary Cardiology Associates, a group of cardiac specialty practices in northern Virginia and Maryland, and the Swedish University of Agricultural Sciences in Uppsala, Sweden, to expand the database. At the 2017 ACVIM Forum in June 2017, Dr. Borgarelli reported that, to date, the database contains clinical information from 2,053 dogs of 104 breeds. He said that follow-up examination data is available for about 30% of the dogs. This study is scheduled to terminate in October 2020.
At a September 14, 2017 meeting of the ECVIM-CA (European College of Veterinary Internal Medicine - Companion Animals) in Malta, Dr. Borgarelli will present another report on findings from this database, titled "The LOOK Mitral study: is there any standard treatment for dogs with mitral valve disease?"
May 2017: Dr. Borgarelli's ongoing mitral valve shape comparison study adds more data. In a May 2017 article, the international team of veterinary cardiologists (G. Menciotti, M. Borgarelli, M. Aherne, P. Camacho, J. Häggström, I. Ljungvall, S. M. Lahmers, J. A. Abbott) which have been investigating the shape (morphology) of dogs' mitral valves over the past two years (see our March 2017 and December 2016 and May 2015 news items), reports finding that healthy cavalier King Charles spaniels have smaller mitral leaflets and less "tenting" height (flatter) than do healthy dogs of other breeds. (See Figure 2, below.) They conclude:
"The MV of CKCSs is flatter and has reduced tenting compared to the MV of other breeds. These morphologic features could confer a mechanical disadvantage, and play a role in the predisposition of this breed to the early development of myxomatous mitral valve disease."
May 2017: Cardiologist Mark Rishniw says "Not so fast!" in prescribing pimobendan to all heart-enlarged MVD dogs. In an April 2017 article, USA board certified veterinary cardiologist Dr. Mark Rishniw (right) takes a very critical look at the EPIC Study report. First he warns that determining whether a dog's heart actually is enlarged is not so easy using x-rays alone. He writes:
"Given that many clinicians struggle to correctly identify cardiomegaly in small-breed dogs from radiographs and tend to over-interpret cardiac enlargement, the investigators stressed that the diagnosis should be made with the benefit of echocardiography. Obviously, many clients will not be able to afford echocardiography, and clinicians will be faced with the decision based on radiographic evidence alone." (Emphasis added.)
He questions the basis for the EPIC Study authors' optimism about starting all heart-enlarged MVD-affected dogs on pimobendan, regardless of the extent and/or rapidity of the enlargement. From the EPIC Study authors' viewpoint, he writes:
"Essentially, the risk of developing CHF or dying was almost halved, regardless of how bad the dog’s disease was going into the study. On the face of it, this sounds great. Based on this information alone, every dog with MMVD and left atrial enlargement (correctly identified!) would benefit from pimobendan treatment. Not so fast! The decision to treat a dog requires additional information to be considered. First, the baseline risk of developing CHF needs to be determined, i.e., what is the chance that this dog will actually develop CHF at some point in the future?" (Emphasis added.)
He then takes into account the statistics from the study and asks this ultimate question:
"Is 'earlier' treatment better than 'later' treatment? The survival curves provide clues to this answer. ... Now, if there was a clear benefit of 'earlier' rather than 'later,' we might expect the survival curves to diverge, ie., continue to move further and further apart. But they don’t. For the majority of the study, they remain parallel. So, the benefit with more severely affected dogs is about 300 days, and the benefit with the least severely affected dogs is about 300 days. This suggests that taking the more measured approach of waiting until a dog exhibits evidence of disease progression before instituting therapy is not compromising that dog nor reducing the benefit of the drug. And, dogs that were never going to progress to more severe disease and never develop CHF would not be subjected to needless drug administration (and needless expenses)." (Emphasis added.)
EDITOR’S NOTE: Dr. Rishniw's objective approach to the EPIC Study report is in stark contrast to the broadbrush of Dr. Philip Fox, below here. First, Dr. Rishniw points out that determining whether a small dog's heart is enlarged from an x-ray is not so easy, and that "many clinicians ... tend to over-interpret cardiac enlargement". This alone is a scary factoid, considering that the EPIC Study's minimum x-ray parameter for determining enlargement in all dogs, regardless of breed, is a VHS value of 10.5+, a measurement so low that most all cavaliers with no MVD whatsoever would be candidates for treatment with pimobendan, if only x-rays were relied upon.
He acknowledges that dog owners may "not be able to afford echocardiography, and clinicians will be faced with the decision based on radiographic evidence alone." (This is consistent with our own concerns, expressed in our March 2017 blog article, "Will general practice vets cut corners to prematurely prescribe pimobendan to MVD-affected cavaliers?") A simple answer to that circumstance would be: If for whatever reason you don't perform the echocardiogram, then don't prescribe the drug.
Then Dr. Rishniw analyzes the EPIC Study's own statistics to observe the falsehood of the EPIC Study authors' simplistic notion that any and all MVD-affected dogs with enlarged hearts, regardless of the degree or rapidity of enlargement, would benefit from pimobendan. As Dr. Rishniw says, "Not so fast!" and that "a more measured approach", looking into the details of each dog's MVD progression, is called for before determining if and when pimobendan may be warrranted.
Finally, Dr. Rishniw focuses on the economics of starting pimobendan too early. He writes that dogs which would likely never progress to congestive heart failure (CHF) ought "not be subjected to needless drug administration (and needless expenses)." He raises the heretofore unspeakable suggestion that the EPIC Study's unwarranted conclusion (that all MVD-affected dogs with any heart enlargement need pimobendan before CHF) would be a tremendously unnecessary expense (which may be explained by the drug manufacturer's 100% financial underwriting of the EPIC Study -- including hotels, meals, and travel for participating cardiologists -- and its hoped for additional sales of its very expensive drug).
By mentioning that starting pimobendan too early may result in "reducing the benefit of the drug", Dr. Rishniw may be suggesting another possible downside of starting pimobendan before it is truly needed -- that the patients may develop a tolerance to the pimobendan, thereby decreasing its effectiveness. Drug tolerance is a pharmacological concept describing the patient's reduced affinity to a drug after sustained exposure to that drug. This means that starting the drug earlier than necessary can result in having to increase the dosage later on to achieve the same beneficial effect. Even worse, at some point the drug may become totally ineffective.
In a January 2017 article, veterinary cardiologist Mikaela Mueller (right) impliedly concurs with Dr. Rishniw's viewpoints on the EPIC Study. She wrote:
"One of the major concerns with the EPIC study is that many dogs with only mild enlargement never experience clinical signs of congestive heart failure in the first place, so treating them long-term with pimobendan does not change their clinical outcome. Luckily, it appears to be a very safe medication for the majority of patients, but it is not a cheap medication to give for years when it does not change the outcome. Since we do not have a good way of predicting which dogs with mild disease will progress to clinical signs, it becomes difficult to decide whether or not to recommend pimobendan for some patients. This is where the art of clinical practice comes into play. Each patient is an individual who deserves personalized thought and attention. If a patient has mild cardiomegaly and is already 16 years old, it is far less likely that the patient will progress to congestive heart failure during his or her lifetime than a different patient with similar disease who is only 5 years old."
Like the white-coated sanitation guys cleaning up behind the elephant parade, Drs. Rishniw and Mueller are critically analyzing the EPIC Study's own statistics, which the study's authors neglected to do themselves. The bottom line is that no cavalier owner should jump at the prospect of giving pimobendan to their dogs unless and until a very careful, thorough study -- "a more measured approach" -- is conducted for each patient, to determine the likelihood that the drug will do any good at the current stage of the dog's MVD.
It is very unfortunate that these observations, drawn directly from the EPIC Study's own data, were not discussed by the EPIC Study authors themselves. The EPIC Study report needs to be retracted and re-written, so that no clinicians are misled by its lack of critical analysis of its own statistics. The authors had 18 months following the end of the study (March 2015 to September 2016) in which to draft a thorough, objective review in accordance with the veterinary motto: Do no harm. But, unfortunately, they instead published a conclusion that could have been written by the drug manufacturer's press agent.
(See our Blog article, The EPIC study’s bluster about pimobendan unravels as critical analysis finally takes hold, for a more detailed commentary on this issue.)
May 2017: Cardiologist Kristin Jacob narrowly interprets the EPIC Study results. In a May 2017 article, Maryland board certified veterinary cardiologist Kristin A. Jacob gives a narrow interpretation of the EPIC Study report, confining pimobendan treatment to MVD-affected dogs with "advanced" or "significant" Stage B2 heart enlargement, as distinguished from "mildly enlarged". She also requires that the diagnosis be made "based on chest radiographs + echocardiogram with cardiologist".
May 2017: Cardiologist Philip Fox claims EPIC Study makes echocardiography optional in prescribing pimobendan before heart failure. In a Fall 2016 newsletter column, USA veterinary cardiologist Dr. Philip Fox (right) asserts that in determining when to start administering pimobendan to MVD-affected dogs under the EPIC Study, either x-rays or echocardiography may be used. Specifically, he writes:
"In light of these findings, clinicians should change how they diagnose and manage MVD. Dogs with heart murmurs should be screened early, rather than wait for clinical signs of coughing or respiratory distress to develop. Assessment can be effectively made using history and physical examination along with the added benefit of chest radiography and/or echocardiography." (Emphasis added.)
EDITOR’S NOTE: There you have it. Our greatest fear about the terribly flawed EPIC Study report is that it would encourage veterinarians to skip echos entirely and diagnose heart enlargement solely based upon x-rays. (See our March 2017 blog article, "Will general practice vets cut corners to prematurely prescribe pimobendan to MVD-affected cavaliers?", for more details.)
Why the fear? What is wrong with using only the dog’s x-ray to determine if its heart is enlarged to prescribe pimobendan, you may ask? Well, in the EPIC Study, x-rays are used to calculate the dog's Vertebral Heart Score (VHS). The EPIC Study's species-wide VHS parameter for deterimining heart enlargement and starting pimobendan is any VHS value above 10.5. EPIC provides absolutely no breed-specific parameters, much less any case-by-case recommended parameters. It is VHS > 10.5 for every dog!
With the EPIC Study's x-ray parameter of VHS > 10.5, a whole lot is terribly wrong for our cavalier King Charles spaniels. You see, the average heart-healthy cavalier, with no enlargement whatsoever, has a VHS value significantly above 10.5. It is troubling that the EPIC Study report ignores the fact that normal, heart-healthy cavaliers may have VHS measurements as high as 11.7, which is notably higher than EPIC's 10.5+ criterion for beginning pimobendan treatment. Considering that nearly half of the dogs in the EPIC Study were CKCSs, this oversight is rather inexplicable and potentially life-threatening for our breed.
The only saving grace the EPIC Study lead authors must have had is that, hopefully, no veterinarian would rely solely upon an x-ray before prescribing the drug. Hopefully, all vets would also perform the M-mode echocardiography necessary to arrive at the other two parameters for determining if the dog's heart is sufficiently enlarged. (Which is laughable, of course, because how many general practice vets have M-mode echocardiograph ultrasound devices at their clinics, much less know how to use them?)
So now we even have a board certified veterinary cardiologist (who participated in the EPIC Study, by the way -- his name is on it) irresponsibly suggest that heart enlargement may be diagnosed by x-rays alone before starting pimobendan. And, he wrote this in an advice column directed to general practice veterinarians!
The bottom line is that the thoughtlessly-worded EPIC Study report needs to be retracted and re-written, if cavaliers' lives are to be saved by pimobendan, instead of being destroyed by that drug. If a cardiologist who actually participated in the EPIC Study does not understand how to follow it, how can we expect our general practice vets to do so?
May 2017: Columbian researchers find a variation of gene COL1A2 may play a role in causing MVD in canines. In a December 2016 report, a team of Columbian veterinary researchers (Orlando A. Torres-García [right], Rey-Buitrago, M., Acosta-Virgüez, E., Bernal-Rosas, Y., Infante-González, J., Gómez-Duarte, L.) investigated variations of the COL1A2 gene (within the CFA14 region) in 50 MVD-affected and 80 control Poodles. (The CFA14 region was identified in the September 2011 study of 241 cavalier King Charles spaniels, as being associated the CKCS's hereditary mitral valve disease.) The Columbian veterinarians found that "the allele T of the rs22372411 variant was over-represented in MMVD patients compared with healthy controls." They concluded:
"Our results show for the first time an association of the rs22372411 COL1A2 gene variant with susceptibility to canine myxomatous mitral valve disease."
May 2017: Detroit hospital physicians find Neladenoson may reverse hind leg weakness in dogs in heart failure. In a May 2017 abstract, a team of researchers at Henry Ford Hospital in Detroit (HN Hani Sabbah, RC Gupta, V Singh-Gupta, K Zhang, J Xu) report on the success of Neladenoson (a partial adenosine A1-receptor agonist) in improving the function of mitochondria in the skeletal muscles of dogs in heart failure.
Mitochondria are organelles in the muscle cells, which take in nutrients, break them down, and create energy rich molecules for the cell. As heart failure progresses in MVD-affected dogs, the mitochondria reduce in size, resulting in reduced capacity to create energy.
The researchers opine that treating dogs in heart failure with Neladenoson can potentially reduce or reverse exercise intolerance and skeletal muscle weakness.
May 2017: Mayo Clinic researchers engineer a designer natriuretic peptide to mediate kidney impairment by furosemide. In a May 2017 abstract, Mayo Clinic researchers (LMG Meems, Y Chen, GJ Harty, GE Harders, BK Huntley, SR Iyer, DM Heublein, JC Burnett Jr.) report on the success of their engineered designer natriuretic peptide "NPA7" as co-therapy with diuretics (specifically here, furosemide) in treating ten dogs in acute decompensated heart failure (ADHF). They noted that furosemide (FURO) alone lacks vasodilatory actions, impairs kidney function, and activates the renin-angiotensin-aldosterone system (RAAS). They found NPA7 to decrease vascular resistance, reduce pulmonary capillary pressure, increase renal blood flow, increase urinary flow and sodium excretion. They conclude:
"In conclusion, in experimental ADHF, NPA7 is a vasodilatory therapeutic with cardiac unloading, diuretic and natriuretic actions. FURO is more diuretic, but is associated with significant renal impairment, vasoconstriction and RAAS-activation. In addition, pre-treatment with NPA7 enhances natriuresis and diuresis while preserving kidney function. Priming with NPA7 may therefore represent a novel renoprotective strategy for treatment of ADHF. Importantly, this study underscores the need for future studies assessing the impact of timing of diuretics on treatment effects of novel therapies in patients with ADHF."
May 2017: Synthetic BNP injections potentially can offset RAAS activation in dogs in CHF. B-type natriuretic peptide (BNP) is a natriuretic, diuretic, vasodilatory, and anti-remodeling hormone produced by myocardial cells in response to heart failure due to MVD (and other causes of heart failure). ("Natriuretic" means: causing the excretion of an excessively large amount of sodium in the urine.) BNP is activated during heart failure to counteract the effects of activation of the renin angiotensin aldosterone system (RAAS) in the heart, kidneys, and blood vessels. However, as the MVD progresses, the dog's ability to produce active BNP declines, lessening its ability to counter the effects of RAAS activation.
In a May 2017 article, US investigators (M.A. Oyama [right], P.F. Solter, C.L. Thorn, J.A. Stern) discuss the feasibility, safety, and tolerance of injecting synthetic canine B-type natriuretic peptide (syncBNP) in four healthy dogs and two dogs with stage B1 mitral valve disease, including a cavalier. They also gathered data regarding the effect of syncBNP on plasma cGMP, kidney function, and RAAS. The found that syncBNP was feasible, well tolerated at all doses, and safe, and that it significantly increased median plasma cGMP. They recommended further studies using syncBNP for treatment of MVD.
EDITOR’S NOTE: We were a bit confused by this article, because two years earlier, two of the same researchers -- Drs. Chloe Thorn and Mark Oyama -- opined in a July 2015 abstract that "targeted reductions in NT-proBNP result in improved outcomes in dogs with CHF secondary to MMVD."
In response to our query, lead investigator Dr. Oyama explained:"BNP is a hormone made by the heart that is actually beneficial to heart function and helps reduce congestion and disease severity.
"The NT-proBNP form of BNP has been previously studied as a marker of heart disease and measure of disease severity. NT-proBNP is an inactive by-product of activation of the parent BNP molecule. The presence of high NT-proBNP in dogs with heart disease and failure indicates that they are attempting to make large amount of BNP (and hence lots of NT-proBNP appears in the circulation) in order to stay out of heart failure, but the increased amount is insufficient to prevent heart failure in the later stages of disease.
"Thus, despite high levels in heart failure, dogs might be considered to still have a BNP 'deficiency'. Giving additional BNP in the active form might help improve signs of congestion. In humans, supplemental short term BNP in the hospital helps improve clinical signs."
April 2017: Texas A&M cardiologists fine tune cardiac troponin I measurements of MVD progression. In an April 2017 article, a team of Texas A&M veterinary school investigators (Randolph L. Winter [right], Ashley B. Saunders, Sonya G. Gordon, Matthew W. Miller, Jan S. Suchodolski, Jörg M. Steiner) applied the concept of biologic variability (BV) testing to concentrations of cardiac troponin I (cTnI) in periodic blood samples of 10 healthy and 28 MVD-affected dogs (including 14 [50%] cavalier King Charles spaniels). They noted that the use of a standard sensitivity cTnI assay was insufficiently sensitive to quantify and study changes in cTnI concentration in both healthy dogs and MVD-affected dogs in their study. They argue that long-term serial measurements of cTnI changes helped predict the MVD end-points of onset of heart failure and death. They suggest that such periodic testing may provide more information for predicting survival time than a single measurement.
A companion article, published in January 2017 by a sub-set of the same Texas A&M team, used biologic variability to examine N-terminal pro-brain natriuretic peptide (NTproBNP) samples in the same group of dogs. See this link to our review of that article.
EDITOR’S NOTE: This report appears to be a postive step towards making biomarker blood testing of the progression of MVD much more accurate in predicting the onset of heart failure and death. However, what is the point of these cardiac biomarker tests? Is it to predict when heart failure may be imminent? If so, so what? Before the EPIC Study report, heart failure was the bright line for the start of medicating dogs with MVD. But now that the EPIC Study report tells us the bright line no longer is heart failure but now is heart enlargement, we see less need to focus upon the threshold of heart failure at all.
And, of course, "Biologic Variability" is vet-speak for periodic repeat testing. So, how much more is this all going to cost the dog's owner, over and above a one-shot cTnI or NTproBNP test? Try multiplying whatever one test costs by five or ten times.
April 2017: UK Kennel Club spokesman trashes the MVD Breeding Protocol. In a statement included in a DogWorld.co.uk article published in April, 2017, UK Kennel Club secretary Caroline Kisko (right) announced that the Kennel Club rejects the MVD Breeding Protocol because it requires "breeding from older bitches." The protocol, which was introduced in the UK in 1996 and has been endorsed by the UK Cavalier Club, calls for not breeding any cavalier until they reach the age of 2.5 years. The protocol has been proven effective in reducing the early onset of mitral valve disease in offspring. Ms. Kisko in effect ridiculed the protocol by declaring that 2.5 year old CKCS dams are "older bitches".
April 2017: Brazilian researchers find a quality of life questionnaire can accurately predict approaching cardiac deaths of dogs. In a March 2017 article, a team of Brazilian investigators (Célia M. C. Strunz, Mário Marcondes-Santos, Julio Yoshio Takada, Fernanda S. Fragata, Antônio de Pádua Mansur) compared usual mitral valve disease (MVD) measurement devices (e.g., clinical, laboratory, and echocardiographic evaluations) with the results reported by the owners of 36 dogs suffering from MVD, by answering a series of 17 questions in the "Functional Evaluation of Cardiac Health Questionnaire" (see below). The questions are mainly related to respiratory signs, difficulties with mobility (such as walking and climbing stairs), physical activity, irritability, appetite, sleepiness, and frequency of urination and vomiting. They found that NT-proBNP levels and high quality life score were independently associated with impending death. They concluded that the score is easy to apply and does not require any technology, only a veterinarian and an observant owner.
March 2017: Lung ultrasound exams can accurately diagnose early signs of pulmonary edema and may predict onset of congestive heart failure. In a March 2017 article, a team of Italian researchers (Tommaso Vezzosi [right], T. Mannucci, A. Pistoresi, F. Toma, R. Tognetti, E. Zini, O. Domenech, E. Auriemma, S. Citi) used lung ultrasound (LUS) to examine the conditions of dogs in different stages of mitral valve disease (MVD), to distinguish lung patterns leading to congestive heart failure (CHF). They report detecting "B-lines" (also called ultrasound lung rockets) representing interstitial edema. The number and distribution of these B-lines correspond to the presence of extravascular fluid in the lungs and indicate the severity of pulmonary edema (PE) and stage of its progression. Dogs in Stage B1 of MVD had absent or rare B-lines in 14 of 15 cases (93.3%); dogs in Stage B2 had absent or rare B-lines in 16 of 18 cases (88.9%); all dogs in Stage C without radiographic signs of PE, had absent or rare B-lines; dogs in Stage C with radiographic signs of PE, had numerous or confluent B-lines in 18 of 20 cases (90%). They concluded:
"Our findings indicate that LUS has good diagnostic accuracy in identifying cardiogenic PE and might be useful in the staging of dogs with CVHD [chronic valvular heart disease]. Lung ultrasound examination is a new, quick, and noninvasive diagnostic tool for the cardiologist, radiologist, or intensive care specialist. It should be considered as complementary to thoracic radiography, and particularly useful when radiographic findings are unclear or in severely dyspneic dogs. In the future, it would be interesting to evaluate the utility of LUS in the chronic management and serial monitoring of dogs with CVHD under treatment."
March 2017: Slovenian researchers report correlations between NT-proBNP and CoQ10 concentrations in dogs receiving cardiac treatment. In an April 2017 article, Slovenian investigators (Alenka Nemec Svete, Barbara Verk, Alenka Seliškar, Katerina Tomsič, Petra Jazbec Križman, Aleksandra Domanjko Petrič [right]) compared NT-proBNP, antioxidant, and CoQ10 concentrations in dogs with various cardiovascular diseases and the effect of cardiac treatment on those concentrations. The report finding:
• Total antioxidant capacity (TAC): Antioxidant variables were not altered in the dogs with cardiac disease, regardless of the stage of cardiac disease or treatment. Plasma TAC values were higher in those receiving treatment than in those not receiving treatment; however, the difference was not significant.
• NT-proBNP: Serum concentration of the cardiac biomarker NT-proBNP increased significantly with the stage of heart failure, although there was no significant difference between affected dogs that were or were not receiving treatment. A significant negative correlation between serum NT-proBNP concentration and plasma CoQ10 concentration was identified in the dogs that were receiving cardiac treatment.
• CoQ10: Lower plasma CoQ10 concentrations were likely associated with greater severity of CHF. Plasma CoQ10 concentration was significantly higher in affected dogs that were receiving treatment, compared with affected dogs that were not receiving treatment. Plasma CoQ10 concentration in dogs that were not receiving cardiac treatment was lower than that in healthy dogs and significantly lower than that in dogs that were receiving cardiac treatment, which may be evidence of CoQ10 deficiency in dogs with cardiac disease in the absence of treatment.
In summary, NT-proBNP increases with the severity of heart failure (CHF), and treatment did not reverse that trend. CoQ10 levels decreased with greater severity of CHF. CoQ10 concentrations were significantly higher in affected dogs receiving treatment, indicating a CoQ10 deficiency in affected dogs without treatment.
March 2017: Korean researchers find that serum homocysteine concentrations increase as MVD progresses in dogs. In an April 2017 article, Korean cardiologists (Chang-Min Lee, Da-Min Jeong) led a team (Min-Hee Kang, Seung-Gon Kim, Jae-Ik Han, Hee-Myung Park) in examining serum homocysteine in 63 dogs to determine if there is any correlation between homocysteine concentrations and the worsening of mitral valve disease. Homocysteine is an essential amino acid metabolite of methionine that is recycled into methionine or converted into cysteine by vitamin B. They found significant correlations between serum homocysteine concentrations and each stage of MVD (Stages B1, B2, C, D). They concluded that the measurement of serum homocysteine concentration may be useful in predicting the severity of MVD in dogs.
March 2017: Thai researchers find long-term treatment of Stage B dogs with sildenafil (Viagra) prevented progression of MVD. In a March 2017 report of a 180-day study of 30 MVD-affected dogs (none were cavalier King Charles spaniels) in Stage B1 or Stage B2 (non-symptomatic), a team of Thailand investigators (Anusak Kijtawornrat [right], Siripen Komolvanich, Nakkawee Saengklub, Prapawadee Pirintr, Pakit Boonpala, Chollada Buranakar) treated half of the group with sildenafil (Viagra, Revatio) (a/k/a sildenifil) versus a control group. Sildenafil is a selective phosphodiesterase-5 inhibitor that has been demonstrated to delay ventricular enlargement in humans and experimental animals. They found:
• The stroke volume (the volume of blood pumped from the left ventricle per beat) at day 30 was significantly higher in the sildenafil group.
• The LA/Ao (left atrial-to-aortic ratio) and the MR jet area were significantly lower beginning at day 30, day 90, and day 180.
• The 2D-LA (2-dimentional left atrium size) was significantly lower at day 90 when compared with control group.
• The differences of NTproBNP (a natriuretic peptides test biomarker in cardiac disease) from baseline were significantly lower when compared with control group at the same timepoint, day 90 and day 180. (Click here for details about natriuretic peptides tests.)
"In conclusion, this study suggested that long-term treatment with sildenafil prevented aggravation of disease progression as suggested by several echocardiographic indices (i.e. SV, LA/Ao, MR jet area, 2D-LA) and reduced NTproBNP level at the indicated timepoints in dogs with asymptomatic mitral valve degeneration."
EDITOR’S NOTE: Previously, sildenafil has been prescribed for MVD-affected dogs already in heart failure if pulmonary hypertension is also detected. Pulmonary arterial hypertension, as a complication of mitral valve disease, is higher diastolic or systolic pulmonary arterial pressure than normal pressure. This high pressure may lead to increased right ventricular pressure and right atrial chamber enlargement, leading to possible right side heart failure. In this new study, the authors state that sildenafil already has been demonstrated to delay left ventricular enlargement in humans and experimental animals.
March 2017: Japan's Masami Uechi reports 92% success rate in 600+ open heart surgeries for MVD. In an October 2016 abstract, Japanese veterinary surgeon Masami Uechi (right) reported on the results of his team's cardiopulmonary (CPB) -- also known as open heart -- surgical mitral valve repair of over 600 toy breed dogs. Chordae tendineae were replaced with expanded polytetrafluoroethylene, and a mitral annulus plasty was performed. (For more information about CPB and mitral annulus plasty, click here.) The results:
• The grade of cardiac murmur was significantly reduced to 0/6–3/6 three months postoperatively.
• The heart shadow was reduced in the chest X-rays.
• Echocardiography confirmed the marked reduction in mitral regurgitant ratio and the left atrial dimensions.
• Mitral valve repair reduced enlarged cardiac size by reduction of regurgitant rate.
• Currently perioperative survival rate is 98% and discharge rate is 92%.
• With the improvement in general condition, body weight increased.
• By 3 months after the operation, many dogs were not on medication.
He concluded that:
"Open heart surgery using CPB can be performed safely in small breed dogs. Mitral valve repair is an effective therapy for DMVD with severe MR. Postoperative complications include pancreatitis and thrombosis, which may be reduced by future advanced techniques."
Dr. Uechi subsequently reported, in January 2017, that he has performed MVD repair surgery on nearly 700 dogs over the previous 12 years, with an 85% survival rate.
March 2017: Tricuspid valve replacement with cow or pig valves has significant complications. In a March 2017 article by a team of UK researchers (P. Bristow, J. Sargent, V. Luis Fuentes, D. Brockman), they reported on tricuspid valve replacements in nine dogs with severe valve regurgitation and signs of heart failure. All of the dogs were suffering from tricuspid valve dysplasia, a congenital malformation more common in larger breeds than the cavalier King Charles spaniel. None of the nine dogs were cavaliers. The surgical procedures included cardiopulmonary bypasses. Four of the dogs died due to complications during hospitalization. Of the five dogs discharged from the hospital, one died due to an unrelated injury seven days later. Of the four remaining dogs, they survived a median of 533 days after receiving the cow (bovine) valve. The researchers acknowledge that some of the complications may have been due in part to their relative inexpericence when compared to the successes of the surgical group at Colorado State University.
March 2017: 3-D echocardiograms show differences in shapes of mitral valves of MVD-affected dogs versus healthy dogs. In a March 2017 article, an international team of cardiologists (G. Menciotti, M. Borgarelli, M. Aherne, S. Wesselowski, J. Häggström, I. Ljungvall, S.M. Lahmers) used real-time transthoracic three-dimensional echocardiography analysis (RT3DE) on 113 dogs, including 13 cavalier King Charles spaniels affected in varying stages of mitral valve disease. The 3-D echos enabled the investigators to compare the morphology of the mitral valves (MVs) of healthy dogs (none were CKCSs) and MVD-affected dogs. They report that the study demonstrated that the MVs of MVD-affected dogs differed from those of healthy dogs in several morphological aspects. In particular, the affected dogs had an increased sphericity and a decreased saddle shape of the MV annulus, as well as a decreased tenting height, area and volume. See Figure 1. The study also reportedly demonstrated significant differences in multiple 3-D echo MV measurements between dogs in varying stages (B1, B2, C) of MVD.
February 2017: Austrian heart clinic offers mitral valve repair surgery on MVD-affected dogs in heart failure. Dr. Peter Modler (right) has announced that he is performing surgical mitral valve repair on a routine basis to dogs with advanced degenerative mitral valve disease. Thus far, he has concentrated on treating cavalier King Charles spaniels in congestive heart failure. His open-heart surgical procedure includes installing a Gore-Tex annuloplasty ring around the valve, and also replacing diseased valve chords with Gore-Tex, while the dog is on cardiopulmonary bypass.
Dr. Modler's clinic is located in Sattledt, Austria. His contact information is: email: email@example.com; telephone: +43 7244 8924; website: www.tierklinik-sattledt.at; address: Traunkreis Vet Clinic - Tierklinik Sattledt, Kirchdorfer Strasse 7, A-4642 Sattledt, Austria. He advises that he is able to provide travel and accommodation assistance, as well.
His exclusion criteria for surgery are:
• Severe pulmonary hypertension (more than 60 mm Hg)
• Clinical symptoms of syringomyelia
• Severe concomitant diseases (e.g. kidney failure, liver failure, malignant neoplasia)
For more information about Dr. Modler's surgeries, on our website, see this October 2015 item.
February 2017: Serum proteins are found to be differentially expressed in cavaliers with MVD. In a February 2017 article on a study of twelve cavaliers, an Italian team reported finding eight serum proteins which were differentially expressed between groups of moderately (M) and severely (S) affected CKCSs with MVD and a control group of healthy cavaliers. These proteins were found to be significantly related to the progression of the disease. In the M group versus healthy dogs complement factor H isoform 2, inhibitor of carbonic anhydrase, hemopexin, dystrobrevin beta isoform X7 and CD5 molecule-like resulted to be down-regulated, whereas fibronectin type-III domain-containing protein 3A isoform X4 was up-regulated. In the S dogs versus healthy group complement factor H isoform 2, calpain-3 isoform X2, dystrobrevin beta isoform X7, CD5 molecule-like and l-2-hydroxyglutarate dehydrogenase resulted to be down-regulated. Complement factor H isoform 2, calpain-3 isoform X2, dystrobrevin beta isoform X7, CD5 molecule-like and hydroxyglutarate dehydrogenase were found to be down-regulated in mild affected group versus healthy dogs. All of these proteins except complement factor H followed a decreasing trend according to the progression of the pathology. They concluded that the differential expression of serum proteins demonstrates the possibility these might be valuable for the detection and monitoring of the disease.
February 2017: Japanese researchers find left atrium strain can predict heart failure in MVD-affected dogs. In a February 2017 article, a team of veterinary researchers at Hokkaido University in Japan (K. Nakamura, S. Kawamoto, T. Osuga, T. Morita, N. Sasaki, K. Morishita, H. Ohta, M. Takiguchi) examined 52 dogs in various stages (Stages B1, B2, C, and D) of mitral valve disease (MVD), including two cavalier King Charles spaniels (CKCS) in Stage B2, to determine the variations in the extent of strain in the left atrium in the differing MVD stages. "Strain" is "the longitudinal shortening and lengthening of the LA wall, allowing the quantification of all 3 LA functions: as reservoir, conduit, and booster pump." They used speckle-tracking echocardiography, a novel, angle-independent imaging method that allows assessment of strain and strain rate, using the tracking of acoustic speckle patterns. They found that there were no significant differences in parameters of LA strain between the Stages B1 and B2 groups. However, LA longitudinal strain during atrial contraction and during ventricular systole were significantly lower in Stages C and D than in Stages B1 and B2. They concluded:
"In conclusion, the results of the present study indicate that LA longitudinal strain was significantly lower in dogs in the advanced stages [Stages C and D] of MMVD. LA longitudinal strain during atrial contraction was the best predictor of the presence or history of CHF. LA strain assessed on conventional echocardiography and radiography could add meaningful information to confirm the presence of CHF in the clinical setting. Further studies are needed to determine the clinical implications of these findings for treatment decisions and/or prognosis determination."
January 2017: Nutri-Plus Gel stimulates the appetite of a cavalier in Stage C MVD suffering severe weight loss. In a November 2016 article by a team of French cardiologists and specialists (J. Bouvard, C. Misbach, V. Gouni, C. Damoiseaux, A.M.P. Petit, V. Arqued-Soubeyran, E. Trehiou-Sechi, J.L. Pouchelon, G. Chaix, V. Chetboul), they reported on the use of a palatable complementary feed composed of high-energy ingredients (glucose syrup, soybean oil and cod liver oil), hydrolyzed animal proteins, vitamins and oligo-elements, called Nutri-Plus Gel, in five case studies.
Case Report 4 was of a female 13-year-old cavalier King Charles spaniel (right) in Stage C2 (advanced heart failure) of mitral valve disease, which had lost 1.5 lbs. in the previous month and now weighed 11.5 lbs. She exhibited signs of fatigue, lack of appetite, and diarrhea. Her MVD treatment had been the standard six medicines for cavaliers in heart failure. They reported:
"Nutri-Plus Gel was also prescribed to stimulate appetite, limit the already considerable loss in body weight (10% of the initial weight in one month), and facilitate treatment compliance (six drugs in all, requiring eleven oral doses). During the follow-up visit one week later, the owner reported that the digestive and cardiac symptoms had disappeared (stage C1). One month later, a gain in weight was noted (200 g [0.44 lb.]). Two years after this episode, the dog was in good general condition and no change in the medical treatment was proposed, as the symptoms had not returned. As the animal’s weight is now stable, Nutri-Plus Gel is recommended solely on demand, during phases of hyporexia (infrequent to date, according to the owner)."
January 2017: Dr. Borgarelli seeks cavaliers in heart failure for minimally invasive mitral valve repair. Dr. Michele Borgarelli at Virginia Tech veterinary school is testing the feasibility of minimally invasive repair of the mitral valve using the Harpoon TSD-5 device developed by Harpoon Medical Inc. of Baltimore, Maryland. The device is designed to anchor artificial cords on the flaps of the valve, to replace the vavle's natural chordae tendieae. The replacement cords are made of expanded polytetrafluoroethylene (ePTFE).
Dr. Borgarelli is seeking candidate dogs for a study to assess the efficacy and long-term effects of using the Harpoon Medical TSD-5 device. Dogs in Stage C, heart failure with significant enlargement, and weighing over 11 pounds. Details of the study are available here. To apply, or for more information, contact Mindy Quigley, Clinical Trials Coordinator, telephone 540-231-1363, email firstname.lastname@example.org.
January 2017: N-terminal BNP predictions of MVD status get more complicated. In a January 2017 article by a team of Texas A&M University researchers (Randolph L. Winter, Ashley B. Saunders, Sonya G. Gordon, Jesse S. Buch, Matthew W. Miller), they focused upon the inherent variability of the cardiac biomarker N-terminal pro-brain natriuretic peptide (NTproBNP) in all dogs -- both healthy and MVD-affected -- and how those random variations, called biologic variability, affects the accuracy of population-based reference ranges of NTproBNP readings. They measured NTproBNP in healthy dogs and dogs in stages B1, B2, and C of mitral valve disease, to estimate biologic variability and calculate an Index of Individuality (IoI) for each dog. Of the 28 MVD-affected dogs in the study, 14 -- 50% -- were cavalier King Charles spaniels, along with 10 healthy control dogs. They found that MVD-affected dogs had a lower inherent variability of NTproBNP compared to healthy dogs, and that, as a group, MVD-dogs required a change of 58.2% for NTproBNP to be outside the range of inherent biologic variability and indicate a change in disease. They determined that population-based reference ranges for NTproBNP may have limitations. They stated that:
"It is important for veterinarians to have an understanding of how much a biomarker value could change over time due to randomness vs. disease progression in an individual dog. ... Monitoring serial individual changes in NTproBNP values may be clinically relevant in addition to using population-based reference ranges to determine changes in disease status."
EDITOR’S NOTE: This study highlights the fallibity of cardiac biomarker natriuretic peptide tests to predict the stage of MVD and the onset of heart failure in MVD-affected cavaliers. We have found that such blood tests have been used as a crutch for veterinarians who are insecure in their own judgment based upon traditional tools such as auscultation and signs such as breaths-per-minute. This study suggests that a one-time test may not provide an accurate result, and that many repeats of that test are required over an extended period of time.
December 2016: Cardiac Education Group recommends treating Stage B2 MVD-affected dogs with pimobendan based only upon x-rays. In a December 2016 newsletter, the Cardiac Education Group (CEG), a team of veterinary cardiologists including Drs. John D. Bonagura, Barret Bulmer, Whit M. Church, Sonya G. Gordon, Brian A. Scansen, Alan W. Spier, and Rebecca L. Stepien, has proposed a short-cut version of the parameters recommended in the EPIC Study report, which is based solely upon the Vertebral Heart Score values determined from x-rays, skipping entirely any measurements taken from echocardiograms. It bases its x-ray-only parameters on situations in which “an echocardiogram is not available” or “the client declines echocardiography”. The CEG states:
“If an echocardiogram is not available and only thoracic radiographs are performed, the CEG recommends starting pimobendan in dogs with heart murmurs of grade 3/6 or louder only when the VHS exceeds 11.5 vertebral bodies or an incremental increase of greater than 0.5 vertebral bodies per 6 months is accurately documented. ... In situations where the client declines echocardiography, the thoracic radiograph path can be followed in the primary care practice.”
The CEG goes on to acknowledge that:
“ACVIM guidelines recommend both imaging methods for optimal evaluation of a dog with suspected MMVD. The EPIC trial did not investigate a cutoff for cardiac enlargement by VHS alone at which to start pimobendan therapy. This algorithm represents the consensus of the CEG to initiate therapy when echocardiography is not available, but is not based on evidence.”
EDITOR’S NOTE: This is a stunning -- even jaw-dropping -- effort to water-down the recommendations of the EPIC Study report. The only saving grace of the EPIC Study report is that it requires that two precise minimum echocardiographic measurements be met, in addition to the arbitrary, species-wide VHS value of >10.5, before prescribing pimobendan to MVD-affected dogs before heart failure. The CEG openly admits that “The EPIC trial did not investigate a cutoff for cardiac enlargement by VHS alone at which to start pimobendan therapy.” And, the CEG also admits that its x-ray-only parameters are “not based on evidence.”
In essence, by these admissions, the only professional course of action for the CEG to take would have been to not make any such x-ray-only recommendation at all. One must wonder why the CEG is doing this. Could it be that it was pressured by the manufacturer of Vetmedin -- which fully funded the EPIC Study -- to go out on such an irresponsible limb? We ask because, as the CEG's newsletter also states, “The CEG is sponsored by an educational grant from Boehringer Ingelheim Vetmedica, Inc.”
December 2016: Study shows healthy cavaliers' mitral valve structure differs markedly from other breeds. In a September 2016 abstract, an international panel of cardiologists (G. Menciotti, J. Häggström, I. Ljungvall, M. Aherne, S.Wesselowski, J. A. Abbott, M. Borgarelli) used 3-D echocardiography to compare the mitral valves of 22 cavalier King Charles spaniels with 41 other dogs of 18 different breeds. They measured the dimensions of the mitral valve's annulus (see diagram at right), tenting (see diagram at left below), leaftet areas, and several other categories.
They found that cavaliers had significantly smaller annulus diameter, annulus height, tenting height, tenting area, normalized tenting volume, posterior leaflet length, normalized posterior leaflet area, and a greater annulus sphericity index. They concluded that the mitral valve of healthy CKCSs was more circular and had less tenting, compared to other breeds.
The investigators intend to pursue further research into these differences and determine whether they explain the cavalier's predispostion to an earlier onset of MVD and to a faster progression to heart failure.
December 2016: Tufts' researchers test mesenchymal stem cell (MSC) treatments to improve MVD-affected dogs in heart failure. Beginning in 2016, a research team at Tufts' University's Cummings veterinary school's Regenerative Medicine Laboratory, led by Dr. Andrew Hoffman (right), is conducting a study of ten MVD-affected dogs in congestive heart failure (determined by fluid in the lungs), which are being injected with mesenchymal stem cell (MSC) treatments to determine, first, if the therapy is safe for the dogs, and, second, will result in improved cardiac function, as determined by echocardiography, cardiac biomarkers, and quality of life. The study is titled, "Allogeneic Umbilical Cord Tissue (Wharton Jelly) Derived Mesenchymal Stem Cell Therapy for Chronic Valvular Disease and Associated Congestive Heart Failure".
December 2016: Polish researchers find four cell markers signal left atrium enlargement in MVD-dogs. In a December 2016 study by a team of Polish researchers (Izabela Janus (right), Małgorzata Kandefer-Gola, , Rafał Ciaputa, Agnieszka Noszczyk-Nowak, Urszula Pasławska, Massimiliano Tursi, Marcin Nowak), they examined the cell markers: (a) desmin, a standard cardiomyocyte marker; (b) vimentin, a typical cell marker expressed in mesenchymal cells; (c) periostin, a novel marker for myocardial remodelling; and (d) caspase-3, a marker of cell apoptosis. They compared them in dogs with end-stage dilated cardiomyopathy (DCM) and dogs with MVD and a control group of unaffected dogs. Their research focused upon the enlargement of the left atrium in the diseased dogs. They reported that changes included: (a) irregularity of desmin cross-striation and desmosomes; (b) a higher amount of vimentin-positive cells; (c) a change in the periostin expression pattern from cytoplasmic to extracellular; and (d) a lower expression of caspase-3. The alterations reportedly were more pronounced in the DCM group than in the MVD group. They concluded that, during heart failure, the pattern of desmin, vimentin, periostin and caspase-3 expression alters in the left atrium, regardless of the cause; that the changes are more pronounced in dogs with DCM than in dogs with MVD and similar left atrial enlargement. See also this research team's January 2016 report, below.
November 2016: UK Kennel Club approves MVD testing scheme for cavaliers. In a November 2016 press release, the UK Kennel Club announced that it has approved a health testing scheme for cavalier King Charles spaniels, with the intended result of "dramatically" improving the heart health of the CKCS. The program will consist of veterinary cardiologists examining cavaliers to determine if each dog has a mitral valve murmur. An echocardiograph scan also will be performed and sent to Dr. Lisbeth Høier Olsen in Denmark, for her to measure the heart. Each dog will be issued a certificate from the University of Copenhagen, with both a murmur and mitral valve prolapse score. The Kennel Club will record the certificate results on the dog's registration record and made available publicly. The Kennel Club also intends to update MVD breeding recommendations for cavaliers.
November 2016: Simon Swift calls for parents/grandparents of UK show cavaliers to meet MVD breeding protocol -- only 4% of CKCSs have been meeting that protocol. In a letter to the Veterinary Times published in October 2016, cardiologist Simon Swift called for the UK Kennel Club to require that the parents of all show CKCSs be tested and cleared for MVD at age five years. If the parents are not yet five years old, then he writes that the show dogs' grandparents meet that test standard. He is referring to the MVD Breeding Protocol, which the UK Cavalier Club has endorsed but which the two US breed clubs have refused to endorse.
He also noted:
"Examining dogs on the database for the period between 2006 and 2010 showed only four per cent of dogs had followed this breeding advice -- that is, had parents or grandparents tested clear older than five years."
EDITOR’S NOTE: Dr. Swift's observation that only 4% of cavaliers being bred in the UK in accordance with the MVD Breeding Protocol is a sad acknowledgement that nearly all CKCS breeders are more concerned about their kennels' success than about the health and welfare of the dogs they produce.
October 2016: Thai cardiologists recommend "ECG monitoring should be performed in dogs chronically administered with pimobendan." In a June 2016 article by a team of Thai researchers (Sirilak Disatian Surachetpong [right], Nisarat Boonlue, Pasorn Pupa, Waratsarin Boonsathitanan, Sumanee Rakthaidee, Tanawan Mangklabruks, Siriwan Sakarin), they report the results of examining the clinical records, including electrocardiograms (ECG), of 29 small and medium sized dogs (none were CKCSs), which had been treated for mitral valve disease with pimobendan. They found that 10 of the 29 dogs -- 34% -- had developed cardiac arrhythmias following at least a month's treatment with pimobendan. Types of cardiac arrhythmias included atrial fibrillation, sinus tachycardia, second degree AV block, ventricular premature beat, and junctional premature beat. Most of dogs with cardiac arrhythmias had atrial fibrillation. They concluded that "cardiac arrhythmias may develop in some dogs treated chronically with pimobendan", and that "ECG monitoring should be performed in dogs chronically administered with pimobendan."
October 2016: Tawian cardiologists find anemia increases with MVD progression and predicts mortality. In an October 2016 article, a team of Taiwan researchers (Ivarosa Bing-Ye Yu, Hui-Pi Huang) found in 114 MVD-affected dogs that the presence of anemia increased with the progression of MVD and was associated with the severity of heart failure. They stated that anemic dogs in heart failure had shorter median survival times (13 months) than non-anemic dogs in heart failure (28 months), and that anemia was a predictor of mortality.
October 2016: Korean researchers find cystatin-C or cystatin 3 (Cys-C) and symmetric dimethylarginine (SDMA) as useful biomarkers of MVD progression to heart failure. In a September 2016 study by a team of Korean cardiology researchers (Bum-Sul Choi, Hyeong-Sun Moon, Sang-Hyuk Seo, Changbaig Hyun [right]), they examined serum concentration levels of two kidney function biomarkers -- Cystatin-C or cystatin 3 (Cys-C) and symmetric dimethylarginine (SDMA) -- which appear to play roles in predicting new-onset or deteriorating kidney diseases. Their goal was to evaluate these two renal disorder biomarkers in dogs with mitral valve disease (MVD) at varying degrees of heart failure. They found that serum Cys-C and SDMA concentrations were not correlated to age or body weight, but closely correlated to the severity of heart failure and echocardiographic markers of heart enlargement. The study found progressive elevation in renal markers in dogs with advancing MVD, suggesting that the reduction of glomerular filtration rate (GFR) might be worsened with the progression of cardiac dysfunction. They concluded that their study demonstrated that the glomerular filtration rate (GFR) -- a common complication in advanced stages of heart failure -- was decreased in dogs with MVD in earlier stages of heart failure, based on results from serum Cys-C and SDMA tests, and therefore, earlier intervention for preventing renal injuries even in asymptomatic MVD dogs is necessary for the successful long-term management of heart failure in MVD-dogs.
September 2016: The EPIC Study concludes that pimobendan can prolong pre-heart failure by 15 months in MVD-affected dogs with echo and x-ray evidence of heart enlargement. In a September 2016 article, an international team of veterinary cardiologists report that the administration of pimobendan to MVD-affected dogs with echocardiographic and radiographic evidence of heart enlargement results in prolonging the pre-heart failure period by approximately 15 months over non-treatment (a placebo), which represents a substantial clinical benefit.
To be included in the study, a dog had to be 6 years of age or older, have a mitral valve murmur of at least Grade 3 of 6, have echocardiographic evidence of advanced MVD consisting of characteristic valvular lesions of the mitral valve, regurgitation through the mitral valve (MR) on the color Doppler echocardiogram, and have echocardiographic evidence of left atrial and left ventricular dilatation. All dogs entering the study met or exceeded three different heart size criteria. They are, first, the left atrial-to-aortic ratio (LA/Ao) ≥ 1.6. Second, the normalized left ventricular internal diameter in diastole (LVIDDN) ≥ 1.7. Third, radiographic evidence of enlargement with a vertebral heart score (VHS) >10.5. The researchers warn that:
"... it should be borne in mind when interpreting these results that all dogs included in the analyses also met the echocardiographic inclusion criteria and these results therefore might not be generalizable to all dogs with a VHS > 10.5 in the absence of concurrent echocardiographic measurements and a confirmed diagnosis of MMVD."
Therefore, to apply the results of this study to future treatment of MVD-affected dogs, an x-ray of the heart, showing a VHS over 10.5, is not sufficient by itself, and that the two echo measurements must also be confirmed.
Of 354 dogs in the study, 161 (45.5%) were cavalier King Charles spaniels (CKCS) -- the largest breed group. Therefore, the results of this study obviously are of supreme importance to owners of cavaliers. Of those 354 dogs, 178 of the dogs were treated with pimobendan (77 CKCSs), and 180 received the placebo (81 CKCSs). Of those 178 dogs treated with pimobendan, 59 (33.1%) reached congestive heart failure (CHF), 15 (8.4%) died of cardiac-related deaths during the treatment. The others had not reached CHF by the time the study ended. The authors explained that:
"Although a greater number of dogs in the pimobendan group experienced spontaneous cardiac death (12 versus 5), the proportion of dogs in each group experiencing this event was not significantly different."
"Chronic oral administration of pimobendan to dogs with echocardiographic and radiographic evidence of cardiomegaly secondary to MMVD, in the absence of concurrent cardiovascular medication, results in the prolongation of the preclinical period, and is safe and well tolerated. The median time to the onset of CHF or cardiac-related death was prolonged by approximately 15 months, and the risk of a dog experiencing this event was reduced by approximately one-third; the majority of the benefit observed was attributable to delaying the onset of CHF. This substantial degree of prolongation of the preclinical period is f clinical relevance and is of importance to veterinarians and owners of dogs affected by this common disease."
So, the bottom line is:
(1) The dog must be in Stage B2 of mitral valve disease; AND
(2) Have a murmur of at least Grade 3; AND
(3) The dog must NOT be on any other cardiac medication; AND
(4) An echocardogram must be conducted and show valvular lesions of the mitral valve, regurgitation through the mitral valve (MR) on the color Doppler echocardiogram, and have echocardiographic evidence of left atrial and left ventricular dilatation; AND
(5) X-rays showing evidence of enlargement with a vertebral heart score (VHS) greater than 10.5.
This essentially means that once the MVD-affected dog develops a Grade 3 murmur and an x-ray showing enlargement, the owner should have a board certified veterinary cardiologist perform the echo exam.
EDITOR’S NOTE: This long-awaited and highly vaunted report is nevertheless loaded with unanswered questions. It is as if the research team proceeded with blinders and were led with rings through their noses. A few examples:
• The recommended x-ray and echo measurement parameters were set at the outset of the study, rather than scientifically determined as a result of the study. Since the conclusion of the EPIC Study includes very precise minimum heart measurement criteria (VHS >10.5; LA/Ao ≥ 1.6; LVIDDN ≥ 1.7), one would have hoped that the researchers made those determinations by a careful analysis of the results of the study. But, no, the exact opposite was the case. The lead researchers made up those parameters before the study even began. And they did not re-visit those parameters after the study ended, to determine if their initial determinations are safe and otherwise appropriate. The fact is that at least one of the those three parameters -- the VHS measurement -- is so off base for cavaliers that it can be life-threatening.
• The average heart-healthy cavalier has a VHS value above 10.5. It is troubling that the study report fails to note that normal, heart-healthy cavaliers typically have VHS measurements as high as 11.7, which is notably higher than the 10.5+ criterion for beginning pimobendan treatment. Considering that nearly half of the dogs in the study were CKCSs, this oversight is rather inexplicable and potentially life-threatening.
Bizarrely, the researchers' footnoted citation justifying this VHS score is an article which expressly states:"The use of breed-specific VHS values is needed for the VHS method to have a high specificity for normal heart size."
It previously has been customary when cardiologists determine heart enlargement using VHS values, to compare the current x-ray with previous ones, such as a baseline x-ray. Indeed, the ACVIM's 2009 Consensus Statement specifically recommends, for Stage B dogs, to obtain baseline x-rays. It states:
"Thoracic radiography is recommended in all patients to assess the hemodynamic significance of the murmur and also to obtain baseline thoracic radiographs at a time when the patient is asymptomatic for CVHD."Therefore, it is perplexing as to why this EPIC Study, being hyped as "top tier" by its chief lead researcher, ignores breed-specific VHS values, and more importantly for cavaliers, ignores the individual patient's specific VHS value compared to the dog's baseline x-ray.
But if the manufacturer's goal is to sell more pills, then reducing the threshold VHS value to significantly below the average score of a healthy cavalier, will do just that -- sell more pills. Let's face it, the CKCS breed will be its biggest customer.
• The study glosses over pimobendan causing sudden deaths. It also is disappointing that the study does not go into any details about 8.4% of dogs being treated with pimobendan and which suffered "spontaneous" cardiac-related deaths while only in Stage B2. While the authors do acknowledge that "concerns had previously been raised about possible detrimental effects of the administration pimobendan to dogs with preclinical MMVD", they provide nothing to explain why pimobendan played a role in those sudden and unexpected Stage B2 deaths. To the contrary, they seem to be patting themselves on the back for even including any data on these premature cardiac deaths, stating:"If our primary endpoint had focused exclusively on the onset of CHF, with dogs that died being censored, it might have appeared that we were choosing to ignore potentially detrimental effects of the treatment."Well, it certainly does appear that they have chosen to ignore those detrimental effects. Instead, they minimize these 8.4% premature deaths of pimobendan-treated dogs by stating:"We found, not unexpectedly, that only a small number of dogs met the primary endpoint in this way. Although a greater number of dogs in the pimobendan group experienced spontaneous cardiac death (12 versus 5), the proportion of dogs in each group experiencing this event was not significantly different."How many of the suddenly dead pimobendan group dogs were cavaliers? We are not told. What if all of the dead pimobendan dogs were cavaliers? (That is not so far-fetched, considering the unreasonably low VHS threshold of >10.5.) That would amount to 15.5% of all of the CKCSs in the pimobendan group. If 15.5% of the cavaliers in the pimobendan group died suddenly, would that make a "significant" difference?
In a prior peer-reviewed study of 317 human patients, the researchers found that: "In both pimobendan groups combined the hazard of death was 1.8 times higher than in the placebo group", and those researchers made a big deal of that finding. Ironically, in this EPIC Study, the death hazard of pimobendan was 2.4 times higher than the placebo group, and the EPIC Study researchers just blow that significant fact off like it does not matter a whit.
How can they conclude that pre-CHF dosing of pimobendan "is safe and well tolerated", when nearly 10% of the dogs died cardiac-related deaths suddenly while being given pimobendan, and the researchers made no effort to find out those dogs' precise causes of death? Well, that is what the manufacturer wanted them to conclude. "Safe and well tolerated" was one of the two main goals for the EPIC Study. So, by minimizing the significance of all of the pimobendan-caused sudden deaths, that goal of "safe and well tolerated" has been attained.
• The study ignored the affect of pimobendan on contractility and systolic function of the dogs' hearts. Despite the researchers acknowledging that "concerns had previously been raised about possible detrimental effects of the administration pimobendan to dogs with preclinical MMVD", they did not bother to report measurements of the contractility and/or fractional shortening of the dogs' hearts during the treatment period. Since prior peer-reviewed studies cited above have shown that "long-term administration of PIMO in dogs with asymptomatic MVD is associated with an increase in systolic function and, concomitantly, a progressive worsening of MVD with development of specific mitral valve lesions", this periodic measurement could have predicted (and presumably avoided) the sudden deaths of 8.4% of the pimobendan dogs. That is another messy little detail which would not have made the manufacturer very happy.
When a study ignores these previously detailed, scientifically determined hazards of the premature administration of pimobendan (over-stimulating the well-compensated heart's contractility), and instead the study is based upon superficial appearances (an enlarged heart), that study can easily lead to false positives. In such a case, it really does not matter that the current cohort study includes a larger number of dogs than the previous clinical ones. What matters is the damage done -- and to be done in the future -- because of the risks taken. The failure to examine that damage -- in this case, the causes of death of nearly 10% of the dogs in the pimobendan group -- aids and abets the potential for those false positives. Minimizing the negative results points to a manufacturer-driven study.
• The report excludes the study's own evidence of pimobendan shortening life spans after CHF. While it is not at all clear in the published article, at the ACVIM conference in June 2016, where the results of this study were orally presented to attending cardiologists, it was reported that once the dogs reached CHF, the subsequent life spans of the pimobendan dogs were shorter than the life spans of the placebo dogs. It therefore suggests that once CHF develops, life expectancy actually shortens for dogs treated with pimobendan, relative to untreated dogs. The researchers have not included this information in their article, but that data raises the question of whether the shortened life span of CHF dogs treated with pimobendan during Stage B2 is due either to drug toxicity or to an acquired tolerance to the pimobendan.
The report does state that, "The median time to death by all causes was 1059 days in the pimobendan group [83 dogs] and 902 days in the placebo group [103 dogs]". (Emphasis added.) But it fails to break out the numbers of dogs which died of MVD or MVD-related disorders. So, the data which the authors provide on this topic in their report is pretty much worthless, and they are silent on the topic which would have been most relevant: How much longer, or shorter, did pimobendan dogs live than did placebo dogs before dying MVD-related deaths?
One of the lead investigators. shortly after publication of the EPIC Study, stated that, "We intend to publish at least one further paper relating to the study, which will provide longitudinal follow up on dogs in the study." That is well and good, of course, but unless that further paper is published promptly, there will be another undue delay -- like the 18 month one between the March 2015 press releases and the report itself -- in finding out what value pimobendan, if any, may have in extending the lives of MVD-affected dogs. Meanwhile its manufacturer will be able to continue to bask in the unsubstantiated hype and promises that pre-CHF administration of pimobendan will not only delay the onset of heart failure, but also extend the lifespans of the dogs. For example, that same lead investigator reportedly told the UK Telegraph in October 2016 that, "This is a major breakthrough in treatment and could extend the lives of dogs around the world." "Could" is the operative word there, because no evidence has been presented in the published report that pimobendan added to the longevity of any dogs dying of mitral valve disease.
• The researchers provide no breed-specific information. There were 360 dogs in this study. Nearly half of them were cavalier King Charles spaniels. And yet, the report includes no data specific to cavaliers -- or to any other breed, for that matter. The authors had a year and a half after the conclusion of the trial, to sift through the data and analyze every aspect of them, before publication. But no breed-specific breakdown is to be found. No breed is going to be more affected by this study than the CKCS. This is just about the least informative study of the safety and effectiveness of any drug with a prior record of toxicity, in this century.
• The report precludes treating pre-CHF dogs with any other cardiac medications. Since the EPIC Study excluded any dogs being treated with cardiac drugs other than pimobendan, this means that previous common protocols, such as prescribing an ACE-inhibitor (e.g., enalapril or benazepril) to MVD-affected dogs in Stage B2, are out the window from now on. In fact, the authors brag about not needing any other medications in Stage B2, stating:"An additional strength of the study is the absence of the confounding effect of any concurrent cardiovascular medications".This is an added benefit to Vetmedin's producer, conveniently giving it a peer-reviewed monopoly on pre-CHF treatment of MVD-affected dogs.
• The authors try to defend Vetmedin's manufacturer's total financial control over them. Interestingly, the authors bend over backwards to justify the full funding of this study by the manufacturer of Vetmedin. They essentially explain that, 'that's the way it is in the veterinary field.' Specifically, they state:"that the majority of published clinical trials are sponsored by industry. In the veterinary field, there are no large independent funding organizations comparable to the National Institutes of Health (NIH) that are likely to be able to (or wish to) fund a study of the magnitude of the one we describe; therefore, such studies are only likely to be achieved with industry sponsorship. Potential explanations of the increased likelihood of industry-sponsored research having positive findings include the following: Industrial sponsors might be more likely to support studies that are likely to succeed, industrial sponsors might design studies with an inappropriate comparator group, or there might be publication bias with unsuccessful studies being less likely to be published."There is a term used in the scientific research field for this type of defensive excuse making: "publication bias", and the authors even use it in the quote above. When they write, "... unsuccessful studies being less likely to be published", they could add, "unsuccessful results within studies" to the list of those being less likely to be published. And it is also apparent in the next topic discussed here: the glaring conflict between the March 2015 press releases and the actual findings in the September 28, 2016 journal article.
• The report flatly contradicts the braggadocious press releases issued 18 months earlier. But the absolutely most irresponsible fact to be drawn from this report is the March 2015 press releases issued by the three lead researchers, which unqualifiedly stated:"The interim analysis indicated that there was clear evidence of benefit of the administration of pimobendan in prolonging the time to the primary endpoint of the study, which was a composite of the development of left-sided congestive heart failure, or death presumed to be cardiac in origin. The interim analysis did not raise any concern over the safety of pimobendan administration.” (Emphasis added.)"A mid-study analysis in mid-February 2015 indicated that pimobendan is clearly beneficial and did not raise any concern over the administration of pimobendan." (Emphasis added.)Nowhere in any of those self-laudatory press releases did any of the researchers warn of the vital importance of first performing two precise echocardiographic measurements and a radiographic measurement before dosing pimobendan to MVD-affected dogs prior to CHF.
Since the researchers knew in advance of those press releases what the essential parameters were for the dogs participating in the trial, they easily could have included those parameters in their press releases. But they did not. And so, for 18 months, from March 2015 to September 2016, every cardiologist and internal medicine specialist and general practice veterinarian was intentionally misled about the essential parameters which had to be met before prescribing pimobendan! This obviously indicates the danger of veterinary researchers ignoring their professional judgment and instead signing their names to such irresponsible advertisements which must have been pushed upon them by the manufacturer with the checkbook.
September 2016: Pimobendan significantly prolonged survival time and reoccurrence of pulmonary edema in CHF dogs. In a September 2016 report, a team of Japanese veterinary cardiologists compared the affect of pimobendan added to conventional therapy among three groups of a total of 197 dogs with pulmonary edema and congestive heart failure (CHF). The study included twelve cavalier King Charles spaniels. The groups consisted of 64 dogs which received a standard dose of pimobendan plus conventional therapy, 49 dogs receiving a low dose of pimobendan plus conventional therapy, and 84 dogs receiving only conventional therapy. The conventional therapy consisted of diuretics, angiotensin-converting enzyme inhibitors (ACEIs), and digoxin. The researchers found that the dogs given pimobendan had significantly longer survival times than the group without pimobendan, although there was no difference in the survival between dogs given standard and low doses of pimobendan. However, they also found that pimobendan tended to prevent the reoccurrence of pulmonary edema in a dose-dependent manner.
September 2016: Brazilian vets propose using the Cardiothoracic Ratio (CTR) to measure heart enlargement. In a September 2016 article, a team of Brazilian veterinary researchers propose using the Cardiothoracic Ratio (CTR) to measure heart enlargement. The CTR is a scheme previously proposed by others for assessing human heart enlargement. Using the "dorsoventral" x-ray of the dog's heart (see the photo at right here, from the article), the CTR is calculated by adding the largest distance from the heart's vertical center line to the right side of the heart (MR) and the largest distance from that line to the left side (ML). Then divide that combined amount by the greatest thoracic diameter (MTD).
CTR = MR + ML
In that article, the Brazilian researchers compared the VHS with the CTR in poodles and concluded:
"Our results demonstrated that VHS and CTR showed strong correlation in their measurements, suggesting that CTR, constantly used in humans, could be considered as a tool to assess the size of the heart silhouette in dogs of the poodle breed."
September 2016: CSU vets aptly summarize using anesthesia on MVD-affected dogs. In the August 2016 issue of Clinician's Brief, Colorado State University veterinarians Khursheed Mama and Marisa Ames thoroughly summarize the current views on the use of anesthesia on dogs in varying stages of mitral valve disease, as well as with common concurrent disorders. They state:
"Proper anesthetic management of patients with cardiac disease depends on the nature and severity of the disease. In a broad sense, the anesthetic approach to the cardiac patient is different for compensated vs decompensated heart disease. In addition, concurrent disease and requisite supportive therapies can cause decompensation of previously compensated heart disease. Understanding the underlying structural abnormalities and resultant physiologic consequences can influence the anesthesia protocol, periprocedural monitoring, and plans for emergency interventions."
August 2016: The EPIC Trial's final report is expected soon. The EPIC Trial is a 360 dog study by 36 cardiologists to determine if and when pimobendan can safely and effectively be prescribed to dogs affected by mitral valve disease but before heart failure -- that is, dogs which are "asymptomatic"*. The final report has been accepted by the publisher and is expected to be published soon. Roughly 45% of the dogs in the study were cavalier King Charles spaniels.
* Asymptomatic means that the dog has mitral valve regurgitation but does not display any signs or symptoms of heart failure, such as lung congestion, coughing, lethargy, hind leg weakness, etc.
The report will show that treatment with pimobendan of some MVD-affected dogs prior to heart failure will lengthen the time period before the onset of heart failure, over dogs which were given only a placebo. We may expect to find that the recommendation with be to start dosing pimobendan once the dog is determined to have moderate to severe mitral valve regurgitation and significant heart enlargement as determined by two specific echocardiograph measurements and one x-ray measurement. Also, other echo parameters, such as the fractional shortening percentage, will be a factor in making the determination.
An overall consequence of this report likely will be that cardiologists and internal medicine specialists will be playing a much larger role in treating dogs with asymptomatic MVD, because of the requirement of careful measurements of the heart using ultrasound, to determine if pimobendan would be an appropriate drug to start before heart failure.
July 2016: Japanese researchers find serum fatty acids differ between dogs with and without MVD. In a July 2016 article by a team of Japanese cardiologists and others (Hiroki Yoshimatsu, Hirotaka Matsumoto, Masanari Minamoto, Ryohei Suzuki, Yohei Mochizuki, Takahiro Teshima, Hidekazu Koyama), they studied 30 dogs with various stages of mitral valve disease, including seven cavalier King Charles spaniels, to determine whether serum fatty acid concentrations in dogs with MVD differ from those in normal dogs (12 healthy dogs, including 1 CKCS). They found that several fatty acid concentrations were significantly lower in dogs with MVD, and that some of these concentrations and ratios correlated with echocardiographic parameters.
June 2016: USA study finds small breed dogs in heart failure live 100+ days longer if treated by cardiologists. In a July 2016 article by a pair of Virginia cardiologists (Bonnie K. Lefbom [right], Neal K. Peckens), they studied 26 small breed dogs in congestive heart failure due to mitral valve disease and compared the survival times of MVD-affected dogs treated solely by primary care veterinarians with the survival times of MVD-affected dogs treated in collaboration by primary care vets and board certified cardiologists. They found that dogs which received colaborative care had a median survival time of 254 days, while dogs treated only by primary care vets had a median survival time of 146 days. They also found that the longer vets can keep alive dogs in heart failure, the more revenue the primary care vets earn.
June 2016: Studies find that most published research findings are false and that most clinical research is not useful, with clinical evidence becoming an industry advertisement tool. In a June 2016 article, "Why Most Clinical Research Is Not Useful". Prof. John P. A. Ioannidis (right) of the Stanford University medical school reports that most clinical research is not useful. His article follows one he wrote in August 2005, titled "Why Most Published Research Findings Are False" and another more recently, in May 2016 titled "Evidence-based medicine has been hijacked". He defines clinical research as experimental intervention studies, which include all types of investigation that address questions on the treatment, prevention, diagnosis/screening, or prognosis of disease or enhancement and maintenance of health. He states that "clinical evidence [is] becoming an industry advertisement tool".
June 2016: Researchers may have an explanation for why ACE-inhibitors often are ineffective in treating cavaliers prior to heart failure. In a June 2016 abstract, an international team of cardiologists (Kathryn Meurs, Maria Josefine Reimann, Lisbeth Høier Olsen) studied the angiotensin converting enzyme (ACE) activity in 62 cavaliers for variations in responses to ACE-inhibitor therapy. They found that the DNA of a large majority of these CKCSs -- 61% -- had common ACE mutation (polymorphism) which results in them having a lower baseline level of ACE activity.
June 2016: Tufts study of 43 dogs (9 CKCSs) shows median survival time in Stage D MVD is nearly a year. In a June 2016 abstract, a team of Tufts University researchers (Amelie Beaumier, John E. Rush, Lisa M. Freeman) reviewed 43 cases of dogs in Stage D of mitral valve disease (MVD). Nine of the dogs were cavalier King Charles spaniels. In summary:
• Median duration between diagnosis of congestive heart failure (CHF) and Stage D was 157 days.
• Median duration between diagnosis of Stage D and death was 311 days.
June 2016: FDA approves an appetite stimulant for ill dogs which will not eat. The USA's Food & Drug Administration (FDA) has just approved the canine appetite stimulant Entyce (capromorelin). Capromorelin is a ghrelin receptor agonist which mimics the activity of ghrelin, a hormone which reportedly causes a sense of hunger. This drug may be helpful for cavaliers in end-stage MVD -- Stage D -- which refuse to eat. The FDA approval was issued on May 16, 2016 and grants exclusivity to its owner, Aratana Therapeutics, Inc., through February 25, 2020. The product is expected to be available as a prescription drug beginning in February 2017. For more information, check out this webpage.
April 2016: Researchers summarize pimobendan's adverse effects reported in dogs with mild mitral valve insufficiency. In a March 2016 article, a team of Japanese veterinary researchers summarized the current peer-reviewed studies finding that pimobenan can cause adverse effects, including the acceleration of mitral valve degeneration, in dogs. They stated:
"Pimobendan (PIMO) can cause adverse effects, such as mitral valve degeneration, in dogs. ... Despite the benefits of treatment, adverse effects have been reported with the use of PIMO in dogs. In a case report of two dogs with mitral insufficiency, a long-term administration of PIMO worsened mitral regurgitation and ventricular hypertrophy. Similarly, in dogs with mild mitral insufficiency, the long-term administration of PIMO was shown to worsen mitral regurgitation and valve lesions. Adverse effects on mitral valves were considered to occur because of increasing cardiac contraction, but it was unclear whether PIMO directly affected the mitral valves."
April 2016: Dutch government singles out cavaliers in a study asking "Are purebreds really less healthy than crossbreeds?". The Dutch Ministry of Economic Affairs, Agriculture and Innovation has commissioned a study to answer the questions:
• Are purebreds really less healthy than crossbreeds?
• Is there a difference even between a purebred with pedigree and its look-alike without?
• What can be done if so?
Utrecht University has been assigned to research this pilot project:
"To what extend occur harmful breed characteristics and heritable disorders in The Bernese Mountain Dog, The Dutch Shepherd Dog, the Cavalier King Charles Spaniel and the Maine Coon Cat in the Netherlands?"
In September 2016, the university will publish a list with the most important disorders in the cavalier in the Netherlands. See this April 2016 article for more details.
April 2016: Orthopedic Foundation for Animals (OFA) creates new database for MVD. As of April 1, OFA has joined with the American College of Veterinary Internal Medicine (ACVIM) to create a new “Advanced Cardiac Database” to distinguish between congenital and what OFA has labeled “adult-onset” cardiac diseases. It will serve two primary purposes:
“1. Develop an appropriate screening protocol for adult onset cardiac diseases; and
2. Begin collecting better data on cardiac disease prevalence and progression in the purebred dog.”
According to OFA, the examinations for the Advanced Cardiac Database must be performed by board certified veterinary cardiologists. This is a huge step forward for OFA. Previously, practitioner veterinarians have been allowed to perform these tests for OFA’s database purposes.
The most significant change will be the reporting procedure to OFA. Previously, the only copy of the veterinarian’s exam report was given to the dog’s owner, to either submit to OFA for its database or to not do so. Hereafter, the new OFA advanced cardiac examination forms will be in triplicate. Regardless of whether or not the owner sends his copy of the form to OFA for official certification, the examining cardiologist will retain one copy of the form and submit it to OFA and the ACVIM. As in the past, one copy of the completed exam form will be given to the dogs owner. The cardiologist will submit a copy of the form to OFA, to be used only to record results on its database, in order to collect better heart disease prevalence and progression data by breed. If the cardiologist also performs an echocardiogram, the new form’s echo section is far more detailed, to collect statistics regarding flow rates, velocities, etc.
The dog’s owner’s responsibility for obtaining an official OFA clearance certification number remains the same as in the past. Owners must submit their copy of the completed, signed form to OFA along with the filing fee. OFA clearances under the Advanced Cardiac Database will be valid for only 12 months. If the owner wants the adult onset cardiac clearance to remain current, repeat exams will be necessary.
For more information, see OFA’s press release here.
March 2016: Study shows that the heart x-ray and echo sedative dexmedetomidine can cause false diagnoses of MVD and heart enlargement. Dexmedetomidine often is used to sedate dogs before heart x-rays and echocardiographs. In a January 2016 report, a team of Taiwan researchers examined the effects of dexmedetomidine on six heart-healthy dogs undergoing chest x-rays and echocardiograms to determine if the sedative caused any changes in the resulting measurements. They found that the x-rays and echos performed after dosing dexmedetomidine resulted in significantly higher measurements of the vertebral heart score and cardiac size, and that moderate to severe mitral regurgitation and mild pulmonary regurgitation occurred in all six dogs. They concluded:
"Findings indicated that dexmedetomidine could cause false-positive diagnoses of valvular regurgitation and cardiomegaly in dogs undergoing thoracic radiography and echocardiography."
February 2016: UK Kennel Club's 2014 Health Survey shows 10 years is the average lifespan of CKCSs. In a February 2016 report, the UK Kennel Club published its 2014 breed health survey of the cavalier King Charles spaniel. The most commonly reported disease condition in live CKCSs was heart (cardiac) murmur. The leading cause of death was cardiac related at 37.67% of the reported deceased dogs. The median longevity for the cavalier was 10 years. By comparison, the 2004 Health Survey results were similar except for the breed's average lifespan. The median longevity for the cavalier King Charles spaniel in the 2004 survey was 11 years, 5 months, which was significantly higher than the 10 years in the 2014 report. In both surveys, the most commonly reported disease condition in live dogs was heart (cardiac) murmur. Similarly, the most commonly reported cause of death was cardiac (heart) failure, at 42.8% of the reported deceased dogs in 2004.
February 2016: NC State's Kate Meurs researches causes of MVD in cavaliers. Dr. Kate Meurs (right) a board certified cardiologist and geneticist at North Carolina State University's veterinary school, is heading a research team which hopes to identify genetic variants that lead to the development of mitral valve degeneration in cavalier King Charles spaniels (and other breeds), and use that information to innovate treatment and prevention plans for dogs with high-risk DNA variants. She stated:
“I firmly believe that once you really understand a disease etiology, you can most effectively develop treatments for the primary disease, and gradually remove or at least reduce the disease prevalence in the population.”
She has received an award of funds for this research from the Morris Animal Foundation, and she is seeking funds from other sources.
February 2016: UK researchers find cell changes are similar in cavaliers and mixed breeds with advanced MVD. In a February 2016 article by a team of UK cardiology researchers (C.-C. Lu, M.-M. Liu, G. Culshaw, Anne French [right], B. Corcoran), they compared the cellular changes in six cavalier King Charles spaniels (CKCS) with four mixed breed dogs, all with severe mitral valve disease (MVD). They found no significant differences in the cell marker expression in the two groups and concluded:
"In conclusion, this study confirms that there is no evidence for inflammatory cell involvement in canine MMVD, that the cell changes appear similar for CKCS as for other dogs, and that the changes in cell numbers in MMVD are possibly due to cell proliferation. This study suggests that MMVD is not a heterogeneous disease, at least in terms of cellular changes and that the CKCS form of the disease differs only in its time of onset and speed of progression. However, the pathogenesis of MMVD is unknown and it is possible different mechanisms could result in the same end-stage findings. From these studies it would be reasonable to presume that studies of any dog with MMVD are applicable to all dogs and breeds."
January 2016: Japanese researchers find the right ventricular Tei-index (RVTX) "strongly correlated with early death in dogs with MMVD". In a January 2016 article, a team of Hokkaido University, Japan, veterinary researchers (K. Nakamura, T. Morita, T. Osuga, K. Morishita, N. Sasaki, H. Ohta, M. Takiguchi) calculated the "right ventricular Tei-index" (RVTX)* of 30 dogs diagnosed with MVD by echocardiograph. The dogs were included in Group A (19 dogs) if they survived a year from their first echo, and in Group B (11 dogs) if they suffered cardiac-related death within that year. A lack of tricuspid regurgitation (TR) velocity in 2 of the 11 dogs in Group B disqualified them. All of the remaining 9 Group B dogs (which died during the first year) had increased RVTX (≥0.61). Three of the dogs with lower RVTX (<0.61) died before the study ended but after the first year, and the 18 other dogs with lower RVTX were alive when the study ended.
Notwithstanding the small number of dogs involved, the researchers concluded:
"The results of the present study indicate that RVTX is strongly correlated with early death in dogs with MMVD. Although several echocardiographic variables were significantly different between the two groups, we found that RVTX, a variable that corresponds to the RV function, was the most significant independent predictor of mortality. This study demonstrates that RV function analysis may be the most reliable prognostic indicator for dogs with MMVD."
* In 1995, Dr. Chuwa Tei (right) devised an index of myocardial performance (the Tei index) that evaluates the left ventrical (LV) systolic and diastolic function in combination. The Tei index reportedly is a reliable method for the evaluation of LV systolic and diastolic performance, with advantages over previous indexes and prognostic value in many kinds of heart disease. Calculation of the Tei index is a number calculated from the ratio of time intervals (a-b/b) determined by pulsed Doppler echocardiography. See this December 1995 article, this November 1996 article, and this January 2005 article.
January 2016: Researchers find dogs' heart enlargement in cases of MVD and DCM has disease-specific causes and not just volume overload. In a January 2016 article, a team of Polish veterinary researchers (Izabela Janus [right], Agnieszka Noszczyk-Nowak, Marcin Nowak, Rafał Ciaputa, Małgorzata Kandefer-Gola, Urszula Pasławska) studied 16 dogs with dilated cardiomyopathy (DCM) and 15 with chronic mitral valve disease (MVD or CMVD) to determine the diseases relationship to enlargement of the dogs' hearts' left atrial chambers. None of the dogs were cavalier King Charles spaniels; the MVD-affected breeds were: 10 mixed-breed dogs, 2 dachshunds, 1 Cairn terrier, 1 miniature pinscher, and 1 German pinscher. They concluded:
"Dogs with dilated cardiomyopathy show a different distribution of connective tissue, have less severe intra-myocardial arterial narrowing, and have more severe degenerative changes in the cardiomyocytes of the left atrium compared to dogs with chronic mitral valve disease. The changes noted in the atrial tissue from dogs in both groups resemble lesions noted in the ventricular tissue of dogs with the same diseases. Those differences may indicate that the atrial enlargement noted in DCM and CMVD has a different, disease-specific underlying mechanism and does not result only from volume overload."
December 2015: Study shows that the severity of asymptomatic MVD shows no association with serum C-reactive protein concentrations. In a March 2016 report, Swedish and Danish cardiologists (M.J. Reimann, I. Ljungvall, A. Hillström, J.E. Møller, R. Hagman, T. Falk, K. Höglund, J. Häggström, L.H. Olsen) studied 188 dogs (156 of them being cavalier King Charles spaniels) with varying degrees of mitral valve disease (MVD), to determine whether serum C-reactive protein (CRP) concentrations are associated with the severity of MVD, using an automated canine-specific high-sensitivity CRP assay called "Gentian hsCRP". They found that serum CRP concentrations were mildly increased in dogs with congestive heart failure due to MVD, but that the severity of MVD in asymptomatic dogs showed no association with serum CRP concentrations.
December 2015: Dr. Josh Stern gives up on finding MVD-free cavaliers for genetic research. At the AKC Canine Health Foundation's 2015 National Parent Club Canine Health Conference, held in St. Louis, Missouri in August, veterinary cardiologist Josh Stern (right) of the University of California, Davis, spoke of the current status of genetic research into mitral valve disease (MVD). He said that MVD is so widespread among cavalier King Charles spaniels that researchers have not been able to find enough MVD-free ("normal") CKCSs over the age of 10 years, to be able to work with for genetic research. He spoke of finding only three normal 10+ year old cavaliers out of 400 tested. He subsequently told us that he was hoping to identify 48 CKCSs that are unrelated within 3 generations and have a normal echocardiogram at 10 years and was unable to find them. He explained that, in order to be considered a "control", the dogs must be old enough to expect that they would not develop MVD at a later date. He wrote:
"Echocardiogram is the screening test that we require and it must be performed by a cardiologist. The 400 dogs mentioned were screened on both coasts and many places in between. They were not all over ten years - so please don't get the wrong idea. I'd love to find 400 senior cavaliers to screen but that doesn't seem very feasible despite our best attempts. If you have a dog that meets this criteria - please let me know! Feel free to email me if you are interested in supporting this research in some way! Jstern@ucdavis.edu."
As a result, he has turned his focus to another breed with a high incidence of MVD, the whippet. He is searching for a genetic marker associated with early-onset or severe MVD status in that breed. Dr. Stern is the principal investigator in the "Identification of genetic variants associated with myxomatous mitral valve degeneration in the whippet dog through whole-genome sequencing", sponsored by the AKC Canine Health Foundation, the Whippet Health Foundation, and the American Whippet Club. Hopefully, cavaliers will benefit indirectly from this ongoing research. Here is a link to his most recent whippet heart research.
As for his cavalier research, Dr. Stern has not given up. He explained:
"We are simply taking a different approach to the genetics of this condition and searching for genetic reasons that some CKCS have this as an early or more severe disease than others. This eliminates the need for such a large control group and has worked in other breeds recently! The prevalence in the cavalier is extremely high. This is not such a challenge in other breeds. It necessitates a fresh approach and that's what we are working on!"
November 2015: Japanese surgeons study differences in mitral valve chordae tendineae to determine where surgical repairs are most needed. In an October 2015 article, a team of Japanese veterinary heart surgeons examined the physical differences in the chordae tendineae (chords) supporting the mitral valve, particularly the anterior leaflet of the valve. They found from echo exams of 12 MVD-affected dogs, including 5 cavalier King Charles spaniels, that in 75% of them the regurgitation was occurring from the tip of the anterior leaflet (AL) of the valve. (See diagram at right.*) They also found that the tip of the AL (also called marginal chords) was secured by chords which were thinner than those attached to the base of the AL (also called strut chords). They noted that the strut chords are wider than the marginal chords, and that the chords' strength is proportional to their cross-sectional area, and that, therefore, although the marginal chords have smaller loads than the strut chords, they might be prone to elongation and breakage, due to fatigue, because they are so thin. They noted that their studies suggest that although the strut chordae tendineae, attached to the base of the AL, might be slightly elongated, they were not the main cause of MR. The researchers further found that the pathological change was more severe in the posterior half of the AL than in the anterior half -- that the posterior half of the AL might be more affected than the anterior half because of its broader area, which subjects it to larger blood pressure loads. They concluded that the marginal chords attached to the tip of the AL might contribute to mitral regurgitation in dogs because those chords are relatively thin. They therefore recommended that in mitral valve repair surgery, the marginal chords should be reconstructed, since they secure the tip of the valve cusp in the left ventricle for a good closure -- coaptation -- of the mitral valve. (See diagram at right above.*) They also pointed out that the posterior half of the AL might require more artificial chords because it is broader than the anterior half of the AL.
* Diagram is from Carpentier’s Reconstructive Valve Surgery. Carpentier A, Adams DH, Filsoufi F. 2010; Saunders; Elsevier.
November 2015: Denmark Kennel Club proves a rigorous mandatory MVD breeding protocol works. In a November 2015 article, a team of Danish and Swedish cardiologists (A.C. Birkegård, M.J. Reimann, T. Martinussen, J. Häggström, H.D. Pedersen, L.H. Olsen [right]) report that the Danish Kennel Club's 2001 mandatory MVD breeding scheme has reduced the risk of having a mitral regurgitation murmur caused by MMVD by 73% among 997 cavalier King Charles spaniels.
Denmark's MVD breeding guidelines are:
1. Dogs examined at 1½ years of age or older were approved for breeding until 4 years of age if cardiac health criteria were fulfilled.
2. To continue breeding after 4 years of age, the dogs had to be reexamined. In January 2007, an additional restriction was added, requiring a reexamination after 6 years of age for male dogs.
3. At all examination time points, dogs were excluded from breeding if they had MVP (mitral valve prolapse by echocardiograph) grade 3 or a mitral regurgitation murmur grade 3 or higher.
4. The degree of MVP was assessed as:
• Grade 0 (≤1.5 mm as the sum of the maximum protrusion of the cranial, caudal and coaption point of the mitral valve according to annulus plane)
• Grade 1 (>1.5 and ≤4.5 mm)
• Grade 2 (>4.5 and ≤7.5 mm)
• Grade 3 (>7.5 mm).
5. Dogs with grade 2 murmurs were excluded if they had:
• MVP grades 2 or 3;
• Mitral regurgitation murmur of 1 at a maximum combined with a MVP grade 2 at a maximum; or
• A grade 2 murmur combined with a degree of MVP not above grade 1.
• Before 2007, dogs with a grade 3 MVP were approved if they had a murmur grade not above 1.
The researchers concluded:
"Our study shows that a breeding scheme based on cardiac auscultation and echocardiography markedly decreased the risk of having a mitral regurgitation murmur caused by MMVD after an 8- to 10-year period. The reduction in risk was only significant for offspring where both parents had been approved by the breeding scheme (PB), not for offspring where 1 or both parents not were approved by the breeding scheme (non-PB). The risk of having moderate to severe MVP (MVP > 1) was not decreased after the 8- to 10-year period, but PB had lower risk of MVP > 1 than did non-PB within the years 2010 and 2011. ... A mandatory breeding scheme based on auscultation and echocardiography findings significantly decreased the prevalence of MMVD over the 8- to 10-year period. Such a breeding scheme therefore is recommended for CKCS."
October 2015: Austrian cardio-surgeon performs mitral valve surgery on cavalier with MVD. In a February 2015 article, Austrian cardio-surgeon Dr. Peter Modler (right) reports on a successful mitral valve replacement surgery on a 6-year-old cavalier King Charles spaniel in congestive heart failure. He stated:
"Because of his rapid deterioration and the poor prognosis with medical therapy alone, mitral valve repair under CPB was discussed with the owners. Even though the prognosis was guarded given the marked systolic dysfunction the owners decided for the surgery. The procedure was scheduled four weeks later. In the mean time Pimobendan was increased to tid, and Spironolactone was added. On the day of surgery, Henri still had some degree of pulmonary edema. Thus, Torasemide was given 6 hrs before surgery. Systolic dysfunction had increased and some ventricular runs were noted on the Sono-ECG. Open heart mitral valve repair was performed (mitral annuloplasty, chordal replacement with Gore-Tex) on cardiopulmonary bypass. Cross-Clamp time was 85 min. After clamp removal and electrical defibrillation the heart started spontaneously in a sinus rhythm and blood pressure was immediately restored. The patient woke up 5 hrs after surgery and was able to walk a short distance after 7 hrs. He is now doing quite well, starts eating and walks around in the yard. The mitral valve coadaption has increased with mild residual regurgitation. Systolic function is markedly impaired but is improving day to day. The prognosis for this patient is still guarded given the number of possible complications and the fact that it is uncertain if systolic function will improve."
October 2015: Japan study of insured dogs shows the cavalier has the highest odds of having a cardiovascular disorder. In an October 2015 article, veterinary reports on 299,555 insured dogs in Japan for one year in 2010-2011 were analyzed for the prevalence of cardiovascular disorder diagnosis. Overall for the year, the prevalence was 2.1%. However, the cavalier King Charles spaniel had the highest odds, with a ratio of 16.2. Of the CKCSs, diagnostic reports of 5,743 were included, of which 779 had at least one claim of a cardiovascular disorder, for a prevalence of 13.6%. Male dogs had increased odds of 1.2, and the dogs had increased odds of having cardiovascular disorder by 1.5 times each year they aged.
October 2015: UK researchers compare echocardiography with cardiac magnetic resonance imaging in assessing MVD. In an October 2015 article, a team of neurologists, cardiologists, and radiologists (J. Sargent, D. J. Connolly, V. Watts, P. Mõtsküla, H. A. Volk, C. R. Lamb, V. Luis Fuentes) while MRI-scanning MVD-affected dogs for neurological disorders, also compared measuring mitral regurgitant fraction by echocardiograph scans and cardiac magnetic resonance imaging (CMR). In the context of human medicine, CMR is considered to be "a non-invasive gold standard" for quantification of ventricular volumes and for clinical evaluation of mitral regurgitation (MR). In this study, by comparing CMR to echocardiogram, the researchers were able to identify the echocardiographic measurements that are the most accurate and useful in screening MVD-affected dogs. Working with the results of 10 dogs, including cavalier King Charles spaniels, they found that echo measurements of vena contracta/aortic diameter and E-wave* velocity had the strongest correlations to CMR measurements of mitral regurgitation. They concluded:
"Measurement of cardiac magnetic resonance imaging-derived mitral regurgitant fraction is feasible but technically demanding. The echocardiographic measures that correlated most closely with cardiac magnetic resonance imaging-derived mitral regurgitant fraction were vena contracta/aortic diameter and E-wave velocity."
* E-wave is the initial rush of blood as soon as the mitral valve opens, causing a peak velocity.
October 2015: Cardiologist George Kramer seeks funding for his Tucker valve to prevent backflow through heart valves. Dr. George Kramer (right), board certified veterinary cardiologist with Ultravet Medical Devices, is seeking funds through an Indiegogo campaign to help finance his research of the "Tucker valve". The mechanical valve is designed to be inserted through the mitral valve or tricuspid valve and block backflow of blood through the valve. His YouTube video is linked here.
October 2015: Dutch researchers determine that the optimum time for daily doses of ACE-inhibitors to dogs in congestive heart failure is expected to be at bedtime. In an October 2015 article, Dutch researchers Jonathan Paul Mochel (left) and Meindert Danhof have developed an integrated pharmacokinetic-pharmacodynamic model that captures the disposition kinetics of the drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers. Based upon their chronobiological investigations, they conclude that the optimal efficacy of ACE inhibitors is expected with bedtime dosing. They note, however, that their research "is not a static and completed piece of work but is, instead, a starting point for further data integration and hypothesis testing."
September 2015: Belgian researchers find the pulmonary-vein-to-pulmonary-artery ratio increases with severity of MVD. In a September 2015 article, a team of Belgian researchers (Anne-Christine Merveille [right] , G. Bolen, E. Krafft, E. Roels, S. Gomart, A.-L. Etienne, C. Clercx, K. Mc Entee) performed echocardiographs on 98 dogs -- 61 of which were affected with mitral valve disease (MVD), including 14 cavaliers -- to determine if the pulmonary vein diameter-to-pulmonary artery diameter ratio (PV/PA) can predict congestive heart failure (CHF). They found that the PV/PA index in control dogs equalled approximately 1 and increased with class of heart failure. They concluded:
"The PV/PA is a simple and reproducible echocardiographic variable that increases with class of heart failure and may help discriminate dogs in CHF from asymptomatic dogs with DMVD. Additional studies are required to determine whether PV/PA might provide additional information in the integrated interpretation of Doppler-echocardiographic indices of left ventricular filling pressures and could be used for rapid assessment of CHF in dogs in a critical care setting."
September 2015: Swedish researchers find echocardiographic variables that can identify pulmonary hypertension in dogs with MVD. In a September 2015 article, a team of Swedish cardiologists (Anna Tidholm [right], K. Höglund, J. Häggström, I. Ljungvall) investigaged the diagnostic value of echocardiographic variables related to pulmonary hypertension (PH) in dogs affected with mitral valve disease (MVD). They studied 156 dogs, including 27 cavaliers. They found that, among MVD-affected dogs, with MMVD, the presence of PH might be suspected with the combination of decreased pulmonary arterial acceleration to deceleration time ratio (AT/DT), increased right ventricular end-diastolic and systolic internal diameters, increased left atrial to aortic root ratio (LA/Ao), and a small or great left ventricular end-diastolic and systolic internal diameter.
September 2015: Tufts researchers find possible cardiac cachexia preventative is well tolerated by dogs in CHF. In a September 2015 study, a team of cardiologists and others from Tufts University's Cummings School of Veterinary Medicine (Lisa M. Freeman, John E. Rush, Suzanne M. Cunningham, Vicky K. Yang, Barret J. Bulmer) tested the myostatin antagonist "CAP-031" on dogs suffering from "cardiac cachexia" (loss of lean muscle mass due to MVD). Myostatin (growth differentiation factor 8 -- "GDF-8") is a protein which under some circumstances can interfere with muscle growth. The study injected a myostatin blocker, "CAP-031", into seven dogs suffering from both CHF and cardiac cachexia, to determine whether the dogs could tolerate the drug and whether it increased their muscle mass. At the end of the four week test, they found no significant changes in body weight, body condition score, appetite, or quality-of-life score; the change in the dogs' muscle condition score was not statistically significant. They concluded:
"The myostatin antagonist appeared to be well tolerated in most dogs. Earlier identification of cachexia is important, and randomized, controlled trials of myostatin antagonists or other drugs to treat cardiac cachexia are needed."
September 2015: Japanese cardiologists find overdose of pimobendan accelerates progression of MVD. In a September 2015 clinical report of a Shih Tzu not in heart failure, the dog ingested an overdose of its prescribed pimobendan. The team of treating cardiologists (Tsuyoshi Tokuriki, Yuichi Miyagawa, Naoyuki Takemura) reported:
"The present report describes the clinical condition of a dog who exhibited previously unreported temporary increases in the T wave amplitude in addition to hypertension, tachycardia, increased grades of cardiac murmurs, increased fractional shortening (FS), and systolic anterior motion of the mitral valve (SAM) following the overingestion of pimobendan."
"These findings suggest that it is necessary to monitor T/R [T wave to R wave amplitude ratio], SAM, and systemic hypertension in dogs who have ingested a large amount of pimobendan."
September 2015: International team of cardiologists and nephrologists issue a Consensus Statement on cardio-renal disorders. In a September 2015 report, a team of 9 veterinary cardiologists and 7 veterinary nephrologists from Europe and North America (J. L. Pouchelon, C. E. Atkins, C. Bussadori, M. A. Oyama, S. L. Vaden, J. D. Bonagura, V. Chetboul, L. D. Cowgill, J. Elliot, T. Francey, G. F. Grauer, V. Luis Fuentes, N. Sydney Moise, D. J. Polzin, A. M. Van Dongen, N. Van Israël) have issued a "Consensus Statement" to increase the awareness of and codify the definition, classification, diagnosis, and management strategies for veterinary patients with cardio-renal syndrome (CRS), with an emphasis on the pathological interplay between the two organ systems. They acknowledge "a growing understanding of the complexity of interplay between renal and cardiovascular systems in both health and disease."
They have observed: "The concept of CRS, which involves a bidirectional pathway of injury wherein disease of either organ directly or indirectly contributes to injury of the other." And they have included a chart showing postulated mechanisms underlying the relationship between heart failure (HF) and renal dysfunction. (Click on the thumbnail chart at right.)
Among their consensus statements, are:
"Statement 8: Thoracic radiography is recommended to assess the presence or absence of congestive heart failure, and echocardiography is recommended to assess cardiac morphology, lesions, and to estimate relevant haemodynamic parameters.
"Statement 9: Renal imaging is recommended to improve diagnosis, prognosis and guide potential therapies in CvRD. Conventional abdominal radiographs and ultrasound are recommended to help detect morphological abnormalities and determine underlying aetiology.
"Statement 10: As the kidney and heart are two organs at risk for damage due to systemic hypertension, and as kidney disease is often associated with systemic arterial hypertension, systemic arterial blood pressure should be systematically monitored in both kidney and cardiovascular diseases. * * *
"Statement 13: ... particular attention should be directed towards the following when managing any form of [CRS]: 1) identification and treatment of elevated blood pressure as per IRIS recommendations; 2) stepwise titration of dosages of diuretics, ACEI, inotropes and/or fluids with frequent monitoring of renal function, body weight, hydration, electrolyte status, and systemic blood pressure (i.e. performed and rechecked within 3–5 days following initiation or dose adjustment of these drugs); 3) proper nutrition, with respect to reduced dietary sodium and phosphate and appropriate protein and caloric intake."
September 2015: Study of healthy hounds finds enalapril suppresses ACE activity but does not suppress circulating RAAS. In an October 2015 study, US cardiologists (A. C. Lantis [right], M. K. Ames, S. Werre, C. E. Atkins) tested enalapril on 16 healthy hounds to evaluate enalapril's ability to suppress angiotensin-converting enzyme (ACE) and also furosemide-induced circulating activation of the renin-angiotensin aldosterone system (RAAS). They found that, as with benazepril, enalapril inhibited ACE activity but did not significantly reduce aldosterone excretion. They concluded, therefore, that " that failure to suppress aldosterone suppression with furosemide stimulation may be a drug class effect."
August 2015: Japanese researchers find that vitamin D concentration declines with the progression of MVD in dogs, including cavaliers. In an August 2015 study, a team of Japanese researchers (T. Osuga, K. Nakamura, T. Morita, S.Y. Lim, K. Nisa, N. Yokoyama, N. Sasaki, K. Morishita, H. Ohta, M. Takiguchi) examined vitamin D concentrations -- specifically serum 25-hydroxyvitamin D (25(OH)D) concentrations -- in 43 MVD-affected dogs, including 4 cavalier King Charles spaniels. They observed that serum 25(OH)D concentration begins to decrease before the onset of heart failure in MVD-affected dogs, and that vitamin D status is associated with the extent of heart enlargement.
August 2015: Thai researchers find plasma Galectin-3 increases with cardiac fibrosis in MVD-affected dogs. In an April 2015 abstract, Thai researchers (S. Sakarin, A. Rungsipipat, S. Disatian Surachetpong) report finding that MVD-affected dogs have more cardiac fibrosis compared to normal dogs, and that plasma Galectin-3 (Gal-3) concentration was increased in MVD-dogs. They concluded that the results suggested that the expression of Gal-3 is associated with cardiac fibrosis. See also, this January 2016 article about the same study, in which these researchers concluded that Gal-3 expression in cardiac muscle was associated with cardiac fibrosis, and that tissue Gal-3 is a candidate of fibrosis biomarker in MVD, but that further investigation of associations between plasma Gal-3 and myocardial fibrosis is necessary.
August 2015: Study of MVD-affected dogs shows a progressive inflammatory component. A team of European cardiologists and researchers (Zoe S. Polizopoulou (right), Christos K. Koutinas, José J. Cerón, Asta Tvarijonaviciute, Silvia Martínez-Subiela, Anastasia Dasopoulou, Malcolm J. York, Ian F. Roman, Mitul Gandhi, Sonal Patel, Peter J. O'Brien) compared serum cardiac troponin I and CRP concentrations in 46 dogs diagnosed with MVD, in an August 2015 report. They divided the dogs by severity of the disease (group I: asymptomatic; group II: mild to moderate CHF; group III: advanced CHF), and they measured concentrations of cardiac troponin I (cTnI), C-reactive protein (CRP), ceruloplasmin (Cp), and haptoglobin (Hp) bimonthly over a 4-month period. The researchers found a "statistically significant difference" in CRP concentrations between MVD-affected dogs as their MVD progressed from asymptomatic to advanced heart failure. They noted that CRP concentrations were "significantly higher" in the asymptomatic group, and that:
"Differences in CRP concentrations between clinical stages of MVD suggest a clinically and therapeutically relevant inflammatory component."
August 2015: UK research points to gene expression causing the transition of cells in the development of MVD in cavaliers. In an August 2015 study published by a team of UK cardiologists and researchers (Chi-Chien Lu, Meng-Meng Liu, Michael Clinton, Geoff Culshaw, David J. Argyle, Brendan M. Corcoran [right]), they examined the mitral valve leaflets of 14 deceased cavalier King Charles spaniels which had suffered from MVD, and compared them with the leaflets of 5 unaffected mixed breed dogs. The aim of their study was to investigate the possibility of re-activation -- meaning post-embryotic -- and recruitment of developmental processes MVD, such as the transition of epithelial cells and endothelial cells to mesenchymal cells.
"Epithelial cells" line the cavities of tissues throughout the body and cover flat surfaces and form glands. "Endothelial cells" line the interior of blood vessels and are the layer that is in continuous contact with blood. Endothelial cells therefore are a specialized category of epithelial cells. "Mesenchymal cells" develop into any types of connective or supporting tissues, smooth muscle, vascular endothelium, and blood cells. "EMT" is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells. Similarly, "EndoMT" is the same process for the transition of endothelial cells to mesenchymal cells. Previous research has shown that EMT and EndoMT contribute to a range of chronic degenerative diseases and cancer metastasis.
The researchers found significant differential expression for genes typically associated with EndoMT -- including markers of inflammation (IL6, IL18 and TLR4), basement membrane disarray (NID1, LAMA2 and CTSS), mesenchymal and endothelial cell differentiation (MYH11 and TAGLN) and EndoMT (ACTA2, SNAI1, CTNNB1, HAS2, CDH5, and NOTCH1). In heart valves of MVD-affected dogs, there was increased expression of these genes, with the exception of NOTCH1, and a reduction in CDH5. Apart from down-regulation of NOTCH1 expression, all other changes support a potential contribution of EndoMT and endothelial migration in the development of MVD.
The research findings confirm the study's aim and "strongly suggest involvement of developmental signalling pathways and mechanisms, including EndoMT, in the pathogenesis of canine MMVD." Most significantly, the findings suggest that, instead of MVD being a degenerative condition, MVD may be due to the development of EMT and EndoMT. The researchers point out that this is the first report of involvement of development signalling pathways and endothelial to mesenchymal transition in canine MVD. They also provide information on biological mechanisms that have therapeutic potential for new drug discovery.
August 2015: Cavalier in congestive heart failure suffers blood clots, a tear in the left atrium wall, and a cardiac stroke. In an August 2015 article, University of Pennsylvania veterinarians (Meg M. Sleeper, Meredith E. Maczuzak, Susan J. Bender) found that a deceased cavalier King Charles spaniel which had been in congestive heart failure due to mitral valve disease, also had suffered from a partial tear of his left atrium wall, and blood clot blockage in his left atrium and right foreleg, and a stroke (myocardial infarction).
July 2015: Fortekor Plus -- combination of benazepril and pimobendan -- gets a green light in Europe. In a July 2015 opinion, the European Medicines Agency's Committee for Medicinal Products for Veterinary Use has recommended granting marketing authorization for Fortekor Plus, a combination of benazepril and pimobendan. The committee warns that the combination "should only be used in patients whose clinical signs are successfully controlled by administration of the same doses of the individual components (pimobendan and benazepril hydrochloride) given concurrently."
EDITOR'S NOTE: A potential drawback to this combination drug, with its fixed ratio of ACE-inhibitor to pimobendan, is that it would prevent the ability of the cardiologist to change the dose of just one of the two drugs and not the other.
July 2015: Shocking survey of UK vets on treatment of CKCS in heart failure is very troubling. In an April 2015 study, a team of UK researchers (T. Davies, S. Everitt, M. Cobb) conducted a survey of general practice veterinarians as to how they would handle a clinical case scenario of a cavalier King Charles spaniel in heart failure. The researchers stated that the proper response would be consistent with the ACVIM's 2009 Consensus Statment. They found that, instead of following the Consensus Statement recommendations, the most common recommendations they would give the cavalier's owner was a change in the dog’s exercise regime (69.6%), and the second most common one was monitoring of, or encouraging loss of, the dog’s weight (28.6%). Fewer than half of the vets would perform an echocardiograph scan, despite being told in the scenario that money was not a limiting factor. The researchers concluded:
"In conclusion, this study has demonstrated that profound variation exists in the management of heart failure in general veterinary practice in the UK despite considerable reliable published evidence supporting the use of many of the agents, and recently guidelines on the management of CCF due to canine degenerative valve disease (Atkins and others 2009); goals of future research should be to investigate why this is the case and importantly what the impact of this variation in approach might have on patient survival."
June 2015: US researchers study microRNAs as possible biomarkers of MVD progression. In a June 2015 study, US researchers (Qinghong Li, Lisa M. Freeman, John E. Rush, Dorothy P. Laflamme) examined the role circulating microRNAs (miRNAs) may play as biomarkers of mitral valve disease. They examined 18 dogs, divided into three groups of six dogs each: (1) Stage A: normal dogs at risk of heart disease; Stage B1/B2: (2) asymptomatic dogs with MVD and mild to moderate cardiac enlargement; and (3) Stage C/D: dogs with MVD and CHF requiring multiple cardiac medications. They found that dogs in Stage B1/B2 or C/D had four upregulated miRNAs, including three cfa-let-7/cfa-miR-98 family members, while seven other miRNAs were downregulated, compared to Stage A. Expression of six of the 11 miRNAs also were significantly different between dogs in Stage C/D and those in Stage B1/B2. They observed that the expression changes were greater as disease severity increased. They concluded that their study suggests that there is an opportunity for using some circulating miRNAs as biomarkers for diagnosis, prognosis or monitoring response to treatment in MVD in dogs.
June 2015: Cardiologist George Kramer competes for Wells Fargo prize for his Tucker valve to prevent backflow through heart valves. Dr. George Kramer, board certified veterinary cardiologist with Ultravet Medical Devices, is competing for a $25,000 prize from Wells Fargo Works, to help finance his research of the "Tucker valve" (at right). The mechanical valve is designed to be inserted through the mitral valve or tricuspid valve and block backflow of blood through the valve. Dr. Kramer needs as many votes for his project on the Wells Fargo Works Project website. You may vote daily for his valve research.
June 2015: Mitrex researchers report success and safety of its device with pigs. In a June 2015 abstract presented at the ACVIM Forum by Mitrex researchers (Jeffrey Solomon [right], Thomas Fogarty, Evan Anderson, Pierluca Lombardi), they report testing ten laboratory swine to evaluate the safety, compatibility, and effectiveness of the Mitrex epicardial annuloplasty device. They state that: (1) the devices were placed without incident; (2) coronary flow, ejection fraction, left ventricular wall motion and mitral valve anteroposterior dimension were normal post implantation and at term; (3) there were no remarkable postoperative events; (4) all subjects survived to term with the exception (due to a non device related complication); (5) the devices were well tolerated causing only minimal to mild fibrosis and chronic inflammation; (6) no significant changes were observed in the myocardium except for muscle fiber atrophy near the tip of the anterior arm; (7) there appeared to be ample tissue over the tip and no danger of perforation in all but one subject; (8) no meaningful changes were noted in cardiac shape, ventricular wall thickness, chamber size, heart valves, and blood vessels. They concluded that: "Myocardial compression necessary to perform epicardial annuloplasty was well tolerated. The Mitrex® device was safe and biocompatible."
June 2015: Cardiologist Rebecca Stepien confirms "no proven benefit" to pimobendan at Stage B2 MVD. In a March 2015 article in the IVIS journal, Veterinary Focus, board certified veterinary cardiologist Rebecca L. Stepien (right) confirms that routine administration of pimobendan has "no proven benefit" in dogs prior to heart failure. Referring specifically to ACVIM's Stage B2, she states: "Currently there is no proven benefit to routine initiation of pimobendan therapy at this stage."
May 2015: PennVet researchers reduce plasma NT-proBNP concentration in MVD-dogs in congestive heart failure. In a June 2015 study presented at the 2015 ACVIM Forum, PennVet cardiologists (Melanie Hezzell [left], Chloe Thorn, Danielle Laughlin, Mark Oyama) report that by tweaking medications (furosemide, enalapril, pimobendan) and adding Aldactazide, they were able to reduce the concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in dogs with chronic congestive heart failure (CHF) due to mitral valve disease (MVD). They noted evidence in human patients with CHF that therapies reducing NT-proBNP improved their outcomes. Fifteen dogs were recruited, with 8 in a control group and 7 in the test group. Depending upon the results of periodic blood tesing over 21 days, if NT-proBNP was above 1500pmol/L in the test group, the researchers would increase the dosages of the medications. They found that:
"In conclusion, a pre-specified treatment escalation algorithm in dogs with stable CHF due to MMVD and with NT-proBNP ≥1500pmol/L resulted in significant decreases in plasma NTproBNP concentration over time. Serum BUN and creatinine measurements significantly increased over baseline in these dogs, suggesting that careful monitoring of renal function is necessary during therapeutic escalation. Further study is warranted to determine whether targeted reductions in NT-proBNP result in improved outcomes in dogs with CHF secondary to MMVD."
May 2015: International team of cardiologists compile echocardiographic findings in older cavaliers. In a June 2015 report to the 2015 ACVIM Forum, an international team of veterinary cardiologists (Jorge Prieto-Ramos [right], Simon Swift, Andrea Corda, Brendan Corcoran , Kim Summers, Iñigo Sanz, Anne French) report on the results of echocardiographic scans of 126 cavalier King Charles spaniels between the ages of 8 and 16 years. All of the dogs had mitral valve thickening and regurgitation, and 98% had tricuspid valve regurgitation. However, only 17% had pulmonary hypertension.
Summary of results:
• Males: 35%; Females: 65%
• Mitral valve thickening and regurgitation: 100%
• Mitral valve prolapse: 88%; severe prolapse: 18%
• Tricuspid valve regurgitation: 98%
• Pulmonary hypertension: 17%
• Remodeling markers: 58%
May 2015: US researchers find pimobendan made no difference on incidence of arrhythmias in dogs in heart failure, compared to a placebo. In a May 2015 report by US researchers at the University of California - Davis (Geri A. Lake-Bakaar [right], Manreet K. Singh, Philip H. Kass, Leigh G. Griffiths), they studied eight small breed dogs with congestive heart failure (CHF) due to mitral valve disease (MVD). They wanted to determine the effect , if any, of pimobendan on the incidence of arrhythmias in MVD-dogs in CHF. They found no significant difference between pimobendan and placebo. However, they had two additional findings: (1) the dogs' quality of life significantly improved two weeks following the start of administration of either pimobendan or placebo; and (2) the average heart rates and sleeping respiratory rates (SRR) of the dogs given pimobendan were significantly lower than those given the placebo. The researchers speculated that the decrease in average heart rate and SRR were due to superior heart failure control with pimobendan.
Researchers do not find a relationship between serotonin in blood
platelets and development of MVD in cavaliers. In a
2015 study, an international team of veterinary researchers (Signe E.
Cremer, Annemarie T. Kristensen, Maria J. Reimann, Nynne B. Eriksen,
Stine F. Petersen, Clara B. Marschner, Inge Tarnow, Mark A. Oyama,
Lisbeth H. Olsen) analyzed blood samples of 62 cavalier King Charles
spaniels (15 healthy dogs; 18 with mild MVD; 19 with moderate-to-severe
MVD; and 10 in congestive heart failure). They were looking for (a) any
relationship between serotonin concentrations in blood platelets
("percentage of serotonin-positive platelets, level of surface-bound
platelet serotonin expression"), and (b) platelet activation, in CKCSs
with MVD. They found no differences in either surface-bound serotonin
expression or platelet activation among the four categories of cavaliers
in the study.
They did observe that dogs with low platelet numbers (thrombocytopenic dogs) had significantly lower serum serotonin concentrations than non-thrombocytopenic dogs. And, they found in 26 of the dogs a "flow cytometry scatterplot subpopulation (FSSP)" of platelets. Dogs with an FSSP had a higher percentage of serotonin-positive platelets, and a higher level of surface-bound serotonin expression, and higher platelet activation, than did dogs without an FSSP. An FSSP was present in 93.8% of the thrombocytopenic dogs and in 29.5% of the nonthrombocytopenic dogs. They concluded from those observations that an FSSP of highly activated platelets with pronounced serotonin binding was strongly associated with thrombocytopenia but not with MVD.
May 2015: US cardiologists find mitral valve measurements are larger for dogs with advanced MVD. In a May 2015 report by US cardiologists (S. Wesselowski, M. Borgarelli, G. Menciotti, J. Abbott), they compared the dimensions of anterior mitral valve leaflets and annulus (the ring-like base of the heart valve that supports the valve's leaflets) of 60 dogs (including 9 cavaliers) with various stages of mitral valve disease to those of 22 normal dogs, using echocardiography. They indexed the measurements to body weights. They found that the leaflet and annulus measurements of MVD-affected dogs in Stages B2 and C all were significantly greater than those in Stage B1 and normal dogs, and that the valve widths of Stage B1 dogs were significantly greater than the normal dogs.
May 2015: ACVIM cardiologists downplay the need for echocardiograms of cavaliers with newly discovered heart murmurs. In a May 2015 report in the Journal of the American Veterinary Medical Association, an international panel of ACVIM cardiologists (Etienne Côté, N. Joel Edwards, Stephen J. Ettinger, Virginia Luis Fuentes, Kristin A. MacDonald, Brian A. Scansen, D. David Sisson, Jonathan A. Abbott) explained the current diagnositic protocols once heart murmurs are detected by stethoscope.
They emphasize the importance of obtaining x-rays of the heart, and they downplay obtaining echocardiograms. They state:
"In adult small-breed dogs with incidentally detected murmurs, serial follow-up of cardiac size on thoracic radiographs [chest x-rays] can be a useful tool to monitor disease progression. For example, CKCS [cavalier King Charles spaniels] with DMVD [degenerative mitral valve disease] may have a VHS [Vertebral Heart Score] that is stable and may not have clinical signs for years, followed by a rapid increase in VHS and, eventually, the development of CHF. ... In the absence of any other clinical signs possibly related to heart disease, geriatric small-breed dogs with systolic murmurs that have a point of maximal intensity over the left apex can be evaluated by thoracic radiography. As mentioned for adult small-breed dogs, thoracic radiographs can provide important prognostic and therapeutic information for patients with presumed or confirmed DMVD: a cardiac silhouette of normal size and shape in a dog that has no overt signs of decompensated heart disease is consistent with mild DMVD, and no treatment currently available appears to alter the progression of DMVD at this stage. Additionally, such radiographs may then provide baseline information for comparison as the disease progresses."
"It is easy to recommend that all patients with incidentally detected heart murmurs undergo echocardiography. A true understanding of the realities and imperatives of clinical practice says otherwise. This report is intended to provide a summary of the patient-, client-, and veterinarian-based factors that can help attending veterinarians recommend whether or not to pursue further diagnostic evaluation of patients with incidentally detected murmurs and the advantages and suitability of various diagnostic approaches." (Emphasis added.)
May 2015: Canadian researchers find that the timing of x-rays during breathing patterns can affect the vertebral heart score. In a May 2015 article, Canadian researchers (Julien Olive, Romain Javard, Swan Specchi, Marie-Claude Bélanger, Catherine Bélanger, Guy Beauchamp, Kate Alexander) compared x-rays taken at varying points during dogs' breathing patterns and found that vertebral heart scores (VHS) can differ by as much as 1.11 vertebral units. They conclude that:
"Clinicians should be aware of the potential influence of these factors when assessing VHS in dogs; in addition to allowing optimal pulmonary assessment, consistently taking radiographs at end-inspiratory tidal volume may help to limit VHS variability attributable to the respiratory cycle. Further research is needed to assess the effects of cardiac and respiratory phases on VHS in dogs with cardiac or respiratory disease."
April 2015: UK review of veterinary records of 1,875 cavaliers shows UK Kennel Club dogs had significantly low MVD diagnoses. In an April 2015 report by UK and Australian veterinarians (Jennifer F Summers, Dan G O’Neill, David B Church, Peter C Thomson, Paul D McGreevy, David C Brodbelt), the veterinary records of 1,875 cavalier King Charles spaniels treated between 2009 and 2013 and on the database of the VetCompass animal health surveillance project, were dissected. Only 75 of the 1,875 cavaliers had a confirmed KC-registration status. Heart murmurs were the highest ranking category of diagnoses (541 dogs, representing 30.9% of study group). overall, the most common disorder category was cardiac, affecting 31.7% of the dogs.
Interestingly, a far lower percentage of UK Kennel Club registered dogs had reported murmurs (12%) compared to dogs of unknown registration status. Regarding this statistic, the authors speculate:
"It is possible that this finding reflects a genuinely lower prevalence of murmurs (and by implication existing or developing heart disease) in KC-registered CKCSs. Bias could have also been introduced (in either direction) by the comparative willingness of breeders to screen for heart murmurs in animals intended to produce puppies for KC registration, but it was not possible to explore this finding using the study data available."
April 2015: UK review of 111,967 dogs' veterinary records confirms that the cavalier ranks highest in MVD cases. In an April 2015 report, Royal Veterinary College (UK) researchers (M.J. Mattin, A. Boswood, D.B. Church, J. López-Alvarez, P.D. McGreevy, D.G. O'Neill, P.C. Thomson, D.C. Brodbelt) examined the veterinary records of 111,967 dogs treated at primary care clinics in 2010 and 2011. The aim of the study was to estimate the prevalence of mitral valve disease (MVD) among those dogs, and to identify risk factors for MVD diagnosis. They found 405 dogs diagnosed with MVD, of which 131 (32.4%) were cavalier King Charles spaniels (CKCS). This percentage was 5 times higher than any other breed and 3 times higher than cross-breeds. Their conclusion confirmed that CKCSs have the highest odds of MVD.
April 2015: Penn Vet seeks cavaliers for new drug test. Dr. Mark Oyama (right) of Penn Vet's cardiology department is asking for volunteer CKCSs with "stable untreated mitral valve disease" to participate in a 6-hour test of the tolerability and effects of a new drug believed to help delay the progression of MVD. Participation will involve a one-day hopital visit in Philadelphia and two injections of the new drug. The investigators will monitor blood pressure and various blood and urine measurements to determine if the drug has favorable effects on fluid retention. Contact: Dr. Mark A Oyama, email: email@example.com, telephone 215-898-2964; click for website.
Editor's Note: As with all such drug studies, CavalierHealth.org urges cavalier owners to ask questions and proceed with caution.
March 2015: Dr. Sleeper moves from Penn Vet to University of Florida. Dr. Meg Sleeper, formerly the cardiology department chief at the University of Pennsylvania in Philadelphia, has transfered to the University of Florida in Gainesville. Dr. Mark Oyama has succeeded Dr. Sleeper as chief of cardiology at Penn Vet.
March 2015: UK researchers develop a clinical severity score (CSS) to predict MVD severity and outcome. In a March 2015 report, a team of UK's Royal Veterinary College researchers (J. López-Alvarez, J. Elliott, D. Pfeiffer, Y.-M. Chang, M. Mattin, W. Moonarmart, M.J. Hezzell, A. Boswood) studied the symptoms and physical conditions of 224 MVD-affected dogs, including 97 cavaliers, to determine risk stratification of MVD-affected dogs and create a clinical severity score (CSS). They found:
"In summary, this study shows that data obtained from history and PE [physical examination], specifically history of cough, exercise intolerance, decreased appetite, breathlessness (difficulty breathing) and syncope as well as murmur grades louder than III/VI and loss of respiratory sinus arrhythmia, are independent indicators of disease progression for DMVD and are predictive of cardiac death. This knowledge can be developed into a scoring system to assist clinical decision making and may improve the interpretation of subsequent diagnostic test results for improved management of cases both in first opinion and referral practice."
March 2015: Researchers determine that moderate to severe pulmonary hypertension worsens outcome of dogs with MVD. In a March 2015 study, an international team of cardiologists (M. Borgarelli, J. Abbott, L. Braz-Ruivo, D. Chiavegato, S. Crosara, K. Lamb, I. Ljungvall, M. Poggi, R.A. Santilli, J. Haggstrom) reviewed the cases of 212 dogs with mitral valve disease, including 30 cavaliers. They concluded that, "In dogs with MMVD, moderate to severe PH worsens outcome."
March 2015: U. of Georgia researchers compare ACE-inhibitors with aldosterone receptor blockers to combat aldosterone breakthrough in MVD-affected dogs. Drs. Amanda Coleman and Amelia Sinkin (right) of the University of Georgia, are researching alternative medications to ACE-inhibitors (ACE-i), to better counteract the role of renin-angiotensin-aldosterone system (RAAS) stimulation in MVD. Recent studies have shown an unexpected and undesirable phenomenon known as “aldosterone breakthrough” (ABT) can occur in some dogs despite being treated with an ACE-i. These researchers hypothesize that treatment with the aldosterone receptor blocker (ARB) telmisartan will be associated with a significantly lower incidence of ABT than will treatment with the ACE-i enalapril, in dogs with advanced MVD.
March 2015: Researchers find gene expression of 5-HT2BR is higher in MVD-affected dogs. In a March 2015 study of the serotonin markers 5-HT2A and 5-HT2B receptors (R) in dogs with and without MVD, an international team of researchers (S.E. Cremer, S.G. Moesgaard, C.E. Rasmussen, N.E. Zois, T. Falk, M.J. Reimann, S. Cirera, H. Aupperle, M.A. Oyama, L.H. Olsen) reported finding gene expression of 5-HT2BR was "significantly higher" in dogs with MVD.
March 2015: Japanese research shows pimobendan causes sudden death in end-stage heart failure in mice. In a March 2015 study, a team of Japanese pharmacology researchers (Miki Nonaka, Sachio Morimoto, Takashi Murayama, Nagomi Kurebayashi, Lei Li, Yuan-Yuan Wang, Masaki Arioka) found that, in mice, pimobendan prevented myocardial remodelling in compensated heart failure (HF) and significantly extended the life span in both compensated and end-stage HF, but that it increased the risk of their sudden cardiac death in end-stage HF.
March 2015: Flanders, Belgium requires MVD and CM/SM testing of cavalier breeding stock. The government of the Flemish region of Belgium announced on March 3, 2015, new breeding rules for cavalier King Charles spaniels, requiring that all breeding stock be tested for mitral valve disease (and Chiari-like malformation and syringomyelia) in order for litters to be registered by the Flemish government. Twenty other breeds also will now have additional testing requirements.
Joke Schauvliege (left), Flemish Minister for Environment, Nature and Agriculture, signed the ministerial decision, which will come into force, along with details of the testing procedures, 10 days after official publication in the government's journal, which is expected to occur in April. The new regulation is the result of a study ordered by Minister Schauvliege two years ago, involving the calculation of the genetic diversity and most common health problems in the 21 breeds, which also includes the Schipperke, Papillon, Bichon Frise, Groenendael, Petit Brabancon, Ardennes cattle dog, Laekenois, Bloodhound, Golden Retriever, Irish setter and border collie.
March 2015: Scottish researchers identify 591 differentially expressed genes related to MVD in cavaliers. In a March 2015 report, a team of Scottish researchers (C-C Lu, M-M Liu, G Culshaw, M Clinton, D A Argyle, and B M Corcoran, right) examined 5,397 differentially expressed canine genes, narrowing down their examination to 591 genes in six to ten biological function clusters -- relevant to inflammation, cell movement, cardiovascular development, extracellular matrix organisation and epithelial-to-mesenchymal (EMT) transition in dogs with mitral valve disease (MVD). They state:
"Considering the biological relevance to MMVD, the gene families of importance with significant difference between groups included collagens, ADAMTS peptidases, proteoglycans, matrix metalloproteinases (MMPs) and their inhibitors, basement membrane components, cathepsin S, integrins, tight junction cell adhesion proteins, cadherins, other matrix-associated proteins, and members of the serotonin (5-HT)/transforming growth factor -β signalling pathway."
February 2015: Ukrainian researchers opine that the small dog genes IGF1 and/or STC2 relate to MVD in cavaliers. In a February 2015 report reviewing previous research into candidate genes causing dwarfism and heart development in dogs, a team of National University of Life and Environmental Sciences of Ukraine researchers speculate on the genetic cause of mitral valve disease in small breeds, particularly the cavalier King Charles spaniel. They conclude that MVD may be due to a mutation of the gene IGF1 (insulin-like growth factor-1), which is connected to small body size in canines. They suggest that if the heart is not reduced at the same scale as the overall smaller dog, the IGF1 mutation may be responsible for excessive compression, leading to valve damage. They further conclude that MVD may be due to mutations in areas closely linked to the STC2 gene, which also is a candidate for the small size, although STC2 is not involved with the development of the heart.
February 2015: Swedish study finds serotonin levels increase in spayed bitches. In a February 2015 report by veterinary doctoral student Elin Larsson, she studied 7 female dogs and 3 males, including on cavalier King Charles spaniel male, she found that "Among the bitches, the serotonin levels tended to increase after castration [sic]. The male dogs were few in number and no obvious changes in hormone levels were shown."
February 2015: German cardiologist examines serum MicroRNAs as diagnostic markers for mitral valve disease. Dr. Gerhard Wess (right), board certified veterinary cardiologist at Ludwig-Maximilians-Universitaet in Germany, is researching MicroRNA molecules in dogs' blood serum to determine if they can serve as diagnostic markers for stages of mitral valve disease. MicroRNAs are RNA molecules which have been found to play key roles in the regulation of gene expression. To corroborate the specificity, a group of dogs with dilated cardiomyopathy will also be included. His project began this month and is expected to continue until January 2016, after which he will publish a report of his findings and conclusions.
January 2015: Korean researchers find link between advanced MVD and pancreatitis. In a January 2015 study of 62 dogs -- 40 with various stages of MVD and 22 healthy ones (none were cavaliers) -- a team of South Korean researchers (D. Han, R. Choi, and C. Hyun) found an increase in serum canine pancreatic lipase immunoreactivity (cPLI) concentrations with the worsening of heart failure signs in the affected dogs. They concluded that pancreatic injury is associated with congestive heart failure (CHF) caused by MVD. They acknowledged that there were limitations to the study, primarily due to the number of dogs and the extent of the assessment of pancreatitis in the dogs. Nevertheless, they stated:
"Despite these study limitations, our study results clearly suggest that the increased serum PLI concentration, to levels accepted as indicating pancreatitis, is a common comorbidity with congestive heart failure. Therefore, regular check-up for serum PLI level is warranted for early detection of pancreatitis from chronic heart diseases."
January 2015: Echocardiographic measures of mitral regurgitation severity and mitral valve pathology enable researchers to reliably predict mortality. In a January 2015 report, UK and Brazilian researchers (Julia Sargent, Ruthnea Muzzi, Rajat Mukherjee, Sharlene Somarathne, Katherine Schranz, Hannah Stephenson, David Brodbelt, and Virginia Luis Fuentes) reviewed echocardiograms of 70 dogs (including 34 cavalier King Charles spaniels) diagnosed with MVD to estimate their survival times. They report that their results proved to be 95% correct.
January 2015: Scandinavian cardiologists find that increased left heart size can predict the risk of congestive heart failure in CKCSs. In a September 2014 report to the 24th ECVIM-CA Congress, Scandinavian veterinary cardiologists S. Eriksson-Palojarvi, K. Hansson, H. Duelund Pedersen, J. Haukka, and J. Häggström examined 225 echocardiograms of 78 cavalier King Charles spaniels over a period of up to 4.5 years. They found that overall, increased left heart size can predice the risk of congestive heart failure in cavaliers with mitral regurgitation due to mitral valve disease.
January 2015: Dr. Oyama seeks serotonin-blocking drug to stop MVD before heart failure. Dr. Mark Oyama (right) of the University of Pennsylvania veterinary school has announced that he aims to develop a serotonin-blocking drug to stop or reverse mitral valve disease (MVD) before congestive heart failure occurs. In previous research, he and his team have found that in dogs with MVD:
• Serotonin activates degenerative changes within the dog mitral valve.
• Drugs that block serotonin receptors reduce this response.
• Cavalier King Charles spaniels and other dog breeds that are predisposed to MVD have increased serotonin in their blood stream and heart tissues.
Dr. Oyama stated that once a new drug is developed, or the best existing alternative is identified, a clinical trial will follow, involving several hundred dogs worldwide with naturally occurring early MVD.
Editor's Note: Join the effort to raise funds for this research. Cavalier Health Fund.
November 2014: Infiniti Medical reports successful results of 6-month trial of its Mitrex mitral valve implant device. In a report to the ACVS Surgery Summit in October 2014, researchers (Drs. Jeffrey Adam Solomon, Pierluca Lombardi, Evan Anderson, Tachi Callas, Mark Juravic, Mark Cunningham, and Thomas Fogarty) for manufacturer Infiniti Medical reported that the results of a six month trial of its Mitrex epicardial annuloplasty device implanted on the beating hearts of ten swine without requiring the use of a cardiopulmonary bypass. Necropsy was performed at 180 days. The researchers found that:
"Coronary flow, ejection fraction, left ventricular wall motion and mitral valve function were normal post implantation and at term. ... Devices were well tolerated causing only minimal to mild fibrosis and chronic inflammation. No significant changes were observed in the myocardium except for muscle fiber atrophy near the tip of the anterior arm. There appeared to be ample tissue over the tip and no danger of perforation in all but one subject. No meaningful changes were noted in cardiac shape, ventricular wall thickness, chamber size, heart valves, and blood vessels. The myocardial compression necessary to perform epicardial annuloplasty was well tolerated. The Mitrex device was safe and biocompatible."
November 2014: UK Prof. Corcoran reports to UK's cavalier club on current research. In a November 2014 report to the UK's cavalier King Charles spaniel club, Professor Brendan Corcoran of the Royal (Dick) School of Veterinary Studies, The University of Edinburgh, updated the club on the topics of Mitral Valve Pathology ("any genetic cause of CKCSs likely affects the age of onset of the disease and not the eventual pathology."); Genetics ("... MMVD in CKCSs is heterogeneous (has different forms) in the way it develops and provides a powerful model to allow us to identify the genes that drive this disease."); Genomics ("The problem is determining what is "cause" and what "effect" is. ... We are interested to know how the expression of these genes might change as dogs get older and as the disease becomes more severe."); and Tissue Engineering ("... what if we could grow our own valves in the laboratory?")
November 2014: A troubling medical treatment study of unsuspecting MVD-affected dogs in heart failure. Ceva Animal Health, a veterinary pharmaceutical company, is sponsoring a stealth-like clinical trial of dogs in heart failure, evaluating what it refers to as a "new medical therapy" called C635 (which we suspect to be Ceva's Cardalis, a combination of the ACE-inhibitor benazepril and the aldosterone antagonist spironolactone) at veterinary schools and cardiology clinics in the USA, including North Carolina State University's veterinary school. If our understanding of the outline of the study is accurate, the study is disturbing because it severely limits medications to be given to the dogs in heart failure (Stage C) which are participating in it. Reportedly, the dogs are divided into three groups, one receiving Cardalis -- Ceva's combination pill of benazepril and spironolactone -- and the second receiving just benazepril, and the third receiving just spironolactone, for up to a year. In addition, the dogs may be given the diuretic furosemide and either digoxin or diltiazem if necessary to control heart rate in artial fibrillation.
EDITOR'S NOTE:The troubling significance of this study is that the ACVIM Consensus Statement currently recommends as medications for MVD-affected dogs in heart failure -- Stage C -- a combination of a diuretic, an ACE-inhibitor, pimobendan, and possibly spironolactone. In this study, it appears that two-thirds of these dogs will receive only the diuretic and ACE-inhibitor or only the diuretic and spironolactone, and none of the dogs will be given pimobendan. It therefore is very important for the owners of any cavaliers asked to join this study to be aware that they could be putting their dogs at great risk of their heart-health by allowing them to be denied a full dose of medications deemed necessary by most cardiologists to manage their heart failure.
November 2014: Tufts University's vet school seeks healthy CKCSs for muscle mass clinical trial. Tuft's Cummings veterinary school needs healthy cavaliers to participate in a clinical trial to evaluate the use of ultrasound to measure dogs' muscle mass. Loss of muscle mass is a common consequence of advanced mitral valve disease and associated kidney disease. Eligible dogs must be from one to five years old and neutered and have no heart murmurs or significant medical conditions. Participating dogs will receive a free examination, x-ray, ultrasound of back muscles, and have a small blood sample collected. If interested, contact Dr. Lisa Freeman, telephone 508-887-4696.
October 2014: Veterinary cardiologist Mark Kittleson dumps on EPIC Trial -- says it has a 50-50 chance. In a September 2014 presentation before the World Small Animal Veterinary Association (WSAVA) Congress, board certified veterinary cardiologist Mark Kittleson (of the School of Veterinary Medicine, University of California-Davis) spoke very frankly about the ongoing EPIC Trial studying whether pimobendan is safe and effective in delaying the onset of heart failure in dogs with mitral valve disease. He said:
"Because this study found pimobendan to be detrimental to dogs with MMVD it is the opinion of the author that further study was warranted prior to exposing 150 dogs to it in a large clinical trial (the EPIC study). Primum non nocere (first do no harm). It is also the opinion of the author that pimobendan should not be administered to dogs with MMVD prior to the onset of heart failure until the results of the EPIC trial are published. ... Will it prolong the time until a dog with MMVD goes into heart failure? That remains to be seen. Given the one study that has been done to date I don’t believe you can give this anything more than a 50:50 chance."
"And so, once again, it is my recommendation that pimobendan not be administered to dogs with mitral regurgitation due to MMVD prior to the results of the EPIC study being published in a peer-reviewed journal."
EDITOR'S NOTE: Dr. Kittleson's comments about the obvious dangers of the premature use of pimonbenan are music to our ears, since we pointed out the same flaws and hazards in our April 2011 blog entry, “Beware the pimobendan/Vetmedin ‘EPIC clinical trial’: There is no upside”, urging that cavalier owners not risk their dogs' lives by allowing them to participate in the study. At the time, we frankly were stunned that so many board certified cardiologists would agree to participate in such a risky study, including some who previously had issued the same warnings about the dangers of giving pre-heart-failure dogs such a drug. Interestingly, the list of names of these 36 cardiologists no longer is present on the Internet, since Vetmedin's manufacturer shut down its EPIC Trial website earlier this year. Dr. Kittleson's use of the bioethics Latin phrase, primum non nocere (first do no harm), certainly has been on our minds for the past 4+ years since the commencement of this life-threatening study.
October 2014: Japanese veterinary heart surgeon summarizes current methods of canine mitral valve repairs. In a September 2014 presentation before the World Small Animal Veterinary Assosciation Congress (WSAVA), Japanese veterinary heart surgeon Isamu Kanemoto summarized the current methods of mitral valve surgeries and their pitfalls for small dogs.
Japanese researchers find left atrial enlargement and function correlate
with prognosis of early death of MVD dogs.
2014 report by a team of Japanese cardiologists (T. Osuga, K.
Morishita, S. Suzuki, T. Morita, N. Yokoyama, H. Ohta, M. Yamasaki, and
Mitsuyosh Takiguchi [right]) of
38 dogs (breeds unidentified) in various stages of mitral valve disease
(MVD), they found that the size of the left atrium (LA) and the LA's
booster pump function strongly correlated with predictions of early
death of the dogs. LA's booster pump function was the most significant
independent predictor of mortality.
They also observed that LA "enlargement does not always result in its functional incompetence. During chronic MR [mitral regurgitation], the left atrium enlarges in size and the LA chamber becomes more compliant. Thus, the enlarged left atrium appears to exert an important compensatory mechanism by buffering the rise in pressure in the atrium and by providing an adequate ventricular filling volume."
October 2014: Another month, another plasma NT-proBNP concentration study shows higher concentrations in dogs with CHF. In an October 2014 study of 291 dogs, including 38 cavaliers, the 16 researchers found that plasma NT-proBNP concentrations once again were higher in dogs in congestive heart failure (CHF) than in dogs with non-cardiac respiratory distress. See last month's entry, below. Can you spell d-e-r-i-v-a-t-i-v-e?
September 2014: Benazepril does not prevent furosemide-induced RAAS activation, in a study of 10 healthy hounds. In a September 2014 study (by A. C. Lantis, M. K. Ames, C. E. Atkins, T. C. DeFrancesco, B. W. Keene, and S. R. Werre) of ten healthy hound dogs, the researchers found that the ACE-inhibitor benazepril did not prevent the activation of the renin-angiotensin aldosterone system (RAAS), a cause of renal dysfunction.
European cardiologists study 78 CKCSs and find high NT-proANP levels
predict future heart failure with 95% confidence factor. In
September 2014 report by a team of Finnish, Swedish, and Danish
cardiologists (Anders S. Eriksson, Jens Häggström, Henrik Duelund
Pedersen, Kerstin Hansson, Anna-Kaisa Järvinen, Jari Haukka, Clarence
Kvart), they examined 78 cavalier King Charles spaniels for 4.5 years
and found that high levels of NP-proANP (over >1000 pmol/l) was 95%
accurate, with a median time to congestive heart failure (CHF) of 11
months, compared to 54 months for cavaliers with lower ANP levels.
They also reported that the risk of CHF increased with a heart rate over 130 beats per minute and a mitral valve murmur grade over grade 3.
September 2014: International study confirms the obvious: the louder the murmur, the worse the MVD. This is a "DUH!" moment. A September 2014 study by an international team of respected cardiologists (I. Ljungvall, M. Rishniw, F. Porciello, L. Ferasin, D. G. Ohad) studied 578 small breed dogs with MVD and found what we have been told for the past 25 years: Murmur intensity reflects MVD severity. However, the details in this abstract are worth reading. Details include: (1) No dogs with grade I or II murmurs had congestive heart failure (CHF), and 90% had no enlargement; (2) 56% of dogs with grade III, 29% of dogs with grade IV, and 8% of dogs with grade V or VI murmurs and not yet in CHF had no enlargement.
EDITOR'S NOTE: Under the "Nothing New Under The Sun" department, this study topic has been performed before, as should be obvious. The Sheldon Cooper character on the television program Big Bang Theory would refer to this 2014 study rather derisively as "derivative". We found a similar study reach similar conclusions, limited to cavalier King Charles spaniels (81 of them, to be precise), published nearly 20 years earlier, in March 1995.
August 2014: Serotonin study shows concentration highest in cavaliers, with or without mitral valve disease . In an August 2014 study by an international team of veterinary cardiologists (S.E. Cremer, G.E. Singletary, L.H. Olsen, K. Wallace, J. Häggström, I. Ljungvall, K. Höglund, C.A. Reynolds. N. Pizzinat, and M.A. Oyama), 45 dogs, including 12 healthy cavaliers and 14 MVD-affected cavaliers, were tested for concentrations of serotonin (5-hydroxytryptamine, 5HT) in their blood platelets and heart valve tissues. The researchers found that 5HT levels were significantly higher in CKCSs than non-CKCSs, and that the 5HT was highest in healthy cavaliers. As for 5HT in the dogs' heart valve tissues, it was significantly higher in mitral valve tissues of dogs with MVD than in the heart tissues of those with other heart disorders. They conclude that serotonin may be a signal for potential MVD. They recommend further investigation of interactions of platelet, valvular, and myocardial 5HT.
August 2014: NC State veterinarians make progress in stem cell therapy for damaged heart tissue. In an October 2014 report, a veterinary research team at North Carolina State University, led by Dr. Ke Cheng (right), has figured out a way to magnetize cardiac stem cells so that they are directed to the hearts of rats and remain there to perform therapeutic effects. A recurring problem with cardiac stem cells is that the heart's constant motion will wash cells out of the heart and into the blood system, where they are wasted. Dr. Cheng has attached metalic nanoparticles from an FDA-approved drug, Feraheme, to cardiac stem cells and used a magnetic field to keep the cells in the heart. The process has resulted in a three-fold increase in cell retention in the rats' hearts.
July 2014: International team of cardiologists find cavaliers have higher serotonin concentrations in platelets . In a July 2014 study, cardiologist researchers from Denmark, Sweden, the USA, and France (S.E. Cremer, G.E. Singletary, L.H. Olsen, K. Wallace, J. Häggström, I. Ljungvall, K. Höglund, C.A. Reynolds, N. Pizzinat, M.A. Oyama) compared serotonin concentrations in blood plasma of 26 cavaliers (12 healthy and 14 with mitral valve disease) and 19 non-CKCSs (8 healthy and 11 with MVD). They found that platelet serotonin was elevated in cavaliers compared to the other breeds. They also found that left ventricular myocardial and mitral valve leaflet tissue in deceased MVD dogs was elevated compared to dogs which died without cardiac disease.
July 2014: Thailand researchers find no difference in serotonin concentrations between healthy dogs and those with MVD, but ... In a July 2014 study by Thailand researchers Tanawan Mangklabruks and Sirilak Disatian Surachetpong, they examined serotonin concentrations in 20 healthy dogs and 23 dogs with MVD. They did not find any difference in either the plasma or the platelet serotonin concentrations between the two groups. They concluded that:
"Circulating plasma serotonin is unlikely a major source of serotonin signaling in canine MMVD. Platelets could be a source of serotonin in canine MMVD through platelet adhesion to the mitral valve; however, the amount of serotonin stored in platelets of healthy dogs and dogs with MMVD is not different."
EDITOR'S NOTE: However, they did not focus exclusively on cavaliers. A July 2013 study of 120 dogs, including 92 cavaliers, found that cavaliers had higher concentrations of serum serotonin (serum 5HT) than other breeds not predisposed to mitral valve disease, and that serum 5HT concentrations decreased with increased left atrial enlargement. They concluded that, "the finding of higher serum 5HT concentrations in dogs predisposed to MMVD (CKCS) and dogs with mild MMVD suggests that alterations in 5HT signaling might play a role in progression of early stages of MMVD."
And in the July 2014 international study described directly above this article, the researchers found that platelet serotonin was elevated in cavaliers compared to the other breeds. And, in the August 2014 study, also above this article, researchers found that 5HT levels were significantly higher in CKCSs than non-CKCSs, and that the 5HT was highest in healthy cavaliers. As for 5HT in the dogs' heart valve tissues, it was significantly higher in mitral valve tissues of dogs with MVD than in the heart tissues of those with other heart disorders.
July 2014: Swedish researchers find high blood NT-proANP concentrations can predict onset of CHF within months. In a July 2014 study, a team of Swedish cardiologists and other researchers, Drs. Anders S. Eriksson, Jens Häggström, Henrik Duelund Pedersen, Kerstin Hansson, Anna-Kaisa Järvinen, Jari Haukka, and Clarence Kvart, examined 78 cavaliers with mitral valve disease over 4.5 years, to evaluate the predictive value of plasma N-terminal pro-atrial natriuretic peptide (NT–proANP) as a marker for progression of mitral regurgitation caused by mitral valve disease. They found that the risk of CHF increased with NT–proANP concentrations above 1000 picomoles per liter (pmol/l). They further found that the risk of the onset of congestive heart failure (CHF) increased with a heart rate greater than 130 beats per minute and a mitral valve murmur grade of 4 to 6.
June 2014: UK's Simon Swift moves to University of Florida veterinary school. Simon Swift (right), board certified veterinary cardiologist and long-time official cardiologist for the UK's Cavalier Club, has moved to the State of Florida and now is a professor at the University of Florida's veterinary school in Gainesville. For well over a decade, Mr. Swift has examined the hearts of thousands of CKCSs at conformation shows in the UK and each year has presented reports and statistics on mitral valve disease at the Cavalier Club's annual general meetings. He is a welcome addition to the board certified cardiologists in Florida.
May 2014: Brazil specialists find pimobendan improves clinical signs of MVD congestive heart failure, compared to digoxin. In a February 2014 report, a team of Brazilian cardiologists and researchers compared 14 dogs in congestive heart failure (CHF) given pimobendan, with 11 CHF dogs given digoxin and 7 CHF dogs given a placebo. All dogs also received doses of ACE-inhibitors and furosemide. They found that the digoxin and placebo groups showed no significant difference throughout the 28 days of treatment. The pimobendan group showed an increased early mitral inflow velocity on day 28, and that serum creatinine increased on days 14 and 28 compared to the baseline, but within normal limits. They concluded that the increase in early mitral inflow velocity on day 28 for pimobendan group is suggestive of diastolic dysfunction improvement, but that this is only one variable related to diastolic function. Only the pimobendan group showed increase in blood creatinine between baseline and days 7 and 28, and this result must be explored in later studies.
May 2014: Japanese researchers find histamine concentration is higher in dogs with MVD. In a May 2014 study by Japanese veterinarians, they studied 28 dogs, including 8 cavaliers, to evaluate whether blood concentration of histamine is associated with mitral valve disease. They concluded:
"In conclusion, the histamine concentration was higher in the population of dogs with CVD [canine valvular disease] compared with the healthy controls. Although the etiopathogenesis of CVD is complex and incompletely understood, it likely involves histamine. Ultimately additional studies are required to determine whether histamine blockers might be useful for the management of dogs with cardiac valvular disease."
May 2014: International team finds link between high-level serotonin-binding and highly-activated blood platelets and mitral valve disease and oversized platelets in cavaliers. In an April 2014 report, a team of researchers from Denmark and the USA studied the levels of serotonin-binding and of platlet activation in 61 CKCSs. They found that cavaliers with moderate-severe MVD and severe MVD tended to have higher levels of platelet activation, and that highly-active platelets and high-level serotonin-binding was strongly associated with oversized platelets. They concluded that further investigation into the significance of serotonin-binding is warranted.
May 2014: French researchers study 134 cavaliers and find their body weights affect echocardiographic interpretations. In an April 2014 study of 134 healthy cavalier King Charles spaniels, a team of French researchers concluded that: "Body weight should be taken into account when interpreting echocardiographic values in CKCS, except for LA/Ao, FS%, and mitral E/A ratio."
April 2014: Study of LCZ696 shows promise in managing heart failure in dogs. In an April 2014 report by an international team of heart specialists, the angiotensin receptor neprilysin inhibitor LCZ696 significantly reduced aldosterone (AL) exposure in 18 healthy Beagle dogs with activated renin-angiotensin system. They concluded that "these results support further development of LCZ696 for the management of cardiovascular diseases."
April 2014: Italian investigator finds cavaliers' MVD is tied to chronic inflammation. In a March 2014 thesis, Italian Ph.D. student Giulia Riscazzi (right) studied mitral valve disease in cavaliers and Cirneco dell’Etna dogs (an Italian hunting breed). She examined serological biomarkers in MVD-affected dogs and compared blood samples from the healthy dogs of the groups with blood samples from the dogs affected by different stages of MVD. She then matched the proteomics results with the clinical and echocardiographic data. She found that "MVD is a pathology that is strictly connected to a chronic inflammation state."
Her conclusions regarding the CKCS:
"The proteomic analysis conducted on our samples and correlated to the clinical results, indicate that the MVD is a pathology that is strictly connected to a chronic inflammation state. The up-regulation of A1AT, IgG, IgM, and the down-regulation of complement C3 and serum albumin are connected with an inflammatory status, that cause a depletion of the components of the complement system, an activation of the acute phase proteins and of the components of immunity response like IgG and IgM immunoglobulins. The hypothesis that MVD could be related to a chronic inflammation was already speculated in the last years, and, based on the present study results, we think that the analysis of the inflammatory mediators in MVD patients could be a great chance to uncover the pathogenic mechanism at the base of mitral valve disease."
EDITOR'S NOTE: Another question which remains is: Is the MVD caused by inflammation, or does MVD cause the inflammation?
April 2014: US study finds low serum vitamin D concentration is associated with poor outcomes of dogs with CHF. In a January 2014 study by a team of US cardiologists, of serum vitamin D concentration in the bloodstreams of 82 dogs (31 with congestive heart failure [CHF] -- 20 with acquired valve disease (AVD) and 11 with dilated cardiomyopathy (DCM) -- and 51 unaffected control dogs, all over 5 years old), they found that low serum vitamin D concentration was associated with poor outcome in dogs with CHF. They suggested that strategies to improve vitamin D status in some dogs with CHF may prove beneficial without causing toxicity.
February 2014: Healthy cavaliers are found to have the highest concentration of proANP out of 9 breeds. In a 2014 study of 535 healthy dogs of nine breeds, researchers found that CKCSs and German shepherds had the highest median proANP concentrations, twice the median concentration in the breed with the lowest concentration, the Doberman Pinscher. There were 34 cavaliers in the study, all from Sweden.
Dr. Penny Watson looks for ties between fibrosis in MVD, SM, and chronic
pancreatitis in CKCSs
Dr. Penny Watson (right) of UK's Cambridge University's veterinary school is
spearheading a new study into whether several of the CKCS breed's hereditary
health problems are the result of the same genetic defect. Specifically, she
intends to explore the possibility that disparate cavalier diseases,
including mitral valve disease (MVD), syringomyelia (SM), and chronic
pancreatitis are connected at the cellular level by unusual patterns of
fibrotic changes. "Pronounced perivescular fibrosis", a feature in dogs with
chronic pancreatitis, also has been tied to a condition of the central
nervous system in cavaliers with SM. Dr. Watson has suggested that
deterioration of cavaliers' mitral valves also may be a result of a process
connected to the causes of fibrosis.
The CKCS breed's documented overabundance of serotonin, a neurotransmitter protein, has been identified as a plausible mechanism which may trigger the development of fibrotic changes in the heart's valves. Her study entails establishing primary stellate cell (SC) cultures from CKCS and define 5HT receptor subtype expression. Stellate cell (SC) activation is a key event in the development of hepatic and pancreatic fibrosis. Serotonin has been shown to activate SCs via 5HT receptors. The study is measuring the response of these cells to serotonin and other stimulators of fibrosis. She then intends to attempt to block SC activation in vitro using 5HTreceptor antagonists. Increased understanding of the factors driving fibrosis will be of benefit to the CKCS and may allow a drug trial in the breed.
December 2013: Cavaliers in congestive heart failure due to MVD have higher concentrations of the coenzyme biopterin than other dogs. A research team of Danish and Swedish cardiologists studied 57 cavaliers with MVD and 27 other dogs to study the status of the coenzyme biopterin (BH2 and BH4) in blood plasma, in relation to MVD. They report in a December 2013 study that age, gender, body weight, passive smoking and plasma and cardiac status correlate with plasma BH2 and BH4 concentrations in dogs. They specifically found that dogs in congestive heart failure (CHF) had significantly higher BH4 and BH2 levels than other dog groups.
December 2013: PennVet cardiologist Meg Sleeper reiterates cavaliers' unfortunate MVD uniqueness. In a chapter of the just released book, "Handbook of Laboratory Animal Science, Volume III, Third Edition: Animal Models", University of Pennsylvania veterinary school's cardiologist Dr. Meg Sleeper (right) has summarized the unique unfortunate MVD dilemma of the cavalier King Charles spaniel. She writes:
"In Cavalier King Charles Spaniels (CKSPs), the disease often occurs at a younger age, and the prevalence in dogs that are older than 10 years of age is 90%. ... One study performed in the United Kingdom demonstrated that 59% of CKSPs older than 4 years of age had evidence of the disease. Similar results were noted in a study performed in the United States, which demonstrated that 56% of CKSP dogs were affected at 4 years of age. The disease starts with the formation of small nodules followed by progressive thickening and contraction of the mitral valve cusps and leakage of the valve. The disease is characterized by a long preclinical period. ... At present, it is not known how chronic valve degeneration is inherited. although a recent study identified two loci associated with the disease in CKSPs."
October 2013: Swedish cardiologists find that pimobendan tops benazepril in reducing heart rate and heart size in cavaliers in CHF. In an October 2013 report issued by Swedish cardiologists J. Häggström, P.F. Lord, K. Höglund, I. Ljungvall, O. Jöns, C. Kvart and K. Hansson, they studied 16 dogs in congestive heart failure (CHF) due to mitral valve disease, including eleven cavaliers. They compared pimobendan to benazepril and found that in dogs with CHF caused by MVD, pimobendan significantly reduces the heart rate (HR), left ventricle (LV) and atrium (LA) dimensions, heart rate-normalized pulmonary transit time (nPTT), and N-terminal proatrial natriuretic peptide (NT-proANP), and increases the ejection fraction, in comparison to benazepril. The reduction in heart size in response to pimobendan treatment in dogs with CHF is in agreement with previous studies, but reductions in HR, NT-proANP, and nPTT in response to pimobendan treatment have not previously been described in naturally occurring MVD.
"Pimobendan improves short-term cardiac function more than benazepril in dogs with CHF caused by MMVD. Pimobendan treatment enables the heart to work at smaller end-systolic and diastolic dimensions while maintaining adequate forward stroke volume. Some of the treatment responses found in neuroendocrine profile might have therapeutic relevance."
October 2013: Thai grad students find ramipril did not improve Stage B2 MVD dogs. In a 2013 study by Thai graduate students Prakit Kohkayasit and Sirilak Surachetpong of twenty dogs (none CKCS) in Stage B2 (right), they found that the ACE-inhibitor ramipril did not affect cardiac chamber size, mitral regurgitation severity and systolic function assessed by echocardiography in 91-day period of treatment.
Our take is this means that ramipril was ineffective in improving the condition of the Stage B2 dogs. It did not reduce the size of the enlarged heart; it did not reduce the amount of regurgitation; it did not positively affect the heart's pumping ability.
QUEST Study shows pimobendan (versus benazepril) slowed progress
congestive heart failure, slowed increase in heart size, maintained higher
body temperature, and
fluid retention. In the QUEST Study (comparing pimobendan with
benazepril and conducted from 2002 to 2006 with 260 dogs in congestive heart
failure [CHF], including 82 cavaliers) the researchers found in a
report that the two medications resulted in similar quality of life
during the study. However, they found that pimobendan conferred increased
time before the progression of CHF and resulted in smaller heart size,
higher body temperature, and less retention of water.
See the September 2008 QUEST Study report, in which the same researchers found that "pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD compared with benazepril plus conventional therapy."
August 2013: USA researchers find pimobendan has no effect upon the RAAS when combined with furosemide. In an August 2013 study, a team of North Carolina State University veterinary researchers report that high doses of pimobendan, when combined with a moderate dose of furosemide, had no greater effect upon six dogs' renin-angiotensin-aldosterone system (RAAS) than did furosemide alone upon six other dogs in the study.
August 2013: Japanese researchers compare carperitide to furosemide in dogs with MVD. In an August 2013 report, a team of Japanese veterinary heart surgeons compared dosing lab dogs with carperitide and furosemide. Carperitide (right), an alpha-human atrial natriuretic peptide, is a human drug which is known to reduce pressure in the left atrial and left ventricle chambers of the human heart. The team reports that both drugs similarly reduced left atrial pressure in six lab Beagles. They found that carperitide had less adverse effects than furosemide because it did not activate the renin–angiotensin–aldosterone system (RAAS). They concluded that additional studies are warranted in clinical patients with degenerative MVD and congestive heart failure.
July 2013: Spironolactone is found safe in study funded by manufacturer of Prilactone. In a July 2013 study of the possible increased risk of adverse events for dogs taking spironolactone in addition to conventional therapies, the researchers concluded that dogs with heart failure receiving spironolactone in addition to conventional treatment are not at a higher risk for any adverse events, death caused by cardiac disease, renal disease, or both, hyperkalemia, or azotemia. The study was funded by the manufacturer of Prilactone.
July 2013: Study finds serotonin levels in cavaliers may relate to progression of early MVD. In a July 2013 international study (Drs. I. Ljungvall, K. Höglund, I. Lilliehöök, M.A. Oyama, A. Tidholm, H. Tvedten and J. Häggström) of serotonin concentrations in 120 dogs, including 92 cavaliers, the researchers found that CKCSs had higher concentrations of serotonin than other breeds, and that dogs with severe MVD had lower serotonin levels than dogs without MVD and dogs with milder MVD. They concluded, therefore, that changes in serotonin levels "might play a role in progression of early stages of MMVD."
July 2013: NC State vet school needs cavaliers for MVD study of activity levels. North Carolina State University College of Veterinary Medicine's Comparative Pain Research Lab is undertaking a study of cavaliers and other breeds, to better understand the effect of heart disease on the quality of life in dogs. Dogs enrolled in the study will have heart disease (causing a murmur) but have not yet developed signs of heart failure, as well as dogs of similar breed, size and age but without significant heart disease. Click here for details. Contact Andrea Thomson, research technician in the Comparative Pain Research Lab, telephone 919-513-6854.
June 2013: US researchers find injections of alginate hydrogel into heart-failure dogs' hearts improves heart structure and function. In a June 2013 study by a team of US cardiologists, they found that injecting alginate hydrogel directly into the left ventricle (LV) of the hearts of 7 dogs in heart failure, increased the thickness of the LV wall, and LV structure and function improved. Alginate is a naturally derived polysaccharide that is used in drug delivery and as cell encapsulation material. The brand name Algisyl-LVR is manufactured by LoneStar Heart, Inc. of Laguna Hills, California.
June 2013: Tufts researchers examine effects of statin drug on dogs with congestive heart failure. A team of researchers at Tufts University's Cummings School of Veterinary Medicine conducted a preliminary study of how dogs in congestive heart failure (CHF) could tolerate atorvastatin (a 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor -- statin) and its short-term effects of CHF. Two of the 12 dogs in CHF were cavalier King Charles spaniels. In their June 2013 report, they found that atorvastatin was well tolerated at clinically relevant doses in both healthy dogs and dogs with CHF.
Significant decreases in total white blood cell (WBC) -- an inflammatory bio-marker -- and neutrophil counts were seen in the CHF group after both 2 and 8 weeks of atorvastatin administration. This effect was seen only in the CHF group, and the WBC count of CHF dogs no longer differed from those of the healthy dogs after statin administration. Post-atorvastatin WBC counts remained within the reference range in all animals and neutropenia was not documented. It is not clear whether the observed decrease in WBC count seen in CHF dogs was the direct result of atorvastatin, or perhaps secondary to overall better control of CHF or habituation to the hospital environment. They did not observe any significant short-term effects on echocardiographic or ECG parameters, quality of life questionnaire, or NT-proBNP.
They stated that the lack of observed improvement in those clinical parameters may indicate that statins are not helpful in dogs with nonischemic heart failure, but the lack of observed effect also could relate to the small number of dogs, short duration of this trial or both. They stated that modest decreases in systolic blood pressure seen in dogs with CHF after atorvastatin administration may have resulted from statin treatment, habituation to the hospital environment, or the effects of concomitant cardiac medications. They concluded that future prospective studies are needed to evaluate the potential clinical benefits of statin administration in dogs with cardiac disease.
Editor's Note: CavalierHealth.org is very skeptical of any value of statin drugs for dogs in CHF. Statins are known to interfere with the production of CoQ10 and are suspected of weakening the heart muscle. Dogs in CHF need both an abundance of CoQ10 and a very strong heart. If reducing inflammation is of value, the solution is to give the CHF dog fish oils. However, many knowledgeable cardiologists do not believe that any significant inflammatory process is involved in MVD. Canine-speaking, statins remain a remedy in search of a disease.
May 2013: Dr. Buchanan reports mitral valve thickening is worst at chordae tendineae contact points. Dr. James Buchanan (right), in a May 2013 article surveying the history of veterinary cardiology, observes that mitral valve thickening occurs mainly in the insertion points of the chordae tendineae into the valves. Regarding CKCSs, he wrote:
"Since the late 1980s Cavalier King Charles spaniels have shown striking breed predisposition evidenced by mitral systolic murmurs in 50% of 5-year-old Cavaliers and 95 - 100% of 10-year-old ones."
May 2013: UK study finds cavaliers at "significant risk" for chronic kidney disease. In a May 2013 study of 107,214 dogs treated in 2010 and 2011 at 89 UK veterinary clinics, the researchers found that cavalier King Charles spaniels and Cocker spaniels were a "significant risk factor" for developing chronic kidney disease (CKD). They also reported that cardiac disease was a significant co-disease with CKD.
May 2013: UK Kennel Club announces MVD as a "candidate" for EBVs. The UK Kennel Club, in its 2012 Dog Health Group Annual Report, announced that mitral valve disease (along with syringomyelia) "are candidates for the development of EBVs [estimated breeding values] but require appropriate data collection procedures to be in place." The report goes on:
"A BVA/KC scheme for syringomyelia was launched in 2012 and once enough data has accumulated through the scheme then EBVs for the condition will become a possibility."
For more information about EBVs, see our webpage on the topic.
April 2013: German researchers find natriuretic peptides not useful to distinguish between grades of MVD. In an April 2013 report, a team of German veterinary cardiologists studied 352 dogs and have found that:
"NPs [natriuretic peptides] in canine MMVD are useful to discriminate between asymptomatic dogs and dogs with CHF. Due to a large overlap of NP-concentrations between the groups, NPs do not seem to be useful to differentiate between dogs in stages B1 and B2. Interpretation of NT-proBNP and proANP values should include consideration of sex-specific differences."
April 2013: Researchers find that cardiac troponin-I could be a biomarker for formation of scar tissue in MVD dogs. In an April 2013 study of 50 dogs affected with congestive heart failure due to MVD, including 20 cavaliers, a team of Swedish and Danish veterinary researchers found that:
"Cardiac fibrosis and arteriosclerosis in dogs with MMVD are reflected by circulating cTnI [cardiac Troponin-I] concentration, but not by aldosterone concentration or renin activity. Cardiac troponin I could be a valuable biomarker for myocardial fibrosis in dogs with chronic cardiac diseases."
March 2013: Prof. Brendan Corcoran reports on MVD research to UK's cavalier club. Royal (Dick) School of Veterinary Studies researchers Brendan Corcoran and Chi-Chien (Fox) Liu reported to the UK Cavalier Club in February that their study has "demonstrated that the damage that occurs to the CKCS valve is the same as occurs to non-CKCS dogs, and in that respect the CKCS is not unique when describing the pathology of this disease."
Further, in their focus upon whether MVD is due to damage to the endothelial cells lining the valve surface, they have isolated and grown "canine valve endothelial cells, generating pure clones (each cell an exact copy of each other), monitoring response to different agents, growing cells in a form of artificial valve and physically injuring the cells. Further work is to be done with the plan to complete by end of 2013." They also are studying whether there is increased expression of genes normally associated with the development of diseased valves. They report that "The gene data should be available in the next few weeks and then will be analysed. On the basis of these results some aspects of Aim 2 will be addressed further."
February 2013: International study finds no statistical relationship between coughing in MVD dogs, due to pulmonary edema, and congestive heart failure. A team of veterinary cardiologists from the UK, US, and Canada examined the medical records of 206 dogs affected with MVD to determine whether a cough is a clinical sign of congestive heart failure (CHF). In their February 2013 report, they found no statistical association between coughing and CHF, identified by cardiogenic pulmonary edema, and that isolated coughing (without shortness of breath or rapid breathing) is a very unlikely sign of CHF in dogs. Instead, their statistics indicated that the coughing typical of dogs with MVD is due to their airways being disrupted by the enlargement of their hearts associated with the MVD.
February 2013: Dr. Oyama hints at new diuretic for MVD. In an interview with AKC's Canine Health Foundation, board certified cardiologist Dr. Mark Oyama of University of Pennsylvania's veterinary school, said:
"Thus far we have high hopes that a new diuretic offers distinct advantages over furosemide, which is the most commonly prescribed diuretic in dogs with heart failure. We are working to establish the efficacy and safety of this diuretic in preparation of planning clinical trials to evaluate its effects as compared to furosemide."
January 2013: Potential Adverse Effects of Omega-3 Fatty Acids in Dogs. Texas researchers report potential adverse effects of Omega-3 fatty acids, including altered platelet function, gastrointestinal adverse effects, detrimental effects on wound healing, lipid peroxidation, potential for nutrient excess and toxin exposure, weight gain, altered immune function, effects on glycemic control and insulin sensitivity, and nutrient-drug interactions. They found that adverse effects are likely to be dose-dependent, which is a significant factor to take into account when weighing the value of this report.
The same enzymes are involved in metabolism of omega-6 and omega-3 fatty acids, resulting in competition between these fatty acids for incorporation into cell membranes and other biological properties. Because diets with alpha-linolenic acid (ALA) have different effects when compared with diets enriched in EPA and DHA, the type of omega-3 fatty acids is crucial information. There are potential risks associated with usage of omega-3 fatty acids.
Clinicians and dog owners alike should understand the adverse effects that may occur with omega-3 fatty acid supplementation, and that potential risks should be assessed in conjunction with the potential benefits. A lesson from this study is that owners should be cautious when using fish oil supplements in the presence of certain concurrent serious diseases such as pancreatitis, thrombocytopenia, and diabetes.
November 2012: Report finds that CKCSs with MVD have higher concentrations of collagen and urinary aldosterone than other breeds. In a November 2012 report, researchers found that left ventricular heart enlargement in dogs with MVD is associated with a decrease in the serum concentration of a marker of collagen type III turnover, and an increase in urinary aldosterone concentration (UAC). They also reported that both serum N-terminal procollagen type III concentration and UAC were higher in Cavalier King Charles Spaniels than in other breeds when other measured variables were controlled for.
October 2012: Spanish researchers devise new method of measuring heart enlargement. A team of primarily Spanish researchers have devised a "simplified vertebral heart scale computation method (Objective VHS)" for determining the extent of enlargement of dogs' hearts affected by mitral valve disease. At least, they claim it is "simplified" and "objective". In their October 2012 report, they assert to have improved upon the Buchanan VHS devised by Dr. James Buchanan in 1995. However, their method requires a mathematic formula to convert their measurements to compare with the Buchanan VHS method. So, whether or not the new Objective VHS method really is "simplifed" may be in the eyes of the beholder.
September 2012: Swedish study shows cavaliers tend to have higher heart rates than Labrador retrievers. A September 2012 study of 33 CKCSs, compared to 41 Labrador retrievers and 15 Dachshunds, by Swedish vets, showed that blood pressure and heart rates for all breeds were higher when owners were not present, and that cavaliers had higher heart rates than Labradors in most settings. The researchers recommend that the dogs' owners be present during blood pressure and heart rate recordings. And as usual, they recommend further studies.
September 2012: NC State Drs. Meurs and Stern plan study of genetics of heart valve degeneration in CKCSs . Board certified cardiologists Kate Meurs (left) and Josh Stern of North Carolina State University veterinary school are beginning a study of the genetics of heart valve degeneration in the cavalier King Charles spaniel. They plan to examine dogs by echocardiograph, DNA, and pedigree. Their goal is to provide a new MVD breeding protocol. Cavaliers of the Northeast (CNE) is cooperating in this study, which begins on October 21, 2012 by examining dogs at the CNE show in Parsippany, NJ. Ideal dogs for the study are (a) young and MVD-affected (moderate to severe MVD) and (b) 8 years and older with no MVD. However, the researchers are interested in examining CKCSs of all ages, affected and unaffected. All involvement in the study and results of screening are confidential.
August 2012: Dr. Andy Beardow lectures on-line about MVD. For an in-depth on-line seminar about the symptoms, diagnosis, progression, and treatment of mitral valve disease, watch Dr. Andrew Beardow, with his terrific active graphics, explain MVD.
July 2012: International team of cardiologists conclude the mean average sleeping respiratory rate of healthy dogs is less than 30 breaths per minute. In the October 2012 issue of Research in Veterinary Science, an international group of veterinary cardiologists, M. Rishniw, I. Ljungvall, F. Porciello, J. Häggström, and D.G. Ohad, observed that respiratory rate monitoring of cardiac patients is recommended by many cardiologists, but that little objective data exist about respiratory rates in apparently healthy dogs when collected in the home environment. They measured the sleeping respiratory rates in 114 apparently healthy dogs. The found that apparently healthy adult dogs generally have mean sleeping respiratory rates less than 30 breaths per minute and rarely exceed that rate at any time.
May 2012: Japanese surgeons report on mitral valve repairs of 48 dogs. A team of 16 Japanese veterinary heart surgeons published their report on 48 mitral valve surgeries on small-breed dogs, including cavaliers. They performed mitral annuloplasties and replaced the chordae tendineae with a carbon and fluorine based synthetic polymer, expanded polytetrafluoroethylene chordal prostheses. 45 of the 48 dogs survived to discharge. In 3 months, murmurs were reduced to as low as 0/6; heart enlargement was reduced; mitral valve regurgitation was markedly reduced. They concluded that "Mitral valve repair with cardiopulmonary bypass can be beneficial for the treatment of mitral regurgitation in small-breed dogs."
March 2012: Penn's Oyama and Sweden's Lord, et al. correspond about periodic x-rays to predict start of CHF in cavaliers. In a round of letters published in the Journal of Veterinary Internal Medicine, Dr. Mark Oyama of the University of Pennsylvania, and Drs. Peter Lord, Kerstin Hansson, Cristina Carnabuci, Clarence Kvart, and Jens Häggström of Sweden corresponded about the latter's September 2011 article on using periodic x-rays to detect the onset of congestive heart failure in 94 cavalier King Charles spaniels. The Swedish team concluded " The true velocity can only be measured with a relatively short time interval. ... [I]t would require frequent (monthly?) monitoring to measure them. ... [M]easured rate of change was affected by the time interval; VHS was of little use to predict time to onset of CHF; a rise of ∆VHS/month above a selected percentile of the values at the interval preceding the last one might be a useful sign of impending CHF; combining interval likelihood ratios for VHS and ∆VHS/month greatly improved the accuracy of diagnosis of CHF. The study shows the value of incorporating the element of time dependency from serial measurements as rate of change, a summary of the response over time of each subject." Read Oyama's letter here and Lord's letter here.
March 2012: UK cardiologist reports on MVD research status. Professor Brendan Corcoran (right), professor of veterinary cardiopulmonary medicine at the Royal (Dick) School of Veterinary Studies in Edinburgh, Scotland, issued his school's Spring 2012 report on the status of the school's research into MVD in the cavalier. He listed them as follows:
1. The genetics of MVD in the CKCS: we have recently published a report supporting the long held view that if inherited in some CKCSs, it is a polygenic (involves many genes) rather than monogenic (one gene) trait. This study is being followed up with a much bigger study which will look at CKCSs that have MVD and are clinically affected, older CKCS with murmurs that are never clinically affected and older CKCSs that never develop murmurs.
2. Pathology of MVD specific to the CKCS: MVD in the CKCS is the same as that for all other breeds of dogs and we plan to present and publish this data as soon as possible. This finding suggests that the early onset of disease in the CKCS, and not the disease itself, is the feature specific to the breed.
3. Novel genes in MVD: We have looked at what genes and proteins are active in the valves themselves (not the same as the genetics of inheritance). The opportunity now exists to look at this more closely with greater accuracy and for it to be affordable. The opportunity now exists to look at a range of genes we suspect might be involved in MVD more closely with greater accuracy and for it to be affordable. The hoped aim is that this will give a better idea as to potential drug targets that could be used to control or even reverse valve pathology.
4. Cell culture systems and tissue engineering: We are actively exploring growing valve cells in the laboratory and taking that one step forward and growing complete valves. This is known as tissue engineering. It allow us to examine ideas on why MVD happens in a controlled laboratory environment. From that we can then try and extrapolate to the real patient, asking questions we would never be able to ask in the live animal. With these artificial valves (see photo at left) we are now able to examine what happens when heart valves are damaged and how valve respond to damage and how might they repair.
For more information, see Dr. Corcoran's full report at the UK Cavalier Club's website.
February 2012: Penn researchers report torsemide appears more effective than furosemide as MVD diuretic. University of Pennsylvania vets, including Gordon D. Peddle and Mark A. Oyama, compared doses of torsemide and furosemide in treating seven dogs with stable congestive heart failure. They found in their 2012 report that "torsemide is equivalent to furosemide at controlling clinical signs of CHF in dogs and is likely to achieve greater diuresis vs. furosemide." See also this October 2011 study of torsemide.
February 2012: Texas A&M researchers find carvedilol "well tolerated" in treating cavaliers with pre-clinical MVD. In a 2012 report, Drs. Sonya G. Gordon, Ashley B. Saunders, Matthew W. Miller and others studied the effect of carvedilol in treating 33 cavaliers and 5 other dogs with Stage B2 MVD (meaning, asymptomatic but with significant valve regurgitation and left-sided heart enlargement). They found no adverse effects and median survival of 48.5 months.
February 2012: Japanese surgeons find Gore-Tex works as mitral valve chord and leaflet replacement. Japanese veterinary surgeons report in a February 2012 article that using an artificial mitral valve chordae tendineae and valve leaflet implant made of expanded polytetrafluoroethylene (ePTFE) "has excellent tissue compatibility and durability and can be effectively used for canine mitral valve repair." ePTFE is made of a carbon and fluorine based synthetic polymer (e.g., Gore-Tex and SoftForm) that is biologically inert and non-biodegradable in the body.
February 2012: An intriguingly titled article, "Myxomatous mitral valve disease in dogs: Does size matter?", wastes our time. Two researchers published this article in the Journal of Veterinary Cardiology, which would lead one to believe that they have something to add to our quest to solve early-onset MVD in the cavalier. Alas, they waste our time. The lesson learned is that if a title has a question mark in it, the authors have no answers. Read excerpts here.
January 2012: UK cardiologists to compare MVD murmurs with echocardiograms of 200 CKCSs. UK cardiologists Simon Swift and Anne French announced that they will study in detail the incidence of MVD is 200 mature cavaliers, using echocardiography in combination with auscultation. They will evaluate the heart valves and heart chamber sizes. They also intend to collect DNA for analysis.
November 2011: UK's Royal Veterinary College seeks cavaliers with asymptomatic MVD for cardiac MRIs. Drs. Julia Sargent, Virginia Luis Fuentes, and Holger Volk are leading a research team at Queen Mother Hospital for Animals which is enrolling cases for a cardiac MRI (cMRI) clinical study in order to validate a new echocardiographic scoring system for assessing the severity of degenerative mitral valve disease in asymptomatic dogs.
They have developed the new echocardiographic scoring system, based upon
a number of different measurements that they believe can offer more reliable
information on the severity of MVD than current echo protocols. They are
testing their new scoring system by comparing it to cardiac magnetic
resonance imaging (cMRI), which is considered the most reliable test for
quantifying valve disease in humans.
Due to the necessity of anaesthetizing the dogs for the cMRIs, the researchers want to recruit dogs already scheduled for MRIs for other reasons, such as syringomyelia examinations. All dogs will undergo conventional echocardiography to assess their heart disease prior to anaesthesia and the MRI scan, and only dogs with stable heart disease will be recruited.
The researchers expect to be able to provide more accurate information for the individual dogs on the severity of their valve disease as a result of the MRI scan, and new echo score. They believe that the scoring system should be particularly useful for standardizing the severity of MVD at entry for clinical studies. Contact Dr. Sargent at firstname.lastname@example.org and Dr. Luis Fuentes at email@example.com
November 2011: UK researchers fail to find genetic differences between early-onset and late-onset MVD in cavaliers. A team of UK cardiologists and geneticists divided 36 CKCSs into groups of early and late onset MVD and assessed whether the distinction is determined by a small number of genetic factors. They report that they came up dry. They concluded:
"There were no regions of highly discrepant homo/heterozygosity in the two groups. Similarly, there was no evidence for loci associated with mitral valve murmur in a genome-wide association study. This analysis suggests that familial occurrence of mitral valve murmur in the CKCS breed is not due to a single major gene effect, indicating that breeding strategies to eliminate the disease cannot be based on genotype information at this time."
This seems to contradict a much more successful report issued in September 2011 by a team of veterinarians from Denmark, Sweden, Germany, England, and France. They reported that they identified two specific locations on cavaliers' chromosomes CFA13 and CFA14 which are associated the breed's hereditary mitral valve disease. They grouped 139 cavaliers with early-onset MVD and 102 old CKCSs with no or mild signs of MVD as controls. Then they conducted a genome-wide association study to find specific locations associated with development of MVD. Read more here.
October 2011: Univ. of Penna. cardiologists study torsemide as alternative to furosemide. University of Pennsylvania veterinary cardiologists report that they have tested the loop diuretic torsemide as alternative to furosemide in dogs with advanced heart failure, including a 12 year old cavalier. They have found torsemide "has several characteristics that make it suitable for treatment of advanced heart failure including longer half-life, increased potency of diuretic action, and anti-aldosterone effects." See also this follow-up report in February 2012.
September 2011: Swedish researchers find periodic x-rays of cavaliers can detect onset of congestive heart failure. A team of cardiologists at the Swedish University of Agricultural Sciences, including Drs. Kvart and Häggström examined periodic x-rays of 94 CKCSs to determine the value of the vertebral heart scale and its rate of increase per month, to predict the onset of congestive heart failure. They concluded in their report that the monthly rate of increase in heart size along the veterbral heart scale was a useful measurement for that purpose. They found that radiographic vertebral heart size (VHS) changes most rapidly in the period of time immediately preceding development of congestive heart failure (CHF). In the 8.6 months preceding CHF, the VHS changed by an average of 0.17 vertebra/month as compared to 0.03 vertebra per month during earlier intervals. This finding raises questions regarding the appropriate timing of radiographic examinations..
September 2011: International study finds specific genetic locations for mitral valve disease in cavaliers. A team of veterinarians from Denmark, Sweden, Germany, England, and France report they have identified two specific locations on cavaliers' chromosomes CFA13 and CFA14 which are associated the breed's hereditary mitral valve disease. They grouped 139 cavaliers with early-onset MVD and 102 old CKCSs with no or mild signs of MVD as controls. Then they conducted a genome-wide association study to find specific locations associated with development of MVD. Read more here. They also stated:
"We will initiate studies of the most promising candidate genes in the 2 candidate regions which hopefully will lead us to the mutations affecting the development of mitral valve disease."
August 2011: UK researchers conclude that leptin may play a role in canine cardiac disease. In an August 2011 report, a panel of UK cardiologists examined the relationship which leptin (a protein produced by dogs' fat cells) may have with MVD and other forms off cardiac disease. They found that dogs in congestive heart failure had significantly higher blood concentrations of leptin than dogs without cardiac disease. They concluded that leptin may "play a role in canine cardiac disease."
August 2011: Belgium researchers find that spironolactone did not extend survival times of dogs with advanced heart failure. See report citation and abstract.
July 2011: Dr. E. Christopher Orton, board certified veterinary surgeon at of the James L. Voss Veterinary Teaching Hospital at Colorado State University (CSU) in Ft. Collins, Colorado and board certified veterinary cardiologist Dr. Allison K. Adams have been conducting clinical trials replacing the mitral valve with an artificial heart valve called MitralSeal. This mechanical valve is designed to be installed using a minimally invasive approach into the beating heart. For details, click here. Dr. Orton may be reached by telephone at 970-297-1250, and e-mail at firstname.lastname@example.org and Dr. Allison's email address is email@example.com
July 2011: Bayer's HECTOR Study fizzles out. Bayer Animal Health's HECTOR Study of a beta-blocker to treat MVD has quietly ended without success. The study, conducted since August 2009 (see introduction announcement) among at least eight veterinary schools and specialty clinics throughout the United States, has ended prematurely due to the interim statistics showing no significant difference between the beta-blocker and the placebo in extending time between grade 3 murmur and onset of heart failure.
June 2011: Cytokine concentrations may indicate MVD progression in CKCSs. In a study of 41 cavaliers and 27 other dogs, Danish and Swedish cardiology researchers have found that certain cytokine concentrations either increase or decrease as the cavaliers' hearts enlarge due to MVD or mitral regurgitation increases. Cytokines are proteins released by cells that effect interactions between cells. The researchers have concluded that there may be a role for cytokines in canine MVD and congestive heart failure.
June 2011: Enlarged heart size reduced after mitral valve replacement surgeries in Japan. Dr. Masami Uechi reports to the ACVIM that mitral valve repair surgeries of 50 dogs with heart enlargement, overall the heart rate decreased and mitral regurgitation reduced, resulting in reduction of the enlargement of the hearts.
June 2011: Advanced electrocardiography can predict severity of MVD in cavaliers. In a June 2011 study by Slovenian and Danish researchers, they were able to use advanced ECG to predict the severity of mitral regurgitation in dogs with MVD. They reported:
"Our results indicate that for a cut-off criteria of MR [mitral regurgitation] 50% jet the five selected ECG parameters could predict the severity of MR caused by MMVD in CKCSs with sinus rhythm with sensitivity 65% (78% with age inclusion) and specificity 98% (92% with age inclusion) (P < 0.05)."
March 2011: Holter monitoring study shows CKCSs have significantly higher heart rates than other small breeds. University of Copenhagen researchers obtained Holter recordings from 54 clinically healthy dogs: 23 cavaliers ("at high risk to develop MVD"), 18 wired-haired Dachshunds ("at moderate risk"), and 13 Cairn terriers ("at low risk"), to compare Holter readings between CKCS and the other breeds. The results showed that the cavaliers had "significantly higher" heart rates. They concluded: "However, further studies are required to clarify the possible influence of high HR [heart rate] in the development of MMVD in CKCS." Read more here.
February 2011: Vetmedin's EPIC trial begins. Pimobendan's developer and manufacturer, Boehringer Ingelheim GmbH, a German pharmaceutical company, which markets the drug under the registered brand name Vetmedin, has enlisted thirty-six board certified veterinary cardiologists throughout four continents, including eighteen in the United States and one in Canada, to participate in a long term study of 360 dogs with mitral valve murmurs, to determine if pimobendan can delay the onset of signs of congestive heart failure. The study, called "EPIC" (for "Evaluating Pimobendan in Cardiomegaly") by the sponsor, is expected to conclude in 2015. Half of the 360 MVD-affected dogs will be given a dose of pimobendan twice daily, while the other 180 MVD-affected dogs will be given a non-medicated placebo until they reach congestive heart failure.
[NOTE: In an April 2011 editorial, CavalierHealth.org has warned against cavaliers participating in this EPIC study, due to the unacceptable risk of the too-early administration of pimobendan to dogs which are not yet in congestive heart failure. If your cardiologist suggests that your cavalier participate in this EPIC Trial, beware and proceed at your dog's risk.]
January 2011: EuroVet offers pimobendan in the UK as "Cardisure". EuroVet Animal Health has introduced pimobendan tablets under the brand name "Cardisure". It also is available in Belgium, Germany, and the Netherlands. See the press release here.
December 2010: Cleveland Clinic researchers find new mitral valve implant device is effective in significantly reducing regurgitation and valve opening dimensions without requiring bypass surgery. In a December 2010 report (following up on this January 2010 report), the same team of Cleveland Clinic researchers inserted the Mitral Touch epicardial annuloplasty device in 13 dogs. All implants took no more than 30 seconds to install. The results were that the mitral regurgitation (MR) grades were reduced, as was the septal-lateral (S-L) dimension of the mitral annulus (the ring that is attached to the mitral valve leaflets). They stated that additional studies are necessary to confirm the long-term maintenance of MR and S-L reductions."
December 2010: Dr. Oyama studies links between cavaliers' giant platelets and MVD. Dr. Mark A. Oyama of the University of Pennsylvania is continuing his research into links between cavaliers' giant platelets and the breed's high incidence of mitral valve disease. His previous research has shown that CKCSs have elevated levels of serotonin (5-HT). The hypothesis is that 5-HT signaling is an important component of MVD in dogs. He suspects that the source of elevated serum 5HT is the blood platelets, since platelets are believed to contain 99% of all circulating 5-HT. It has been recently shown that platelet contents can activate disease changes within the heart muscle of experimental animals. The platelet, heart muscle, and valve-specific content of 5-HT in dogs with heart disease has not been previously reported. Dr. Oyama wants to determine if platelet 5-HT is the source of elevated serum 5-HT in cavaliers with MVD, as well as to quantify the amount of 5-HT in both the left ventricular muscle and mitral valve leaflets of affected dogs. His report is due in December 2011.
October 2010: Vetmedin's "EPIC Trial" has begun. UK cardiologists are conducting a study (the "EPIC Trial") giving Vetmedin (pimobendan) to cavaliers with low grade MVD murmurs to see if the drug will slow the progression of MVD to congestive heart failure. About 300 dogs are participating, with half receiving pimo and the other half a placebo.
October 2010: Japanese cardiologists successfully perform open heart MVD surgery on small dogs, using deep surface-induced hypothermia (sHT) and low-flow cardiopulmonary bypass (CPB). See report summary.
September 2010: Swedish study shows watered-down MVD breeding protocol may not be working. Sweden's Kennel Club and its CKCS Club introduced a watered-down, but mandatory version of the MVD Breeding Protocol in 2001. In this program, dogs are not allowed to breed until four years of age and need a heart auscultation without murmurs within eight months before mating. However, dogs are allowed to breed at an age of 24 months, if the dog and its parents are examined and no murmurs are detected. Male dogs that have a heart auscultation at seven years of age without murmurs are allowed to breed without further heart evaluation. Breeding animals whose parents have heart murmurs before four years of age are not allowed to breed. The result from Dr. Clarence Kvart's investigation indicates that the prevalence of MMVD in six-year-old cavalier King Charles spaniels, born 2001 and 2003, is at least 50% and lacks signs of decrease despite the current breeding program introduced in Sweden 2001.
As a result, the Swedish clubs are considering toughening their relaxed protocol to follow the MVD protocol recommended by Lennart Swenson in 1998.
July 2010: NC State's veterinary college seeks dogs with mild heart murmurs for activity study. The school's press release states: "Does your dog have a heart murmur? If so, he may be eligible for a new study of heart disease! We are enrolling dogs with early heart disease into a clinical trial to measure their activity at home. We will record their activity with a small device (the size of a quarter) that is attached to their collar. Activity will be recorded before, and during treatment with a medication used to treat heart disease. Requirements: The study will require an outpatient appointment with the cardiology service at the Veterinary Teaching Hospital. Your dog will then wear the collar/activity recording device for two weeks, then for another two weeks after twice-daily medication is started. Benefits to you: The study will pay $300 towards the cost of an evaluation by the cardiology service and the cost of the medication. The evaluation includes an extensive health screening. By comparing your pet’s activity before and after addition of the medication, and by comparing activity with that of a similar dog without heart disease, we hope to be able to measure any increase in your pet’s activity and vigor when treated with the medication." Contact Andrea Thomson, telephone 513-513-6854, email firstname.lastname@example.org
May 2010: Dr. Sarah Blott issues her first report on using estimation of breeding values (EBVs). She writes in her May 2010 article:
"EBVs will allow breeders to distinguish between potential parents of high and low risk, after removing the influence of life history events. Analysis of current population structure, including numbers of dogs used for breeding, average kinship and average inbreeding provides a basis from which to compare breeding strategies. Predictions can then be made about the number of generations it will take to eradicate disease, the number of affected individuals that will be born during the course of selective breeding and the benefits that can be obtained by using optimisation to constrain inbreeding to a pre-defined sustainable rate."
April 2010: Univ. of Pennsylvania MVD researchers need blood samples for gene study. The researchers are seeking to identify gene variation, and to verify it as the actual cause of MVD in the breed. Dr. Paula Henthorn asks for blood samples from cavaliers in these categories:
4CKCS with Grade 3 or louder murmur (by cardiologist) at age 5 years or younger.
4CKCS with no murmur (by cardiologist) at age 9 years or older.
4Older dogs which currently have a murmur but were cardiac clear at 9 years of age can be enrolled as long as a copy of the clearance at 9 years of age (or greater) is available.
If possible, they would also like a copy of the pedigree, but it is not necessary for enrollment. Click here for further information and the enrollment form.
If you are interested in making a financial donation to this research project, please send a check written to “Trustees of the University of Pennsylvania” with “Cavalier heart fund” in the memo to Dr. Paula Henthorn, Veterinary Hospital – Room 4033, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA 19104-6010; email: email@example.com; telephone 215-898-8894; fax 215-573-2162. Donations are tax deductible. See also the September 2007 entry below for additional information about this research project.
March 2010: UK researchers report early-onset MVD is "highly heritable" in cavaliers. Drs. Tom Lewis, Simon Swift, John A. Woolliams, and Sarah Blott also found that "selection against the disease should be successful." See report summary.
March 2010: Swedish MVD researchers find cavaliers' most rapid heart enlargement only in last year before congestive heart failure. Drs. Clarence Kvart, Jens Häggström, and others studied 24 cavalier King Charles spaniels with MVD for the rate of change of their heart size before congestive heart failure. They found in their research journal article that "The left heart chambers increase in size rapidly only in the last year before the onset of congestive heart failure."
March 2010: Two recent studies examine connection between cardiac troponin I (cTnI) concentrations and severity of MVD. In a UK study soon to be published in The Veterinary Journal, 120 dogs, including cavaliers, were enrolled, and in a Swedish study in the Journal of Veterinary Internal Medicine, 81 dogs, including 67 CKCSs, were studied. Both groups observed that increases in cTnI concentrations in dogs with poor prognoses, and both also concluded that cTnI has potential in assessing the prognosis and severity of MVD and enlargement of the heart. Both reports also recommend more detailed future studies.
January 2010: Surgically implanted device reduces dimensions of the mitral valve opening and eliminates mitral regurgitation without surgical bypass. In a January 2010 report by a Cleveland Clinic medical team, an epicardial mitral annuloplasty device (right) was implanted on the beating hearts of two dogs in less than 30 seconds. The device reduced the septal-lateral (S-L) dimension of the mitral annulus (the ring that is attached to the mitral valve leaflets) dimension and eliminated mitral regurgitation without requiring the use of a cardiopulmonary bypass. The device, called Mitral Touch, is manufactured by MAQUET Cardiovascular LLC of San Jose, California.
January 2010: Dr. Mark Oyama summarizes research into the possible roles of serotonin (5HT) and transforming growth factor-b in transforming valvular interstitial cells (VIC) into a more active myofibroblast, which is an important component of MVD in cavaliers. See his "insights". Also check out his September 2009 entry, below. Dr. Oyama also suggests that ketaerin, a 5HT-R2A receptor blocker, or GR55562, a 5HT-R1B receptor blocker, may be effective in dealing with serotonin's affect on dogs' mitral valves.
December 2009: Research physicians at the University of Pittsburgh conduct experimental mitral valve repairs on dogs, using radiofrequency ablation (RFA). The RFA energy is applied to the deteriorating valve flaps and chords, resulting in controlled damage which has the affect of qualitatively reducing the leaflet surface and the chordal length. The researchers found that the result of the application of RFA was to reduce the mitral regurgitation by statistically significant amounts. Read the details below.
November 2009: ACVIM's "Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease". A panel of board certified veterinary cardiologists have published a "Consensus Statement, classifying the stages of MVD and the recommended treatment at each stage.
September 2009: The Serotonin Concentration Studies Continue. "Healthy CKCS dogs had significantly higher serum [serotonin] 5HT concentrations than other healthy dogs predisposed to DMVD [degenerative mitral valve disease]," concludes the University of Pennsylvania team studying serontonin's connection to mitral valve disease (see the January 2009 Current Research entry below) in its report to be published in the November/December 2009 issue of the Journal of Veterinary Internal Medicine. They also found that "Dogs with DMVD had significantly higher serum 5HT concentrations when compared with large breed control dogs."
August 2009: Researchers need dogs with Grade 3 heart murmurs. [NOTE: See July 2011 entry: "HECTOR Study fizzles out"] HECTOR Study: Free screening tests -- a consultation ,an echocardiogram, chest radiographs, blood sample analysis and ECG -- are included. At several veterinary schools, the University of Pennsylvania's Veterinary Hospital (VHUP), in Philadelphia, PA, Washington State University's veterinary medicine's cardiology department, in Pullman, WA, the University of Missouri's veterinary medicine teaching hospital, in Columbia, MO, North Carolina State University's veterinary medicine cardiology department in Raleigh, NC, Cornell University's veterinary medicine cardiology department in Ithaca, NY, and Texas A&M University's (TAMU) veterinary medicine's cardiology department, in College Stations, TX, as well as the Animal Medical Center in New York City, and the MedVet Medical and Cancer Center for Pets in Worthington, Ohio, are recruiting dogs for a study evaluating a beta-blocker to treat heart disease due to MVD. All breeds are eligible. The dogs must have at least a Grade 3 murmur, be at least a year old, and have never had any clinical signs of heart disease of any kind.
Dogs included in the study will receive the beta-blocker or placebo, and will be required to return for rechecks four times the first year and twice yearly each year after. The study's title is “Clinical Evaluation of the Efficacy and Safety of a Beta-blocker Medication used to Treat Heart Disease due to Chronic Valvular Heart Disease”.
The beta-blocker being tested is not one of the ones commonly being prescribed and is administered in liquid form. It is a selective andrenoceptor blocker, identified as BAY 41-9202. The researchers hope to have up to 400 dogs participate in the study, over up to a four year period. The study is sponsored by Bayer Animal Health.
June 2009: Japan Surgeons Report Successful Repairs to CKCS Mitral Valves. Nihon University veterinary surgeons have been conducting "mitral valve plasty" surgery on cavalier King Charles spaniels and other small dogs since 2006. Mitral valve plasty involves suture repairs to the mitral valve leaflets and includes the insertion of artificial chords made of a polymer, expanded polytetrafluoroethylene (e-PTFE). They report in a 2009 journal article, "Mitral Valve Plasty in 11 Cavalier King Charles Spaniels", that "these results suggest that mitral valve plasty is beneficial in CKCS with MVD."
While two of their CKCS patients died during the post-operative study due to complications, and three were diagnosed with syringomyelia, the researchers found that among the nine survivors, "at 1 and 3 months after surgery, the left atrial to aortic root diameter ratio ... and the plasma atrial natriuretic peptide level ... were lower than those before surgery ... There were also significant improvements in the number of prescribed cardiovascular drugs 1 month after surgery ... and in the cardiac murmur grade ... ."
January 2009: Colorado State Univ. researchers to test drug inhibiting serotonin in mitral valves. Dr. E. Christopher Orton of the of Colorado State University's James L. Voss Veterinary Teaching Hospital and its Animal Heart Center in Ft. Collins, Colorado, and Dr. Sirilak Disatian, have issued a report on their study begun in June 2008, "Autocrine Serotonin and TGF-beta Signaling in Human Myxomatous Mitral Valve", which has been sponsored by the American Heart Association. The researchers have found that serotonin is created locally in heart mitral valves, thereby causing pathologic changes in the valves, resulting in their malfunction.
Serotonin is made by an enzyme called tryptophan hydroxylase 1 (TPH1). Serotonin then goes into the blood stream where it is picked up by platelets which are involved in blood clotting. Orton's group has shown that TPH1 is present in high levels in abnormal mitral valves from both dogs and humans.
Dr. Orton's group is seeking to find what triggers the enzyme in the valve which produces the serotonin. He plans to start a clinical trial on dogs to examine the impact of a drug that inhibits the enzyme that produces serotonin in the heart.
See also June 2008 entry for Dr. Mark Oyama.
October 2008: UK Kennel Club to Add "Health Plan" to Cavalier King Charles Spaniel Breed Standard. The (UK) Kennel Club announced that it will include a "breed health plan" in the CKCS breed standard, to "ensure that no dog is bred for features that might prevent it from seeing, walking and breathing freely." A meeting to include representatives of the UK's cavalier club and cardiologists is set for December 1. The club expects to issue the CKSC health plan by early 2009.
The UK club also is asking the UK government to "give it statutory powers to make its established Accredited Breeder Scheme compulsory throughout the country. If successful, this would mean that all breeders who are not part of the scheme and who have not officially confirmed their willingness to follow the health standards set by the Kennel Club would be unable to produce or sell puppies within the law." Additionally, the UK's cavalier breed club is "now required to adopt the Kennel Club's Code of Ethics, to ensure that their practices fall in line with Kennel Club policy for putting the health and welfare of puppies first. This includes a clause that explicitly forbids the compulsory culling (killing) of healthy puppies." See website www.thekennelclub.org.uk
September 2008: UK Kennel Club and British Veterinary Association Plan Possible Heart Testing Protocol for Cavalier Breeding Stock. On September 15, 2008, the UK Kennel Club and British Veterinary Association representatives met with representatives of UK cavalier King Charles spaniel clubs to discuss introducing a heart testing scheme, which would be applied to CKCS and three other breeds. The test results would be published in the Kennel Club's breed registration quarterly supplements and on the progeny's registration certificates. The group plans to meet again in December to consider adopting the scheme. The UK Kennel Club also is looking at ways by which breeders could access health results of dogs/ bloodlines. This service will be available to breeders and pet owners.
July 2008: ACVIM Announces "ARCH" -- New Registry of Cardiac Health. The board certified cardiologists of the American College of Veterinary Internal Medicine (ACVIM) have introduced a new registry, ARCH, to certify dogs' hearts are clear of mitral valve disease and other genetic heart disorders. ARCH certifications are issued only by board certified veterinary cardiologists. Look for the ARCH symbol and check out the website.
June 2008: Serum Serotonin Concentration Is Elevated in CKCSs. University of Pennsylvania Drs. Jason W. Arndt, Mark A. Oyama, and C. A. Reynolds have completed initial research showing that CKCSs have higher levels of serotonin (5-HT) than other breeds which are pre-disposed to MVD. (CKCS, 903.9 [321.5] ng/ml vs. non-CKCS, 536.0 [153.7]; P50.004). The team studied 51 dogs, including 32 cavaliers, which either were affected with or pre-disposed to MVD (CKCSs as a breed are pre-disposed to MVD), plus 28 control dogs. They report: "In humans, elevated serotonin (5-HT) is associated with development of valvular lesions. Canine mitral valve cells demonstrate dose-dependent 5-HT-mediated ERK1/2 signaling, suggesting a possible link with canine DMVD. ... Our results suggest that 5-HT may play a role in the development of DMVD in small breed dogs, and in particular in the CKCS. Further studies involving the relationship between 5-HT, DMVD, breed, and platelet number, morphology, and function are warranted."
Meanwhile, at Colorado State University, Dr. E. Christopher Orton of the of CSU's James L. Voss Veterinary Teaching Hospital and its Animal Heart Center in Ft. Collins, Colorado, has started a study, "Autocrine Serotonin and TGF-beta Signaling in Human Myxomatous Mitral Valve", which is sponsored by the American Heart Association.
May 2008: Auburn University Researchers Find Possible Link Between Oversized Platelets and MVD in Cavaliers. A team of researchers at Auburn University in Alabama (Drs. B. Davis, M. Toivio-Kinnucan, S. Schuller, M.K. Boudreaux) determined that "a mutation in the gene encoding β1-tubulin correlated with macrothrombocytopenia in CKCS." They concluded that "this information will aid in distinguishing inherited from acquired thrombocytopenia. It also provides insight into the mechanism of platelet production by megakaryocytes, and also may prove useful in understanding heart-related changes in macrothrombocytopenic CKCS with concurrent mitral valve regurgitation." See citation below.
May 2008: Researchers Need Heart Tissue From Deceased MVD Canines. Dr. Allison M. Heaney, board certified veterinary cardiologist, heads a research program at the College of Veterinary Medicine at Washington State University studying the difference in the balance between these proteins affecting collagen in normal cultured mitral valve cells and mitral valve cells cultured from diseased leaflets. Differences that exist between normal and diseased valve cells will help target future research projects and aid in determining the cause of the breakdown of collagen in diseased valve cells.
Dr. Heaney is requesting mitral valve tissue from dogs of any breed that have died or have been euthanized that have significant degenerative MVD. The valve tissue will be used to culture cells from the tissue in order for the researchers to study the disease from a cell culture perspective. For inclusion in the study, dogs need to have a diagnosis of degenerative mitral valve disease from their veterinarian (if echocardiography findings are available, those should be provided as well) and the owner needs to be willing to let their referring veterinarian remove the mitral valve from the dog after it dies or is euthanized. The tissue should be removed within 2 hours of death or euthanasia.
She requests that the anterior mitral valve leaflet (the larger leaflet most associated with the septum and aorta) -- but if there is any confusion the entire mitral valve can be shipped and they can collect the anterior mitral valve leaflet once it arrives here. The sample should be shipped in phosphate buffered saline. If needed, the researchers can ship tubes of phosphate buffered saline for sample collection. The sample should be shipped on ice overnight to the address below. For more information, contact Dr. Heaney or her research technician, Marsha Robertson, at Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University 100 Dairy Road, Pullman, WA 99164-1120, telephone 509-335-0711, fax 509-335-0880, email firstname.lastname@example.org, websites: www.vetmed.wsu.edu.This study is supported by AKC Canine Health Foundation, webpage www.akcchf.org/news/index.cfm?article_id=249
May 2008: DNA Project Needs UK Cavaliers. Simon Swift, MA VetMB Cert SAC MRCV, at the University of Liverpool, heads a DNA study of cavalier King Charles spaniels. The study is based upon a novel genetic method intended to discover the genes behind mitral valve disease in the CKCS. The researchers need 100 cavaliers with early onset MVD (defined as developing mitral insufficiency before age 4 years or developed signs of heart failure before 8 years) and 100 CKCSs with late onset MVD (dogs over 10 years without a murmur or with very mild mitral insufficiency). The group also is currently working to locate qualified dogs in Sweden and Denmark, as well as the UK.
If you live in the UK and have a dog which meets these standards, contact Mr. Swift about obtaining blood samples and pedigrees: (1) Dogs under 4 years with a loud murmur. (2) Dogs under 8 years that have developed heart failure. This does not necessarily mean a cough. They should also have breathlessness, weight loss, and exercise intolerance. They should also need medication. (3) Dogs over 8 years with no murmur or a very quiet one. A cardiologist should examine the dog. There will no charge if the examination is coordinated with Mr. Swift at a participating centre. The researchers are prepared to travel to examine large groups of dogs. The team is rganising a health clinic in Bagworth on September 27, 2008. If you can attend with a suitable dog, please bring your pedigree.
You may contact Mr. Swift at: Small Animal Teaching Hospital, The University of Liverpool. Leahurst, Chester High Road, Neston, Cheshire CH64 7TE; telephone (0151) 795 6100, fax: (0151) 795 6101, email email@example.com, website www.liv.ac.uk/sath/index.htm
March 2008: Reducing Rejection of Replacement Mitral Valves. Dr. E. Christopher Orton of Colorado State University’s Animal Heart Center in Ft. Collins, Colorado leads a team researching the use of "tissue engineering" to build a better replacement for canine heart valves. “All replacement heart valves in use today are based on non-living tissues and have limitations,” said Dr. Orton in an interview published in CSU's Insight magazine, Spring 2008 issue. “In humans, there are two options, a mechanical valve that requires the patient to be on blood thinners for the rest of their lives, or a bioprosthetic valve, using a pig valve fixed with glutaraldehyde. Humans can tolerate these valves, but dogs not so much. As a species, dogs are more likely to reject foreign tissue.” Dr. Orton’s work focuses on tissue engineering that studies methods for removing antigens from living tissues and repopulating the tissue with the animal’s own cells.
The team is developing new methods for screening a large number of proteins for antigenicity -- the degree to which a substance induces an immune response, across species. To accomplish this, Dr. Orton's team is using proteomics to look at all of the proteins in the tissues used for bioprosthetic heart valves.
Proteomics is a new focus in the field of biotechnology that enables a system-wide analysis of proteins produced by cells. With proteomics, researchers can detect proteins that elicit an immune response, and subsequently identify the protein antigen, categorize the antigens into broad groups according to their origin, and then place them into smaller categories according to structure, type, physical and chemical properties.
By exposing separated proteins to naturally-occurring and acquired antibodies, Dr. Orton seeks to determine which proteins are responsible for the antigenicity of biomaterials, and this knowledge can be used to develop strategies to selectively remove those proteins. This study is expected to provide important insights about the bioprostheses and about tissue transplantation in general.
September 2007: Indentifying DNA markers and altered genes that predispose cavaliers to develop early-onset MVD: Drs. Margaret M. (Meg) Sleeper, Petra Werner, and James Buchanan, of the University of Pennsylvania's School of Veterinary Medicine, are conducting a genetic analysis of CKCS hearts and blood samples, with the goal to identify DNA markers and altered versions of genes that predispose cavaliers to develop early-onset mitral valve disease. The inclusion criteria are CKCSs that develop from grade 3 to grade 6 MVD murmurs before the age of 5 years; and their immediate relatives (parents, siblings, and grandparents); and dogs over age 6 years without murmurs. They are obtaining samples consisting of: 3 mls of EDTA blood. For more information about sending blood samples to this project, contact either the ACKCSC trust's Bettina M. Sterling, email Sterlingtoys@aol.com, or Dr. Werner, telephone number 215-898-8894, email firstname.lastname@example.org. An application form is available by clicking here. Drs. Sleeper and Buchanan are board certified cardiologists. Dr. Buchanan has contributed over sixteen years of his time to research of MVD in the CKCS. Dr. Werner, who has a doctorate in molecular genetics from the University of Zürich, has been leading a team of researchers at the Center for Comparative Medical Genetics and Section of Medical Genetics at the School of Veterinary Medicine, University of Pennsylvania for the past ten years in developing a genetic map of the canine genome.
The American Cavalier King Charles Spaniel Club's charitable trust's Darcy Fund is helping to underwrite this research, and the ACKCSC trust is actively participating in the project by collecting selected blood samples and pedigrees during health clinics around the United States. Financial donations to support this research project may be made by sending checks payable to "Trustees of the University of Pennsylvania", with "Cavalier Heart Fund" in the memo, directly to Dr. Petra Werner, Room 4033, Ryan Veterinary Hospital, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA 19104-6010. Donations are tax deductible.
June 2007: Dogs needed for reduced rate Ohio State study to improve ultrasound imaging for diagnosing congestive heart failure: Dr. Karsten E. Schober of the cardiology department at the Ohio State University's College of Veterinary Medicine in Columbus, Ohio is looking for dogs with diagnosed heart disease to be a part of a non-invasive study titled: "Can better imaging predict heart failure?". The researchers seek to utilize cardiac ultrasound to identify and stage congestive heart failure (CHF) in dogs. Dogs with asymptomatic dilated cardiomyopathy (DCM) and degenerative mitral valve disease (MVD) and dogs with CHF caused by MVD or DCM will be enrolled.
Any dog with DCM or MVD -- unless treated with high doses of diuretics and no concurrent systemic disease -- is eligible. Participating dogs would be examined twice at the Ohio State Veterinary Hospital, five to fourteen days apart. During these two visits, the dogs will be given a complete physical examination, chest x-rays, an echocardiogram, blood pressure measurement, and a blood sample drawn. Benefits for dog owners include low cost examinations (50 percent cost reduction for the first visit and free second visit), short scheduling and waiting times, and important contribution to a research study that can improve the health of dogs. The results of this study may help to earlier diagnose CHF, better stratify cardiovascular risk, tailor therapy to specific dog needs, and reduce the exposure of personnel and animals to the ionizing radiation required for repeated thoracic radiography.
Contact: Dr. Schober, telephone 614-292-3551, email email@example.com, or Laura Spayd, telephone 614-292-3551. Also visit http://www.vet.ohio-state.edu/2404.htm
June 2007: 3-D echocardiographics and image reconstruction of cavaliers with MVD: Dr. Mark A. Oyama at the School of Veterinary Medicine, University of Pennsylvania, is leading a team of investigators to determine whether the heart valves of dogs with MVD possess inherently different geometrical characteristics when compared to those of non-affected dogs. They propose using a novel 3-D echocardiographic technique and specialized image reconstruction to visualize the geometry of the valve annulus and valve leaflets in greater detail. They intend to correlate the valve geometry with disease severity, ventricular function and geometry, and conventional 2-D echocardiographic measurements of mitral valve disease.
June 2007: Pathophysiological aspects of early mitral valve diseases in cavaliers: Dr. Inge Tarnow, at the University of Copenhagen's Department of Animal and Veterinary Basic Sciences, heads a group of specialists studying pathophysiological aspects of early mitral valve disease in cavaliers, including changes in platelet function, hemostatic changes, and prognostic factors. They currently are performing a large longitudinal study of 100 cavaliers with examinations (echocardiographic and blood tests) at ages 2, 4, and 8 years.
June 2007: DNA to discover genes causing MVD. Dr. Clare Rusbridge at the Stone Lion Veterinary Centre in the UK is coordinating an international group of geneticists and other specialists who are researching DNA samples from a variety of categories of cavalier King Charles spaniels throughout the world, in an effort to discover the genes causing mitral valve disease. In an April 2006 research update, Ms. Rushbridge reports that "a full genome scan looking for the causal gene/s of syringomyelia and mitral valve disease is underway!" The Cavalier Health Foundation (associated with the Cavalier King Charles Spaniel Club, USA) has contributed a grant to help underwrite this project. Donations are tax deductible.
Also participating are Marie Pierre Dube, a genetics epidemiologist at the Montreal Heart Institute, and Dr. Zoha Kibar, the molecular geneticist in charge of fine mapping and identification of the gene(s) defective in MVD and syringomyelia in CKCSs, at Centre for the Study of Brain Diseases, CHUM – Montreal. Dr. Kibar reports in the April 2006 update:
"Both Syringomyelia and Mitral valve disease are particularly common in the cavaliers. Such high incidence in a particular breed as compared to other breeds suggests the involvement of genetic factors. The mode of inheritance including the number, identity and relative contribution of the causative genes is not determined yet. The etiology of both conditions could be further complicated by variable penetrance of the various genotypes and the involvement of environmental factors.
"The first step which is genetic mapping is currently underway. Due to the complex inbreeding in the CKCS, a preliminary genetic analysis was necessary to evaluate the informativeness of the genetic markers and hence the feasibility of a whole genome scan in such breed. Consequently, 10 dogs were selected for genotyping with 122 markers distributed among the 38 autosomes and X chromosome. The markers were found to be sufficiently polymorphic and informative. Next, 200 dogs were selected for a whole genome scan, primarily for Chiari malformation. However with additional phenotypic information on mitral valve disease, it is possible to use the same data to map the gene(s) defective in this disease. The whole genome scan was conducted at the Mammalian genotyping Center at the Marshfield Clinic in Wisconsin, USA. The genotyping data will now be analyzed using both linkage-based and association studies. In the latter, we will be taking advantage of the founder effect demonstrated for both these disorders in the CKCS breed.
"This strategy involves: 1) genetic mapping of the underlying gene(s), 2) identification of these defective gene(s) using the positional candidate gene approach and characterization of the mutation(s) and 3) initial functional characterization of the protein(s) encoded by the gene(s). This will help better understand the underlying pathogenic mechanisms for better diagnosis, prognosis and clinical management of these devastating conditions. These studies will also help unravel some of the complexity involved in this malformation in humans and in the embryonic development of the affected structures."
June 2007: Genomic expression patterns of mitral valve tissues from dogs with MVD: Dr. Mark A. Oyama at the School of Veterinary Medicine, University of Pennsylvania, and Sridar V. Chittur, PhD, Center for Functional Genomics, State University of New York at Albany, have published "Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease" in the August 2006 issue of the American Journal of Veterinary Research. Their conclusion is that "Evaluation of global expression patterns provides a molecular portrait of mitral valve disease, yields insight into the pathophysiologic aspects of DMVD [degenerative mitral valve disease], and identifies intriguing genes and pathways for further study."
June 2007: Repairing damaged heart cells by transplanting stem cells: Dr. Mark A. Oyama at the School of Veterinary Medicine, University of Pennsylvania, is investigating whether dogs' damaged heart cells can be repaired by transplanting the dogs' own stem cells into their hearts, a procedure called cardiac cellular transplantation.
January 2007: Studying cellular changes that occur as the mitral valve deteriorates: Dr. Brendan M. Corcoran and Richard Han of the veterinary school at the University of Edinburgh, in collaboration with University College Galway, are conducting studies of the cell type of cavaliers afflicted with MVD, including the cellular changes that occur as the mitral valve deteriorates, assessing affected valves for the presence of a variety of markers that identify cell types, and determining if there is increased cell enzymatic activity which could result in valve destruction. The investigating panel suspects that that reason dogs develop MVD is because of a cell type, known as a valvular interstitial cell, which is malfunctioning and failing to produce normal structural components. These components are crucial to maintaining the valves structural rigidity, its shape and function, and to prevent it from leaking.
The study is looking at the structure and appearance of the valve cells using electron microscopy, thereby enabling the researchers to characterize the differences between normal and abnormal cells. The immediate aim of the studies is to prove these cells are abnormal, in what way they are abnormal, and why they are abnormal. In conjunction with that work, they are hope to determine procedures to isolate normal and abnormal cells and investigate the function of the cells in a controlled laboratory environment. See Dr. Corcoran's 2004 article, "Identification of surface morphologic changes in the mitral valve leaflets and chordae tendineae of dogs with myxomatous degeneration", in the American Journal of Veterinary Research.
The Scottish study also involves evaluating the changes in the structural elements (collagen and elastin) in the valves, using routine and special stains for light microscopy, and looking at the expression of immunoglobulins in affected dogs. In a February 2006 interim report, the researchers stated that they are "confident that there are recognisable changes in the cell types that are crucial for maintaining healthy valves, and preliminary data suggests this is resulting in altered protein expression by the valve cells." According to the February 2006 interim report, Richard Han is leading two other projects related to the Scottish study. In the first, he is looking into "the structural change in the valve, particularly the spatial arrangement of the matrix, which gives the valves their structural rigidity and which is disorganised in disease." The researchers are using a powerful x-ray technique to investigate this problem.
Also, Mr. Han is leading a second related study, which is of innervation (nerve supply) of the mitral valve. Dr. Corcoran states that, "We know that a derangement of nerve supply has an adverse affect on valve function and we suspect on valve cells. This study is using immuno-histochemistry to map the innervation of the valve in normal and diseased dogs."
In their January 2007 report to the U.K.Cavalier King Charles Spaniel Club, the researchers state that their work is divided into five categories: (1) Immunohistochemical localization and identification of cell types in affected valves; (2) Quantification of cellular changes in diseased valves; (3) Identification of alteration in connective tissue elements and the factors that control these elements; (4) Evaluation of alteration in endothelial cell morphology and function; and (5) Analysis of differential protein and gene expression in diseased valves.
Dr. Corcoran concludes in his January 2007 report that, "We have identified fundamental changes in the valve that were not previously known and we have also identified the nature of change that occurs with disease progression. We have begun to look at the more fundamental changes that occur at the gene expression level and the consequence of changes in gene expression, namely what protein are expressed or absent. Like all research, this project has answered some questions, but has also raised new questions that will need investigation. Historically, we have known very little about the mitral valve disease in either dogs or humans and by its very nature this type of research slowly fills in the gaps in our knowledge hopefully eventually leading to the answer to the question of why does mitral valve disease occur."
Dr. Corcoran next (as of May 2007) is proceeding to investigate the phenomenon of interstitial cell phenotypic change further, using proteomics (two-dimensional gel electrophoresis) to identify potential proteins of interest. He states that, "From these data, in future studies we would use RT-PCR to identify differential gene expressions and identify potential genes of interest." The American Cavalier King Charles Spaniel Club's charitable trust's Darcy Fund, is helping to underwrite Dr. Corcoran's new area of research. Donations are tax deductible.
Dr. Corcoran may be reached at telephone 0131 650 6070, email Brendan.Corcoran@ed.ac.uk Mr. Han's telephone number is 0131 650 7680.
September 2005: Swedish mortality studies of 350,000+ dogs confirm cavaliers are at highest risk of heart disease death. In two September 2005 articles [Article 1] [Article 2] by a team of Swedish researchers (A Egenvall, BN Bonnett, Å Hedhammar, P Olson) analyzing the deaths of over 350,000 dogs, they not surprisingly found that cavalier King Charles spaniels' leading cause of death is heart disease, and that the CKCS leads the list of breeds dying of heart disorders. They stated:
"Heart disease in the Cavalier King Charles spaniel accounts for over 50% of deaths in that breed (in dogs under 10 years of age) and for over one-quarter of the heart deaths in the insured population. Although heart disease in Cavalier King Charles spaniels is well recognized, these statistics give further insight into the impact of this cause of death in this breed."
Their charts show some interesting comparisons. Figure 1 at left shows the mortality rates for cavaliers' total and diagnostic mortality, as well as for the categories tumours, trauma, locomotor problems and heart. Figure 5 at right shows mortality rate ratios (MRR) from the heart model are shown by breed, age and gender (F-female, M-male) for a few selected breeds, as well as for the baseline.
Table 1 below, as noted, shows the probability of death by ages 5, 8, and 10 years. The full table included 20 other breeds, but the CKCS was at the top of the list.
It shows that, while only 7% of Sweden's cavaliers were dead by five years of age, 23% were dead by eight years, and 48% were dead by ten years.