Introduction

Myxomatous mitral valve disease (MMVD) is by far the most common heart disease in dogs. The disease is characterized by a slow progressive myxomatous degeneration of the mitral valve apparatus with subsequent left atrial (LA) and ventricular (LV) dilatation. MMVD is encountered in all breeds, but the highest prevalence is seen in small to medium-sized dog breeds. The presentation will review newer aspects/knowledge of MMVD, such as disease terminology, disease etiology and pathogenesis, congestive heart failure (CHF) identification, in addition to disease treatment strategies.

Terminology

Consistent terminology in the scientific literature is important for defining a disease. Unfortunately, this disease has many names, such as chronic valvular disease, degenerative mitral valve disease, mitral valve disease, endocardiosis, and more recently myxomatous mitral valve disease. The term "myxomatous" describes a characteristic histologic feature of this disease. Conversely, the term "myxomatous" excludes most, if not all, other forms of mitral valve disease. Although the myxomatous degeneration most commonly affects the mitral valve, any of the four intracardiac valves can be affected. However, the most commonly used descriptor "mitral" does not necessarily exclude involvement of other valves. Thus, it is our opinion that "Myxomatous mitral valve disease" accurately and succinctly defines the pathophenotype of this condition.

Genetic Background

The etiology of MMVD has not been ascertained, but heredity has long been suspected to play a major role owing to the strong association of this disease with certain small to medium-sized breeds. Studies in dogs have shown associations between cardiac status in parents and offspring, both with regard to murmur intensity and MMVD severity. These studies suggest that the disease has a polygenic inheritance; that is, multiple genes influence the trait and a certain threshold has to be reached before MMVD develops. The polygenic mode of inheritance means that a combination of a sire and a dam that both have an early onset of MMVD will give offspring that have, on average, an early onset of MMVD (and CHF). A combination of dogs with late onset will give offspring that manifest the disease at old age or never. In a EU funded study (the LUPA project), genome-wide association study (GWAS) was performed to identify loci associated with early onset of MMVD in Cavalier King Charles spaniels (CKCSs) recruited from several countries in Europe. Two loci, located on chromosomes 13 and 14, were found to be associated with early age of onset of MMVD in dogs. This finding is likely to herald causative mutations in the future, and such discovery will clearly increase the knowledge of disease pathways, and may lead to genetic tests, but no such tests are currently available.

Possible Influence of the Serotonin Signaling Pathway

One or more primary inciting factors likely increase the risk of disease in predisposed dogs, but little is known about the pathogenesis of the progressive degeneration of the leaflets. An interesting development in the pathophysiology of MMVD is the suggested impact of increased activity in the serotonin (5-HT) signaling pathway. Studies have demonstrated increased serum 5-HT concentrations in dogs predisposed to MMVD in comparison to other breeds. One of the studies reported that the serum concentrations of 5-HT decreased at more progressed stages. The finding of higher serum 5-HT concentrations in dogs of breeds predisposed to early onset of MMVD (CKCS) and dogs with mild MMVD suggests that alterations in 5-HT signaling might play a role in progression of early stages of MMVD, and that 5-HT potentially could be genetically linked to the etiologic mechanisms of MMVD in CKCS. Likewise, expression of 5-HT receptors and extracellular matrix signaling molecules have been shown to be altered in diseased mitral leaflets. Possible influence of 5-HT in disease development is currently investigated further by several research groups.

Early Identification of Congestive Heart Failure

MMVD is characterized by chronic progression, and at a certain point, for some dogs, the disease may no longer be compensated for; the forward cardiac output decreases, and the pulmonary capillary pressure exceeds the threshold for pulmonary edema. Early detection of dogs developing decompensated CHF is highly desirable in order to initiate appropriate treatment strategies for dogs affected. Accordingly, there is a need for clinical variables with a prognostic value and which can aid in early identification of mild CHF.

A soft murmur in a small-breed dog with MMVD is indicative that disease severity is mild and a recent published study demonstrated that CHF is unlikely in MMVD dogs diagnosed with soft murmur. Dogs presenting with a precordial thrill rarely have mild disease, and have been shown to have a higher risk of developing CHF and/or pulmonary hypertension.

Several other physical examination - echocardiographical ­ and circulating biomarker variables have also been evaluated in the above-mentioned aspects. At present, echocardiographical estimated left atrial and left ventricular end-diastolic dimension, radiographical estimated vertebral heart score index (VHS), and circulating concentrations of natriuretic peptides and troponin stand out as being most reliable in predicting the onset of decompensated CHF. However, a number of these variables might have acceptable predictive value for groups, but less so for individuals. Furthermore, the performance of the test improves considerably if more than one observation point in time is available, and the closer in time to CHF the dog is.

The above-mentioned tests require imaging and laboratory equipment and expertise. However, respiratory rate in dogs has proved to be a sensitive and specific single diagnostic test for identifying CHF as a cause of respiratory clinical signs in dogs with heart disease. Studies have recently shown that healthy dogs and dogs with subclinical left-sided heart disease had an average sleeping respiratory rate (SRR) below 25 breaths/minute and rarely above 30 breaths/minute. Another study demonstrated that resolution of the CHF resulted in a reduction in respiratory rate into pre-CHF ranges. Frequent monitoring of SRR in the dogs home environment could allow more timely therapeutic intervention or modulation in animals with severe subclinical heart disease (e.g., those with marked left atrial enlargement) or known prior history of CHF.

Management

No medical therapy is currently known to inhibit or prevent the valvular degeneration itself, whereas surgical repair or valve replacement has the potential to improve valvular function. Case series with comparably good outcomes have been reported for surgical mitral valve repair, but this procedure is only available at very few sites in the world, and, therefore, not technically, economically, or ethically possible for most canine and feline patients. The management of MMVD is therefore mainly concerned with improving quality of life by prolonging the preclinical (asymptomatic) phase, ameliorating the clinical signs and improving survival. Much work has been performed in order to investigate if certain drugs could change the progression of disease in asymptomatic MMVD dogs, as this group of dogs is very large. The recently published EPIC trial demonstrated a favorable outcome for pre-clinical MMVD dogs with cardiomegaly treated with pimobendan, compared to placebo-treated dogs, in regard to delaying onset of CHF and extending the overall survival.

Treatment of decompensated CHF is tailored for the individual patient, and often involves concurrent treatment with two or more drugs once signs of CHF are evident. The improved survival is likely to be caused by an alleviation of the heart and the circulation, not by a fundamental change in the pathophysiology of valve degeneration.

References

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2.  Ljungvall I, Hoglund K, Lilliehook I, Oyama MA, Tidholm A, Tvedten H, et al. Serum serotonin concentration is associated with severity of myxomatous mitral valve disease in dogs. J Vet Intern Med. 2013;27(5):1105–12.

3.  Schober KE, Hart TM, Stern JA, Li X, Samii VF, Zekas LJ, et al. Effects of treatment on respiratory rate, serum natriuretic peptide concentration, and Doppler echocardiographic indices of left ventricular filling pressure in dogs with congestive heart failure secondary to degenerative mitral valve disease and dilated cardiomyopathy. J Am Vet Med Assoc. 2011;239(4):468–79.

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6.  Boswood A, Haggstrom J, Gordon SG, Wess G, Stepien RL, Oyama MA, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: The EPIC study-a randomized clinical trial. J Vet Intern Med. 2016:30(6):1765–79.