Myxomatous mitral valve disease (MMVD) is, by far, the most commonly encountered acquired cardiac disease in adult dogs, and the condition is caused by a progressive myxomatous degeneration of the atrioventricular (AV) valves causing mitral valve regurgitation (MR). Indeed, a recent estimation of the mortality caused by cardiac disease in the general canine population indicate that about 7% of all dogs die or become euthanized because of HF before 10 years of age, e.g., the third most common cause for death in dogs in that age interval.¹ Because dogs that undergo post-mortem examination are most commonly those with severe MMVD and MR, it is common to describe the macroscopic appearance of diseased leaflets as thickened and contracted with varying frequency of ruptured chordae tendineae.^2,3 This "classical" description is a manifestation of severe disease, which has progressed over a long time, often several years. The macroscopic findings in cases of mild MMVD may not be apparent and may be overlooked, especially in dogs without clinical evidence of MR. Findings typical for early stages of MMVD include elongated chordae tendineae and enlarged, thickened leaflets with areas showing bulging/ballooning/prolapse towards the atrial side,^4-6 which may be identified on the 2D echocardiogram in the living dog.⁷ With progression, the bulging becomes worse and the free edge becomes thickened and irregular and the lesions spread into other parts of the leaflets.⁴ Within the same valve leaflet one section may look relatively normal while another, neighboring section is moderately or severely diseased. In late stages, secondary fibrosis can cause marked thickening and contraction of leaflets and chordae tendineae. These late stages are usually associated with significant MR and cardiac left-sided enlargement.

Little is known with certainty about underlying etiology and pathogenesis of the progressive thickening and degeneration of the leaflets. An old theory is that the changes are response-to-injury type lesions, i.e., that repeated impact to the leaflets (especially the areas of apposition) results in slowly progressing changes ⁸ As not all dogs develop MMVD, probably one or more primary inciting factors increase the risk of disease in predisposed animals. The nature of these primary initiating factors are currently not known, although certain abnormalities of collagen and other extracellular matrix components have been suggested to predispose to MMVD.⁹ Regardless of the exact nature of the primary inciting factor(s), it has been suggested that it leads to abnormal valve motion, i.e., prolapse of the leaflets, which in turn increase the shear stress imposed on them, both directly through the abnormal leaflet apposition and indirectly through the increased regurgitant flow.^10,11 It is likely that the endothelial damage or loss plays an important role in the progression of the disease because endothelial cells are known to communicate extensively with subendothelial cells (e.g., valvular interstitial cells).^12,13 Endothelial damage may lead to an imbalance in local concentrations of growth-promoting and growth-inhibiting substances produced by endothelial cells. Evidence for such imbalances in diseased canine mitral valves are the reported associations between disease severity and the expression of endothelin receptors and nitric oxide synthase.^14,15 Furthermore, collagen and other matrix components become exposed to the blood in areas of diseased valves where the endothelium appears to be missing and this exposure is expected to promote thrombosis. Although thrombosis may develop as a complication in MMVD dogs, thrombus formation on the mitral valve is uncommon. Its absence in the presence of endothelial damage in MMVD is currently not understood. Increased knowledge and understanding of the actions of these local mechanisms may be of great importance for future treatment of MMVD, because they may suggest ways of treating the actual valve lesions rather than only treating the resulting circulatory disturbances.

Heredity has long been suspected to play a major role for the transmission of MMVD, owing to the strong association of this disease with certain small to medium-sized breeds. Two studies of families of Cavalier King Charles spaniels and families of Dachshunds provide evidence that genetic factors play a large role in the etiology.^16,17 The disease seems to have a polygenic inheritance; i.e., multiple genes influence the trait and a certain threshold has to be reached before MMVD develops.^16,17 Males have a lower threshold than females, which means that males will develop the disease at younger age than females within a family of dogs in which the offspring on average have the same genotype. 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 HF). A combination of dogs with late onset will give offspring that manifest the disease at old age or never. The major role played by genetic factors suggests that other factors, e.g., level of exercise, degree of obesity and diet, play a comparably small role in the etiology. Probably because of this, very little is known about the influence of such factors on the disease. Breeding measures aimed at reducing the prevalence of MMVD have been initiated in many countries in certain breeds such as Cavalier King Charles Spaniels and Dachshunds.

The significance of MMVD in a patient depends on the severity of MR. Low degree of MR caused by MMVD does not lead to any apparent change in any cardiac chamber or wall size or pump function. The forward stroke volume is maintained, and the small regurgitant volume is easily accepted by the left atrium. However, with progression of the valve lesions and increasing MR, the potential loss of forward stroke volume is compensated for by increased total stroke volume, increased force of contraction, remodeling of the left atrium and left ventricle with myocardial hypertrophy and dilatation, increased heart rate and modulations of systemic vascular tonus and extracellular fluid volume. The exact sequence in which these compensatory mechanisms are recruited is currently not fully understood. The cardiac compensatory mechanisms are presumably recruited first whereas the systemic do not appear to be activated until the cardiac mechanisms fail to compensate the MR, i.e., decompensated HF.¹⁸ To some extent, the MR is compensated by a slightly increased heart rate already during compensated phases but this increase is usually not obvious at a clinical examination owing the overall variability of heart rate in dogs.^19,20 However, the heart rate is usually significantly increased in advanced stages of MR with evidence of decompensated HF.^19,21 Myocardial systolic function is relatively well preserved because the ejection into the left atrium at low pressure require little work by the left ventricle compared to other forms of heart disease.^21-23 Dogs may tolerate even severe MR for years. Nevertheless, because of chronic volume overload and the fact that the hypertrophy, while necessary, is a pathologic remodeling, myocardial contractility decreases slowly, even in clinically compensated dogs, but progressively and inevitably.^19,21,24,25 Unfortunately, reliable measurements of myocardial contractility are not readily obtained in MR, and it is currently not known at which stage the depressed myocardial contractility becomes of clinical significance.

Dogs with MR attributable to MMVD usually develop clinical signs of left side HF (cough, dyspnea, lethargy, reduced mobility, increased heart rate), although evidence of right side HF (ascites) may develop in progressed cases.^3,21 Diagnosing moderate to severe HF is usually not difficult as the clinical signs of HF are usually obvious and match the findings on the radiographs, i.e., pulmonary edema and congestion. Likewise, it is usually not difficult to diagnose the MR as it invariably is significant.^3,21 However, mild decompensated HF may be difficult to diagnose owing to the presence of vague clinical signs and that the signs may have gradually developed over a comparably long time. The stage when a patient starts to show clinical signs of MMVD and MR, i.e., have developed decompensated HF, is the end of a process started much earlier with the onset of valve leakage. Over time, the valvular leakage was compensated through a variety of mechanisms, a condition called "asymptomatic" or compensated MR.^3,21 As the valve leakage increase they eventually became incapable of preventing pulmonary capillary pressures from exceeding the threshold for pulmonary edema, and of maintaining forward cardiac output, a condition called "symptomatic" or decompensated MR.^3,21 However, the distinction between these two stages is not clear cut, and it is likely that minor signs of reduced activity and mobility are present even before overt signs of decompensated HF have developed. It is very difficult to objectively evaluate the presence of slight to moderately reduced exercise capacity in most dogs with MMVD and MR, as they are often old small companion dogs, which if obese, have little, if any, demand on their exercise capacity. Furthermore, other concurrent diseases in the locomotor system or elsewhere are common and restrict exercise. Likewise, the hallmark of left side HF, coughing and dyspnea, may be caused by several conditions, such as small airway disease, tracheal instability, pulmonary fibrosis, neoplasia, heartworm disease, and pneumonia.^3,21 An increased heart rate and loss of respiratory sinus arrhythmia may also be indicative of decompensated HF, but heart rate is variable and is increased by many factors such as stress and concurrent disease.^3,20,21 Many of these differential diagnoses can be excluded by different clinical tests, particularly radiography. However, pulmonary findings on the radiographs may also be inconclusive, because early radiographic changes of pulmonary interstitial edema and bronchial pattern resemble the radiographic appearance of chronic airway disease.^3,20,21 The tendency is to over diagnose pulmonary edema of HF.²⁶ Therefore, the most effective mean to separate dogs with early mild decompensated HF from those with other disease is presumably to make the diagnosis based on the combined findings from the clinical examination and from the radiographs, an approach which has been employed in large clinical trials.²⁷ It is also useful to have series of radiographs and evaluate other evidence of left-sided HF that should be present by the time pulmonary edema has developed, such as pulmonary venous distention. If the findings are still inconclusive, re-examination within a week or a 48 to 72 hour trial diuretic therapy with repeat radiographs may help to identify the underlying etiology. In the near future, "bed-side" assays of different endogenous markers of heart disease and HF, such as natriuretic peptides (ANP and BNP), will presumably be available to aid in diagnosing difficult cases.

References

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