Myxomatous mitral valve disease

Myxomatous mitral valve disease (MMVD) or chronic degenerative mitral valve disease is the most common acquired cardiovascular disease in the dog. Characterized by progressive myxomatous degeneration of the leaflets and chordae tendineae of the mitral valve, it causes thickening of the leaflets with consequent regurgitation of blood back through the valve. The valve most frequently affected by myxomatous degeneration is the mitral valve, followed by the tricuspid valve; the semilunar valves are rarely affected by this degenerative disorder. The mitral valve can be affected more or less severely, with involvement of one or both of the leaflets. It has been demonstrated that thickening and prolapse of both the leaflets, evaluated by echocardiography, is associated with shorter survival. MMVD predominantly affects small dogs, with the prevalence increasing with increasing age. Since many years can pass between the diagnosis and the manifestations of heart failure, not all affected subjects progress to this stage in their lifetime.

The Dachshund and the Cavalier King Charles Spaniel are among the breeds of dog most frequently affected by MMVD, suggesting that there is a genetic component to the disease. Although the aetiology is still unknown, the most widely accepted hypothesis is that this is a hereditary disease with a polygenic nature.

PATHOPHYSIOLOGY

The morphological changes in the valve leaflets cause incomplete closure of the leaflets and, therefore, the onset of valve regurgitation. The first phases of mitral regurgitation are usually mild and do not cause any compensatory response. Over time, the progressive degeneration of the valve leads to an increase in regurgitation into the left atrium, thus reducing the cardiac output and triggering activation of compensatory mechanisms such as left ventricular eccentric hypertrophy, activation of the renin-angiotensin-aldosterone system (RAAS) (neuroendocrine mechanism) and an increase in the release of adrenaline and noradrenaline (endogenous catecholamines). The activation of these compensatory mechanisms is able to ensure an adequate cardiac output for a long time.

The increased pressure in the left atrium and dilatation of the atrium, with consequent stretching of atrial myocardial myofibrils, stimulate the release of atrial natriuretic protein (ANP) which initially is able to compensate for the negative effects of the other neuroendocrine systems. Over time, however, the effects of the RAAS, together with those of the catecholamines, prevail over the effects of the ANP, with consequent peripheral vasodilatation (increased afterload) and increased venous return (increased preload).  These two mechanisms cause a rise in left atrial pressure and subsequent venous congestion, resulting in pulmonary oedema (Fig. 1). The chronic increase in pulmonary capillary pressure can eventually induce morphological and structural changes to the pulmonary arteries leading to pulmonary hypertension

DIAGNOSIS

Cardiac auscultation and signalment can enable a presumptive diagnosis of MMVD to be made. In fact, mitral regurgitation can be diagnosed from the finding of a pan-systolic murmur over the left side of the thorax, which is more intense at the apex of the heart; the presence of this type of murmur in an elderly, small dog is suggestive of the diagnosis of MMVD. It is, however, important to remember that mitral regurgitation can be secondary to other cardiac diseases, such as mitral valve dysplasia (a congenital disorder that can be identified by the presence of an apical murmur in young dogs) or dilated cardiomyopathy, which does, however, usually affect large or giant dogs and is normally characterized by a faint murmur.

The affected animal’s owner often reports that the animal has a dry, persistent cough, faints or does not tolerate physical exercise; in order to make a diagnosis in these cases, further diagnostic investigations, such as X-rays, echocardiography and Holter monitoring, are necessary.

The coughing dog
Cough is the clinical sign most frequently reported by owners of small, elderly dogs with a diagnosis of mitral regurgitation. Typically it is a dry, non-productive cough which, if particularly severe, can culminate in retching (the owner reports: “it is as if the dog wants to expel something”). Often the cough can be attributed to other disorders and does not necessarily indicate the presence of pulmonary oedema. Indeed, small dog breeds are predisposed to disorders of the airways, such as tracheal or bronchial collapse and chronic bronchitis.

Even in animals with obvious heart failure, a dry, noisy cough is indicative of a concomitant primary respiratory disorder. In these cases the treatment must be targeted both at reducing the tussigenic stimulus and at treating the heart failure. Finally, it should be remembered that the differential diagnosis of a cough in the elderly dog includes pulmonary neoplasms. It must, therefore, be appreciated that a cough in a patient with MMVD is not necessarily an indicator of heart failure and must not be a decisive factor in establishing the cardiological treatment.

All patients with a mitral valve murmur and cough should undergo chest X-rays to evaluate the possible presence of concomitant respiratory diseases or signs of pulmonary oedema. The left ventricular dilatation associated with mitral regurgitation can worsen a cough because of compression of the left pulmonary bronchus and/or dorsal displacement of the trachea (Fig. 2). In these cases, increasing the dose of diuretic does not resolve the cough. The administration of diuretics to dogs with chronic bronchitis or tracheal collapse may even worsen the signs because of dehydration and consequent dryness of the airways.

It is important to emphasize that collapse of the left main bronchus secondary to atrial dilatation occurs only in cases in which there is a predisposing disorder of the airways. The administration of a cough suppressant in cases of this type may be the best indicated treatment.

The most common clinical signs in subjects with pulmonary oedema are orthopnoea, dyspnoea, exercise intolerance and inability to sleep in the usual position. Any cough present is usually mild and not noisy. Chest X-rays are also fundamental in these cases, being important both for the diagnosis and for monitoring the response to treatment and the evolution of the disease over time.

Chest radiography is the investigation of choice for examining the lung fields, the pattern of the vasculature and the cardiac silhouette. The Vertebral Heart Size (VHS) score is an objective method for evaluating cardiac enlargement. Despite differences between breeds, the VHS score can help to evaluate patients with heart disease. A recent study has established that a VHS score ≤ 11.4 excludes, with a good level of accuracy, that the origin of the cough is cardiac (Fig. 3)

The dog with syncope
Syncope is not uncommon in dogs with MMVD. The distinction between syncope and seizures can be very difficult. In both cases there is a loss of consciousness, possible uncontrolled voiding of urine and faeces and there may be tremors and pedalling. Syncope usually lasts only a short time, is normally unexpected without evident prodromal signs, and the animal recovers within a few minutes.

Possible causes of fainting in MMVD, in order of frequency, are vaso-vagal syncope, due to inappropriate stimulation of the vagal nerve by baroreceptors, and situational syncope, triggered by a particular situation such as cough, excessive tension on the collar, vomiting, deglutination, urination or defecation. Situational syncope is the form of fainting more frequently diagnosed in dogs with MMVD and associated pulmonary hypertension. Other possible causes of syncope include paroxysmal supraventricular or ventricular arrhythmias, which are not always easy to diagnose during an outpatient examination.

A careful history and, possibly, a Holter study are, therefore of fundamental importance for making the diagnosis of syncope. The Holter instrument records electrical activity over 24 hours and can reveal any intermittent arrhythmias that may not be present at the time of an outpatient examination.

ROLE OF ECHOCARDIOGRAPHY IN THE DIAGNOSIS OF MMVD

Chest auscultation and X-rays are sufficient for the diagnosis of MMVD and pulmonary oedema. Echocardiographic examinations can, however, provide further information of diagnostic and therapeutic utility.

First of all, echocardiography can provide confirmation of the diagnosis through visualisation of the typical mitral lesions and prolapse of the valve. Furthermore, it enables staging of the disease through an evaluation of the degree of atrial dilatation and eccentric ventricular hypertrophy (Fig. 4). The dimensions of the left atrium have, in fact, been shown to be a predictive indicator in patients with MMVD. Doppler studies can be used to quantify the regurgitant fraction and obtain information on the possible presence of systemic hypertension by measuring the mitral inflow velocity.

With progression of the disease, the chronic volume overload and the consequent increased left atrial pressure can cause pulmonary hypertension. In patients with this condition echo-Doppler examination can be used to obtain a non-invasive estimation of the pulmonary pressure through measurement of the tricuspid regurgitation velocity. Echocardiography can also be used to evaluate systolic and diastolic function, helping rational planning or modification of treatment. Finally, echocardiography enables the identification of other concomitant disorders which it may or may not be possible to detect by auscultation alone, such as an inter-atrial defect or dysplasia of the tricuspid valve.

ROLE OF BRAIN NATRIURETIC PEPTIDE IN THE DIAGNOSIS OF MMVD

The diagnosis of congestive heart failure is not always easy, particularly if X-rays or echocardiography cannot be carried out. The signs of a dog with cardiogenic pulmonary oedema can be very similar to those of a dog with a primary respiratory problem. In human medicine a laboratory marker capable of distinguishing between pulmonary problems and cardiac ones has long been in use, particularly in the emergency setting in order to triage patients more quickly and economically. A fast test able to discriminate between patients with primary respiratory disorders and those with heart disease would be equally useful in veterinary medicine.

Numerous studies have been published in the literature on the value, for this purpose, of determining levels of natriuretic peptides, in particular ANP and brain natriuretic peptide (BNP), by enzyme-linked immunosorbent assay (ELISA). Several studies have demonstrated that BNP levels are related to the severity of mitral valve disease in several studies. One study showed that for every 10 pg/ml increase in BNP, the risk of death in the subsequent 4 months increased by 44%. Another more recent study demonstrated that a cut-off value of 445 pmol/L was able to discriminate healthy subjects from patients with MMVD with a sensitivity of 83.2% and a specificity of 90%. However, although BNP levels are able to distinguish patients with congestive heart failure from normal subjects quite accurately, they cannot differentiate asymptomatic patients with mild or moderate MMVD from healthy subjects because of the wide overlap of values. It has also been seen that the serum concentration of BNP can differentiate dogs with dyspnoea of cardiac origin from those with dyspnoea secondary to pulmonary disorders, but that it cannot currently distinguish patients with concomitant cardiac and respiratory pathologies. BNP is, therefore, a promising diagnostic investigation that could complement other already available methods for diagnosing heart failure. However, from the data so far available in the literature, it does not seem possible to use it as the only diagnostic strategy in dogs with MMVD and heart failure.

TREATMENT

A dog with MMVD usually has a long asymptomatic phase and there are reports that only 35% of affected animals develop clinically manifest heart failure or die of their disease. It is, therefore, necessary to tailor the treatment to each individual patient based on the results of clinical and instrumental investigations (Table 1).

Table 1. Doses of the main drugs used in MMVD.

Asymptomatic patients
The treatment of asymptomatic patients has always been the subject of discussion. Studies on the use of ACE-inhibitors in asymptomatic subjects have been performed, but have not demonstrated either a slowing in the progression of the disease or an increase in survival, apart from minor changes of little clinical relevance. Thus, at present, there is not convincing evidence in the literature to support the use of treatment in asymptomatic patients.

Symptomatic patients
Symptomatic patients, on the other hand, need lifelong treatment, which can be adapted over time but which must never be interrupted. It should be explained to the owner of a dog with MMVD that the animal can have an excellent quality of life. In fact, in dogs with moderate heart failure the survival after a diagnosis of congestive heart failure is about 2 years.

In the light of published data, the standard treatment for heart failure in patients with MMVD should include furosemide, an ACE-inhibitor and pimobendan. Other commonly used drugs that may be useful in the therapeutic management of such patients include spironolactone, digoxin and amlodipine.

FUROSEMIDE. Furosemide is a life-saving treatment in symptomatic patients with pulmonary oedema. Its diuretic effect reduces the volume overload both acutely and in the long-term. The dose varies up to a maximum of 4 mg/kg tid during chronic treatment. It is fundamental to titrate the drug so that the animal is given the minimum dose able to maintain a stable, clinical condition.

The chronic use of diuretics can induce pre-renal azotaemia. For this reason the renal function of all patients with heart disease receiving diuretics should be monitored periodically.

ACE-INHIBITORS. Diuretics stimulate the RAAS and so animals treated with a diuretic must also be given an ACE inhibitor. Furthermore, there are studies showing that adding enalapril or benazepril to standard therapy (furosemide/digoxin) not only prolongs the life of the animal, but also improves its quality of life.

PIMOBENDAN. This drug is defined an inodilator because it is both a positive inotrope and a vasodilator. Two recent multicentre studies demonstrated that this drug, associated with a diuretic, improves quality of life and prolongs survival. Pimobendan should, however, be reserved for use in symptomatic patients.

SPIRONOLACTONE. This is a potassium-sparing diuretic that was recently registered for use in the dog. By inhibiting aldosterone (sodium-retaining antidiuretic hormone) it not only has a mild diuretic effect, but also potentially reduces the fibrosis and cardiac remodelling that occur secondary to the activation of aldosterone in congestive heart failure.

DIGOXIN. This is a positive inotrope and negative chronotrope. It is indicated for dogs with systolic dysfunction or atrial fibrillation requiring control of heart rate. Digoxin is not tolerated by all patients and it is, therefore, important to monitor blood levels of the drug in order to avoid overdosage, particularly in patients that have lost weight.

AMLODIPINE. This is an arterial vasodilator reserved for use in patients with severe mitral regurgitation in order to reduce afterload and, thereby, the regurgitant fraction. The drug can cause hypotension and it is, therefore, very important to monitor systemic blood pressure in animals being treated with amlodipine. Besides having haemodynamic effects, there are descriptions of amlodipine causing gingival hyperplasia, which regressed following interruption of treatment.

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