HCM: Pathophysiology

By | 2013-06-07

Hypertrophy, Diastolic Dysfunction, and Congestive Heart Failure

Enlarged papillary muscles and a thick left ventricular myocardium with a normal to small left ventricular chamber characterize hypertrophic cardiomyopathy. hypertrophic cardiomyopathy may be mild, moderate, or severe. Severe concentric hypertrophy by itself increases chamber stiffness. In addition, blood flow and especially blood flow reserve to severely thickened myocardium is compromised, which causes myocardial ischemia, cell death, and replacement fibrosis. This has been documented in cats by showing that cardiac troponin I concentration, a protein released into the systemic circulation after cell necrosis, is increased in cats with severe hypertrophic cardiomyopathy. Increased concentrations of circulating neurohormones may also stimulate interstitial fibrosis. Fibrosis increases chamber stiffness (increased pressure for any given volume) further and is probably the primary reason for the marked diastolic dysfunction seen in this disease. The stiff ventricular chamber causes a greater increase in pressure for any given increase in volume when the ventricle fills in diastole. This produces congestive heart failure (i.e., pulmonary edema and pleural effusion).The myocardium from cats with hypertrophic cardiomyopathy also takes a longer time to relax in early diastole, although the clinical significance of this is unknown. When left ventricular hypertrophy is severe, it is common for the left ventricular wall thickness to be twice the normal thickness. Consequently, left ventricular wall thickness is commonly in the 7 to 10 mm range when hypertrophic cardiomyopathy is severe in cats. This severe concentric hypertrophy may encroach on the left ventricular cavity in diastole, decreasing its size, although left ventricular diastolic diameter is commonly within the normal range. The end-systolic volume and diameter are almost always reduced, often to zero (endsystolic cavity obliteration). Global myocardial contractility is normal in humans with hypertrophic cardiomyopathy, and die reduction in end-systolic volume is due to a decrease in afterload (wall stress) brought on by the increase in wall thickness.

Systolic Anterior Motion of the Mitral Valve A phenomenon called systolic anterior motion (SAM) of the mitral valve is common in cats with hypertrophic cardiomyopathy ().

Cats with hypertrophic cardiomyopathy and systolic anterior motion are commonly said to have the obstructive type of hypertrophic cardiomyopathy or hypertrophic obstructive cardiomyopathy (HOCM). In one survey of 46 cats, systolic anterior motion was present in 67%. systolic anterior motion of the mitral valve is the process of the septal (anterior] mitral valve leaflet or the chordal structures inserting on this leaflet being pulled into the left ventricular outflow tract during systole. Here it is caught in the blood flow and pushed toward (and often ultimately against) the IVS. The initial pulling of the mitral valve leaflet toward the left ventricular outflow tract in systole can clearly be seen on many echocardiograms from cats with hypertrophic cardiomyopathy. The grossly enlarged papillary muscles encroach on the left ventricular outflow tract (the region of the left ventricular between the anterior leaflet of the mitral valve and the IVS in diastole) and pull the mitral apparatus structures into the basilar region of the outflow tract. This situation has been reproduced experimentally in dogs by surgically displacing the papillary muscles cranially. systolic anterior motion of the mitral valve produces a dynamic subaor-tic stenosis that increases systolic intraventricular pressure in mid- to late systole. The dynamic subaortic stenosis increases the velocity of blood flow through the subaortic region and often produces turbulence. Simultaneously, when the septal leaflet is pulled toward the IVS, this produces a gap in the mitral valve, creating mitral regurgitation. These abnormalities are by far the most common cause of the heart murmur heard in cats with hypertrophic cardiomyopathy. The process of systolic anterior motion is dynamic — worsening when contractility increases and lessening when contractility decreases. This also makes the murmur dynamic — increasing in intensity with increasing excitement and softening when the cat becomes calmer.

Pleural Effusion Along with pulmonary edema, pleural effusion is common in cats with heart failure. It can be a modified transudate, pseudochylous or true chylous in nature. The most common cause of chylothorax in cats is heart failure. It is unknown exactly why pleural effusion develops in these cats. Two possibilities exist: The first is that left heart failure results in pulmonary hypertension severe enough to cause right heart failure. This does not appear to occur very frequently in cats because it is unusual to identify echocardiographic right heart enlargement, jugular and hepatic vein distension, or ascites in these cases. The second possibility is that feline visceral pleural veins drain into the pulmonary veins such that elevated pulmonary vein pressure (congestive left heart failure) causes the formation of pleural effusion. In the dog the visceral pleura is supplied by pulmonary arteries and drained by pulmonary veins. The dog, the cat, and the monkey have type II lungs.w One characteristic of type II lungs is that the visceral pleura is supplied not by bronchial arteries but by pulmonary arteries.

Presumably this means that the cat visceral pleura is also drained by pulmonary veins. This means that pulmonary venous hypertension secondary to left heart failure could cause pleural effusion in cats as it does in humans.

Pathology of hypertrophic cardiomyopathy

Gross Pathology Cats with severe hypertrophic cardiomyopathy have severe thickening of the left ventricular myocardium (the IVS and free wall), with the left ventricular wall commonly being 7 to 10 mm thick (). The hypertrophy may be symmetrical, involving the entire circumference of the LV, but it may also be asymmetrical. In some cats the IVS is significandy thicker than the free wall, whereas in others the free wall is thicker (asymmetrical hypertrophy). In those cats with primarily septa] hypertrophy, the hypertrophy may be confined to the basilar region of the septum, and in others may be apical. Isolated free wall hypertrophy most commonly occurs in the region between the papillary muscles. As in many pathologic specimens, hearts from cats with hypertrophic cardiomyopathy may undergo contraction (rigor) after death, resulting in a wall thickness that is closer to the end-systolic wall thickness in life rather than the end-diastolic thickness. Consequently, heart weight must be combined with subjective or objective evidence of left ventricular wall thickening to make the diagnosis of hypertrophic cardiomyopathy postmortem. To weigh a cat heart the pericardium should be removed and the aorta and pulmonary artery transected so that no more than 2 to 4 cm are left. Normal heart weight-to-body weight ratio has been reported to be 10.6 +/- 4 g/lb, with cats with hypertrophic cardiomyopathy having a ratio of 13.2 +/-3.1 g/1b. This results in a large overlap between the two groups. In the author’s experience, most normal-sized cats (6 to 12 lb) have a heart that weighs less than 20 g and most cats in this size range with hypertrophic cardiomyopathy have a heart that weighs more than 20 g. Cats with severe hypertrophic cardiomyopathy almost always have a heart that weighs more than 25 g, usually over 30 g, and can be as heavy as 38 g.

The left atrium is often enlarged in cats with severe hypertrophic cardiomyopathy, often markedly so. However, with early, severe disease, the author has identified normal left atrial size in some Maine coon cats. Occasionally a thrombus is present in the body of the left atrium or within the left auricle.

Cats with milder forms of the disease (mild to moderate hypertrophic cardiomyopathy) have lesser wall thickening and a more normal-sized left ventricular chamber. The left atrium may be normal in size or may be enlarged. Papillary muscle hypertrophy may be the predominant lesion.

Histopathology Histopathologically, a wide range of abnormalities exist. In some hearts, only myocyte hypertrophy is evident. On the other end of the spectrum, some cats have moderate to severe interstitial and replacement fibrosis and dystrophic mineralization (20% to 40% of cases). Intramural coronary arteriosclerosis is present in approximately 75% of cats with hypertrophic cardiomyopathy. Intramyocardial small artery disease is not specific for hypertrophic cardiomyopathy because it is also identified in cats and dogs with many cardiac diseases.

In humans, myocardial fiber disarray that involves at least 5% of the myocardium in the IVS is found in 90% of patients with familial hypertrophic cardiomyopathy. Other diseases that produce concentric hypertrophy can also cause myocardial fiber disarray, but this almost always involves less than 1% of the myocardium. In cats with hypertrophic cardiomyopathy, myocardial fiber disarray in the IVS of the same magnitude observed in humans is only identified in 30% to 60% of cases.’ However, myocardial fiber disarray is a consistent feature of hypertrophic cardiomyopathy in Maine coon cats. Sarcomeres also have disarray in human patients with hypertrophic cardiomyopathy. Interestingly, infecting isolated feline cardiocytes with an adenoviral vector containing a full-length mutated human β-myosin heavy chain gene causes sarcomere disruption.

Natural History and Prognosis

The prognosis, as with most cardiac diseases, is highly variable for hypertrophic cardiomyopathy. Some of it is determined by clinical presentation and echocardiographic severity of the disease. Adult cats that are asymptomatic and have mild to moderate disease and no to mild left atrial enlargement have a good short-term (and possibly a good long-term) prognosis. Some, however, may progress to more severe disease and some may die suddenly. Asymptomatic cats with severe wall thickening and mild to moderate left atrial enlargement have a guarded prognosis for developing heart failure in the future. They probably have some risk for developing thromboembolism and may be at risk for sudden death. Cats with no clinical signs but with severe wall thickening and moderate to severe left atrial enlargement are at risk for developing heart failure or often already have mild to moderate heart failure that has gone undetected. These cats are at risk for developing systemic thromboembolic disease and sudden death, although both of these risks appear to be relatively small. Cats presented in heart failure usually have a poor prognosis, but survival time is highly variable. Most die of intractable heart failure. Some develop thromboembolism, and some die suddenly. In one study a MST of 3 months was reported yet some cats (about 20% in one study) in this class stabilize and do well for prolonged periods. The author and colleagues have seen some cats with severe hypertrophic cardiomyopathy live as long as 2.5 years after the diagnosis of heart failure. Some of these cats may develop heart failure when they are stressed and become severely tachycardic and then stabilize after that time. Cats with severe hypertrophic cardiomyopathy and aortic thromboembolism in the aforementioned study had a very poor prognosis with a MST of 2 months.

Hypertrophic Cardiomyopathy: Clinical Manifestations

Differential Diagnoses

Hyperthyroidism and systemic hypertension need to be ruled out as either primary or complicating factors. Hyperthyroidism is usually easy to rule out. Devices to measure blood pressure in the cat, however, are not always readily available, and the technique requires some practice to acquire accurate values. In addition, systolic systemic arterial blood pressure may be increased in a normal cat that is stressed, so repeat measurements of increased blood pressure are preferred before a diagnosis of systemic hypertension is made If systemic arterial blood pressure cannot be measured, one should at least rule out the common causes of systemic hypertension in a cat with left ventricular concentric hypertrophy (i.e., hyperthyroidism, renal failure).

Rarely, infiltrative disease such as lymphoma will produce hypertrophy that is indistinguishable from hypertrophic cardiomyopathy on an echocar-diogram. One such case has been reported. Cats that are homozygous for the dystrophin deficiency seen in hypertrophic feline muscular dystrophy also have thickened but hypoechoic myocardium with hyperechoic foci in the left ventricular myocardium and papillary muscles. The myocardium contains foci of mineralization and no dystrophin.

Precipitating Factors

Certain factors may precipitate heart failure or sudden death in a cat with hypertrophic cardiomyopathy. Stress (cat fight), anesthesia (especially with ketamine), and surgery appear to be factors. The administration of a long-acting corticosteroid also appears to be a factor that either produces or worsens heart failure in cats, presumably through the mineralocorticoid effects of these drugs.

Therapy of Cats with No Clinical Signs

No evidence exists to show that any drug alters the natural history of hypertrophic cardiomyopathy in domestic cats until they are in heart failure. Diltiazem, atenolol, or enalapril are commonly administered to cats with mild to severe hypertrophic cardiomyopathy that are not in heart failure on an empiric basis. Whenever hypertrophic cardiomyopathy is diagnosed in a cat, the veterinarian should explain the situation to owners and try to let them make informed decisions based on their wishes and life styles. Because no intervention is known to change the course of the disease, treatment at this stage is not mandated.

Treatment Goals and General Therapy of Cats in Heart Failure

Cats that present in heart failure have clinical signs referable to pulmonary edema, pleural effusion, or both. Consequendy, therapy is generally aimed at decreasing left atrial and pulmonary venous pressures in these cats and physically removing the effusion. In some cats with severe heart failure, clinical evidence of hypoperfusion (low-output heart failure) may be apparent in addition to the signs of congestive heart failure. The signs may be manifested primarily as cold extremities.

Pulmonary edema is primarily treated with diuretics (almost exclusively with furosemide) acutely and chronically and an angiotensin-converting enzyme enzyme inhibitor chronically, although recent evidence suggests that angiotensin-converting enzyme inhibition may not be that helpful in prolonging survival in cats with hypertrophic cardiomyopathy. Diltiazem and beta-adrenergic blockers, usually atenolol, have been commonly used as adjunctive agents. Recent evidence suggests that diltiazem is not helpful in prolonging survival in cats with heart failure due to severe hypertrophic cardiomyopathy and that atenolol may actually shorten survival time. Plcurocentesis is most effective for treating cats with severe pleural effusion. Furosemide is helpful for preventing or slowing recurrent effusion.

Hypertrophic Cardiomyopathy: Acute Therapy

Hypertrophic Cardiomyopathy: Chronic Therapy

Refractory Heart Failure

Heart failure that is refractory to furosemide and an angiotensin-converting enzyme inhibitor portends a poor prognosis. Another diuretic may be added to the therapeutic regimen. A thiazide diuretic is generally the mast rewarding but is also more likely to cause complications, such as dehydration and electrolyte (sodium, potassium, chloride, magnesium) depletion. Spironolactone, in theory, may have some beneficial effects related to blocking aldos-terone’s actions; however, clinically it rarely results in noticeable improvement, and its efficacy is unproven. A low sodium diet may be helpful, if palatable. This diet can be a commercial one or one that is devised by a nutritional service. Home-cooked diets formulated by the owner are discouraged unless the owner is counseled. If severe systolic anterior motion is present and atenolol is not already part of the therapeutic regimen, it may be added at this stage.