364 Vol. 24, No. 5 May Mississippi State University Damon B. Rodriguez, DVM

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1 364 Vol. 24, No. 5 May 2002 CE Article #1 (1.5 contact hours) Refereed Peer Review Comments? Questions? compendium@medimedia.com Web: VetLearn.com Fax: KEY FACTS Feline hypertrophic cardiomyopathy is a disease primarily of diastolic dysfunction. Feline and human hypertrophic cardiomyopathy often share many similar features, including characteristic myofibrillar disarray. Systolic anterior motion of the mitral valve may result in a dynamic outflow obstruction. Feline Hypertrophic Cardiomyopathy: Etiology, Pathophysiology, and Clinical Features Mississippi State University Damon B. Rodriguez, DVM Angell Memorial Animal Hospital Boston, Massachusetts Neil Harpster, VMD, DACVIM (Cardiology) ABSTRACT: Feline hypertrophic cardiomyopathy (HCM) is characterized by varying degrees and patterns of hypertrophy of the left ventricle. Compromise of the left ventricular chamber size along with some degree of impaired diastolic relaxation results in a reduction of ventricular filling, which can impair forward cardiac output. The myocardium may suffer ischemic injury often caused by abnormal coronary perfusion as well as excess oxygen consumption secondary to severe hypertrophy and tachyarrhythmias. In addition to diastolic dysfunction, feline HCM may be accompanied by systolic abnormalities, usually in the form of outflow obstruction. Physical examination, thoracic radiography, electrocardiography, and echocardiography are important tools in the diagnostic evaluation of HCM. Hypertrophic cardiomyopathy (HCM) is the most common feline heart disease seen in clinical practice and is typically characterized by primary concentric hypertrophy of the left ventricle (LV). 1,2 A thorough understanding of this disease is important in order to treat it in a timely and effective manner. ETIOLOGY Myocardial hypertrophy associated with feline HCM is considered a primary disease because an identifiable disease process, such as systemic hypertension, hyperthyroidism, acromegaly, or congenital cardiovascular defects, cannot be found. Feline HCM is similar to human HCM, which is characterized by an autosomal dominant mode of inheritance. 3 In humans, HCM results from

2 Compendium May 2002 Hypertrophic Cardiomyopathy 365 Figure 1 Histologic section of myocardium demonstrating characteristic pathologic changes associated with feline HCM. There is significant myocyte hypertrophy and disarray as well as infiltration of inflammatory cells within muscle bundles. H&E, original magnification 33. (Courtesy of Dr. Dan Paulsen, Mississippi State University.) Figure 2 Cross-section of a feline heart with HCM demonstrating severe concentric hypertrophy of the LV, resulting in a markedly reduced LV chamber size. (Courtesy of Dr. Roy Pool, Mississippi State University.) abnormal formation of sarcomeric proteins due to mutations in genes that encode for such proteins as the β-myosin heavy chain, cardiac troponin T, and α- tropomyosin. 1,3 The formation of these abnormal myocardial proteins leads to myocyte hypertrophy with sarcomere disarray, the latter being the hallmark of HCM (Figure 1). 2,3 A genetic origin is also suspected in cats based on breeding studies performed in Maine coons. 4,5 Serum growth hormone excess and magnesium deficiency have been investigated as causes for primary feline HCM, but cause-and-effect relationships could not be established. 6,7 Until a definitive underlying cause can be determined, feline HCM should be classified as a primary idiopathic disease. PATHOPHYSIOLOGY Feline HCM is characterized by LV diastolic dysfunction. Hypertrophy is classically concentric and symmetric, involving the interventricular septum (IVS) and LV free wall. However, the hypertrophy may also be asymmetric, primarily involving either the IVS or LV free wall, or it may be segmental, involving only a portion of the IVS or LV free wall. 1,2 Concentric hypertrophy reduces ventricular chamber size and increases myocardial stiffness, thereby interfering with diastolic filling (Figure 2). Myocardial fibrous replacement tissue further decreases ventricular compliance and impairs myocardial relaxation (Figure 3). These changes result in an increased LV diastolic filling pressure, which can increase left atrial pressure and result in pulmonary venous hypertension, pulmonary edema, and possibly pleural effusion and right-sided heart enlargement. 1,2,8,9 Figure 3 Histologic section (trichome stain) of myocardium demonstrating collagen deposition (stained blue) within the interstitium and muscle bundles. (Courtesy of Dr. Dan Paulsen, Mississippi State University.) Diastolic dysfunction may also lead to increased coronary resistance and thus impaired myocardial perfusion. Myocardial ischemia can impair active myocardial relaxation in early diastole and plays an important role in the progression of HCM. 1,10 Abnormal structure and decreased density of intramural coronary arteries have been documented in cats with HCM. 11 These vascular abnormalities of the myocardium were more commonly associated with myocardial sections demonstrating moderate to severe fibrosis. 12 This close association between small vessel disease and fibrosis may imply a causal relationship that contributes to myocardial ischemia and fibrosis in cats. Ischemia of the myocardium secondarily lowers the ventricular fibrillation threshold and increases sensitivity to sympathetic tone that may initiate or perpetuate

3 366 Small Animal/Exotics Compendium May 2002 LV RV IVS Figure 4 Illustrated echocardiogram showing how the hypertrophied IVS can extend into the aortic outflow tract and lead to obstruction of blood flow through the aorta (Ao). Additionally, the septal leaflet (arrow) of the mitral valve is seen coming in contact with the IVS during systole, resulting in a dynamic outflow obstruction. (LA = left atrium; RA = right atrium; RV = right ventricle.) cardiac arrhythmias. 13 Tachyarrhythmias generally increase myocardial oxygen demand, 13 which may also impair active relaxation and lead to myocardial stiffness and reduced ventricular filling. 1,10 Because diastolic filling is inversely proportional to heart rate, 2 supraventricular and ventricular tachyarrhythmias (and even sinus tachycardia) further impair diastolic filling, which can increase outflow gradients and reduce forward cardiac output. 1 Cats with HCM often demonstrate abnormal systolic function in the form of intraventricular pressure gradients, which result in increased wall stress and oxygen consumption. 1,2,10,12 These abnormal pressure gradients are secondary to systolic anterior motion (SAM) of the mitral valve and/or marked thickening of the basilar portion of the IVS that extends into the left ventricular outflow tract (LVOT) during systole. 1,10,12 Asymmetric septal hypertrophy may cause a fixed ventricular outflow obstruction as the thickened septum extends into the LVOT during systole, impairing the passage of blood into the aorta (Figure 4). 2 In this case, the LV must generate higher pressures to overcome this outflow resistance, resulting in increased blood velocity through the LVOT. This increased velocity can create a Venturi effect, pulling the septal leaflet of the mitral valve toward the septum during systole, thus worsening resistance to aortic outflow. 1,2,12 With SAM, the distal tip of the leaflet may have brief or prolonged systolic contact with the septum, thus causing mitral regurgitation in addition to dynamic LVOT obstruction (Figure RA Ao LA 4). 12 The secondary mitral regurgitation caused by SAM can promote increased left atrial pressure and a further increase in LV filling pressure, eventually leading to the development of pulmonary edema. 1,9,14 In a study of 46 cats with HCM, 31 (67%) had echocardiographic evidence of SAM. 12 Cats with dynamic outflow obstruction were found to have elevated aortic outflow velocities and transaortic valve pressure gradients. 8,12 Traditionally, progression of heart failure has been explained by a progressive worsening of pathologic hemodynamic changes, which make the work of a diseased myocardium increasingly difficult. 15 Treatments that attempt to alter these hemodynamic abnormalities without taking into account neurohormonal changes have been disappointing. 15 In the neurohormonal hypothesis of heart failure, cardiac disease leads to hemodynamic changes that activate compensatory neurohormonal responses, which in turn may cause deleterious effects on circulation Cardiovascular disease that decreases cardiac output or blood pressure leads to activation of the renin angiotensin aldosterone and sympathetic nervous systems. This neurohormonal response causes vasoconstriction, increased heart rate, and sodium and water retention, resulting in increased work for an already compromised heart. There is evidence demonstrating that elevated levels of angiotensin II and increased sympathetic tone have a direct toxic effect on cultured myocardial cells. 16,17 Aldosterone, which is secreted in response to angiotensin II, has been shown to induce myocardial fibrosis in rat models. 20 Furthermore, angiotensin II blockade has been shown to reverse myocardial fibrosis in a transgenic mouse model of human HCM. 21 Because fibrosis of the myocardium plays an important role in the progression of HCM, 1,2,10 this may have significant clinical implications in cats. These concepts, however, have not been studied directly in cats with HCM. Treatments that alter neurohormonal effects on the heart could potentially slow progression of heart disease and decrease mortality. This has been supported in human clinical trials. 15 CLINICAL FEATURES History and Physical Examination Although feline HCM occurs most commonly in middle-aged male cats, the disease has been reported in patients ranging in age from 3 months to 17 years, with males comprising up to 87% of those affected. 1,4,10,12,22,23 Presenting complaints are variable and can include lethargy, inappetence, weight loss, hiding, reluctance to socialize with the owner and other cats, syncope, respiratory distress, and posterior paralysis. 2,14,24 Sudden death may also occur. Coughing occurs occasionally but is quite uncommon when compared with dogs

4 Compendium May 2002 Hypertrophic Cardiomyopathy 367 I II III avr avl avf Figure 5 Electrocardiogram of a cat with HCM demonstrating sinus tachycardia and a left-axis deviation (left anterior fascicular block pattern). This is a common conduction abnormality associated with HCM. Note the deep S waves and overall negative deflections in all leads except I and avl. Heart rate = 260 beats/min; mean electrical axis = 60. A with left-sided heart disease. 2,10 A heart murmur, cardiac gallop sound, and/or arrhythmia can often be auscultated in both symptomatic and asymptomatic cats. 1,2,9,25 The most likely cause of an acquired heart murmur in cats is HCM 9 ; however, it is possible to have significant HCM without the presence of either a heart murmur or gallop. Crackles may be auscultated in the lungs if pulmonary edema is present, and muffled respiratory or heart sounds may be present in patients with pleural or pericardial effusion, respectively. The most common, significant complications of feline HCM are left-sided congestive heart failure and systemic arterial thromboembolism. 1,10 The average age of cats with distal aortic thromboembolism is approximately 8 years, with male cats most commonly affected. 25 Signs of thromboembolism as the initial clinical findings associated with HCM have been reported in 12% of cats. 23 The most frequent clinical presentation is an acute onset of hindlimb paresis/paralysis with extreme pain, absent to weak femoral pulses, swollen and tight gastrocnemius muscles, and cyanosis of nail beds and footpads. 1,2,9,10,25 Less commonly, signs referable to embolization of the right brachial artery, kidneys, brain, intestines, spleen, or B Figure 6 (A) Ventrodorsal radiograph of a cat with HCM. Note the characteristic valentine-shaped heart with a wide base associated with biatrial enlargement and a narrow apex. (B) Lateral view of the thorax of a cat with HCM. Note the increased sternal contact and prominent LV, resulting in the appearance of generalized cardiomegaly. liver may occur. 1,2,9,14 Other clinical findings reported with aortic thromboembolism are manifestations of the underlying cardiac disease and can include hypothermia, cardiac murmur, gallop sound, arrhythmia, and respiratory abnormalities (e.g., tachypnea, dyspnea, crackles). 25 A unique clinicopathologic finding that may be seen with thromboembolism is hyperkalemia, which can occur early in the disease but more commonly occurs later as reperfusion of affected tissues takes place. 1,2,10,25 Some cats that present with throm-

5 370 Small Animal/Exotics Compendium May 2002 Figure 7 Lateral thoracic radiograph of a cat with pulmonary edema associated with HCM. Note the alveolar and interstitial patterns that can be seen in the caudoventral and caudodorsal lung fields as well as the prominent pulmonary vascular markings (arrow). A boembolism may not have obvious clinical signs of cardiac disease except for a low-grade murmur. This occurs often with severe cardiac changes and emphasizes why all cats with heart murmurs or thromboembolic disease should receive a cardiac evaluation. 25 Diagnostic Tests Electrocardiographic (ECG) abnormalities are common in HCM and can include changes consistent with cardiac chamber enlargement, atrial fibrillation, ventricular premature complexes, paroxysmal ventricular tachycardia, and atrioventricular conduction abnormalities. 14,22 Arrhythmias occur in more than half of cats with HCM, with the ratio of ventricular to supraventricular arrhythmias exceeding approximately 3:1. 22 About 40% of cats with HCM have a left-axis deviation in the frontal plane (Figure 5). 22 Although ECG abnormalities are common, changes are often nonspecific and the ECG can even be normal in cats with HCM. Nevertheless, ECG abnormalities, when present, often influence the type of therapy that will ultimately be initiated. Therefore, we believe that an ECG should be included in the diagnostic workup for cats with suspected cardiac disease. Heart enlargement and pulmonary edema are common radiographic abnormalities in feline HCM. 1,2,10,14 Classically, a valentine-shaped cardiac silhouette is seen on the ventrodorsal view (Figure 6). Radiographic changes are usually associated with LV and atrial enlargement, but evidence of biventricular enlargement may be identified. Pulmonary edema as well as pleural and pericardial effusions may also be seen in cats with HCM. 2,14 The radiographic appearance of pulmonary edema in cats is highly variable; unlike dogs, which Figure 8 (A) Two-dimensional right parasternal long-axis echocardiographic view of a cat with HCM demonstrating significant hypertrophy of the IVS, which extends into the aortic outflow tract. (B) M-mode echocardiogram taken in the right parasternal short-axis view of a cat with HCM. Note the severely hypertrophied IVS that had a measured diastolic thickness of 0.8 cm (normal, 0.5 cm). (Ao = aorta; LA = left atrium; LVW = left ventricular free wall; RVW = right ventricular free wall; RV = right ventricle.) most commonly have perihilar edema, cats can have diffuse interstitial, multifocal and patchy, or perihilar distributions of pulmonary edema (Figure 7). 2,14 Diagnosis of HCM is generally based on characteristic echocardiographic findings in cats with normal peripheral blood pressure and serum thyroxine levels. When evaluating an echocardiographic study, the most common criterion used to diagnose HCM is diastolic thickness of the IVS and LV free wall (Figure 8), which should not be greater than 0.5 cm. 10,26,27 An early indicator of HCM may be hypertrophy of the papillary muscles. 2 Concentric hypertrophy may result in a reduced measured LV internal diameter. Fractional shortening (an indirect measure of contractility) is usually normal to increased. 1,10 Variations of HCM include right ventricular, asymmetric, and segmental hypertrophy. B

6 Compendium May 2002 Hypertrophic Cardiomyopathy 371 RVW RV IVS echogenic material in the left atrial chamber. Smoke is thought to be an indication of prethrombus formation and suggests that these cats are at extremely high risk for future thromboembolic episodes. 29,30 As a result, the severity of left atrial enlargement has been used by some veterinarians to dictate aggressiveness of antithrombotic therapy. 25,31 LVW Figure 9 M-mode echocardiogram taken in the right parasternal short-axis view at the level of the mitral valve from the same cat in Figure 8. Note the septal leaflet of the mitral valve opening during early diastole (long vertical arrow) and then gradually closing toward the onset of systole (short vertical arrow) but then inappropriately opening during systole (horizontal arrow). This is an example of SAM of the mitral valve, which results in obstruction to outflow through the aorta and mitral regurgitation. (See Figure 8 for definitions.) Systolic abnormalities can be evaluated by determining the presence of LVOT obstruction and SAM using two-dimensional, M-mode, and Doppler echocardiography (Figure 9). 1,10 Doppler echocardiography is used to examine blood flow turbulence, valvular regurgitation, and abnormal blood flow velocities across heart valves. Confirmation of LVOT obstruction requires documentation of an increased LVOT velocity of 2.0 m/second or higher. 12 Obstruction to outflow from the right ventricle can also occur in feline HCM. This is apparently the result of combined hypertrophy of the right ventricular free wall and IVS and is diagnosed by an elevation of the right ventricle outflow tract velocity above 1.0 m/second. 28 Left atrial enlargement is also a common finding in feline HCM but is not always present. 2,14 Left atrial enlargement is clinically important because the severity of enlargement denotes greater diastolic dysfunction and has been implicated to have an inverse relationship to prognosis. 1,12 Furthermore, cats with enlarged left atria are predisposed to forming atrial thrombi with systemic embolization. 25 In some animals with severe left atrial enlargement, spontaneous contrast (also referred to as smoke) may be present within the atrium. This is typically seen echocardiographically as swirling LV CONCLUSION Feline HCM is a disease commonly encountered by primary care veterinarians. Clinical signs associated with feline HCM are often variable and nonspecific. Cats may have advanced myocardial changes secondary to HCM and present asymptomatically with only a slight or intermittent heart murmur. Distal aortic thromboembolism is a devastating complication sometimes seen in cats with HCM. Physical examination, thoracic radiography, and ECG are important components in the diagnosis of feline HCM; however, a definitive diagnosis requires an echocardiographic examination. ACKNOWLEDGMENTS The authors would like to thank Tom Thompson, BA, and Samantha Rodriguez, MEd, Mississippi State University, for their technical assistance. REFERENCES 1. Fox PR: Feline cardiomyopathies, in Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. Philadelphia, WB Saunders Co, 2000, pp Rush JE: Therapy of feline hypertrophic cardiomyopathy. Vet Clin North Am Small Anim Pract 28(6): , Marian AJ, Yu QT, Mann DL, et al: Expression of a mutation causing hypertrophic cardiomyopathy disrupts sarcomere assembly in adult feline cardiac myocytes. Circ Res 77:98 106, Kittleson MD, Meurs KM, Kittleson JA, et al: Heritable characteristics, phenotypic expression, and natural history of hypertrophic cardiomyopathy in Maine coon cats (abstract). J Vet Intern Med 12:198, Kittleson MD, Kittleson JA, Mekhamer Y, et al: Development and progression of inherited hypertrophic cardiomyopathy in Maine coon cats (abstract). J Vet Intern Med 10:165, Kittleson MD, Pion PD, DeLellis LA, et al: Increased serum growth hormone concentration in feline hypertrophic cardiomyopathy. J Vet Intern Med 6: , Freeman LM, Brown DJ, Smith FW, et al: Magnesium status and the effect of magnesium supplementation in feline hypertrophic cardiomyopathy. Can J Vet Res 61: , Bright JM, Golden AL, Gompf RE, et al: Evaluation of the calcium channel-blocking agents diltiazem and verapamil for treatment of feline hypertrophic cardiomyopathy. J Vet Intern Med 5: , Behrend EN, Grauer GF, Greco DS, et al: Feline hypertrophic cardiomyopathy. Feline Pract 24(5):34 37, Fox PR: Feline cardiomyopathies, in Fox PR, Sisson D, Moise NS (eds): Textbook of Canine and Feline Cardiology. Philadelphia, WB Saunders Co, 1999, pp

7 372 Small Animal/Exotics Compendium May Liu SK, Roberts WC, Maron BJ: Comparison of morphologic findings in spontaneously occurring hypertrophic cardiomyopathy in humans, cats, and dogs. Am J Cardiol 72: , Fox PR, Liu SK, Maron BJ: Echocardiographic assessment of spontaneously occurring feline hypertrophic cardiomyopathy: An animal model of human disease. Circulation 92: , Kennedy HL, Brooks MM, Barker AH, et al: Beta-blocker therapy in the Cardiac Arrhythmia Suppression Trial. Am J Cardiol 74: , Behrend EN, Grauer GF, Greco DS, et al: Feline hypertrophic cardiomyopathy. Feline Pract 25(1):9 12, Packer M: The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 20: , Mann DL, Kent RL, Parsons B, Cooper 4 th G: Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 35: , Tan L, Jalil JE, Pick R, et al: Cardiac myocyte necrosis induced by angiotensin II. Circ Res 69: , Lechin M, Quinones MA, Omran A, et al: Angiotensin-I converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophic cardiomyopathy. Circulation 92(7): , Warren SE, Grossman W: Therapeutic approaches affecting diastolic ventricular function. Herz 16(1):33 45, Lijnen P, Petrov V: Induction of cardiac fibrosis by aldosterone. J Mol Cell Cardiol 32: , Lim DS, Lutucuta S, Bachireddy P, et al: Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation 103(6): , Harpster NK: Feline myocardial diseases, in Kirk RW (ed): Kirk s Current Veterinary Therapy IX: Small Animal Practice. Philadelphia, WB Saunders Co, 1986, pp Atkins CE, Gallo AM, Kurzman ID, Cowen P: Risk factors, clinical signs, and survival in cats with a clinical diagnosis of idiopathic hypertrophic cardiomyopathy: 74 cases ( ). JAVMA 201(4): , Bright JM, Golden AL, Daniel GB: Feline hypertrophic cardiomyopathy: Variations on a theme. J Small Anim Pract 33: , Laste NJ, Harpster NK: A retrospective study of 100 cases of feline distal aortic thromboembolism: JAAHA 31: , Jacobs G, Knight D: M-mode echocardiographic measurements in nonanesthetized healthy cats: Effects of body weight, heart rate, and other variables. Am J Vet Res 46(8): , Sisson DD, Knight DH, Helinski C, et al: Plasma taurine concentrations and M-mode echocardiographic measures in healthy cats and in cats with dilated cardiomyopathy. J Vet Intern Med 5: , Harpster NK: Unpublished data. Angell Memorial Animal Hospital, Boston. 29. Black IW: Spontaneous echo contrast: Where there s smoke there s fire. Echocardiography 17(4): , Leung DY, Black IW, Cranney GB, et al: Prognostic implications of left atrial spontaneous echo contrast in nonvalvular atrial fibrillation. J Am Coll Cardiol 24(3): , Harpster NK, Baty CJ: Warfarin therapy of the cat at risk of thromboembolism, in Bonagura JD (ed): Kirk s Current Veterinary Therapy XII: Small Animal Practice. Philadelphia, WB Saunders Co, 1995, pp ARTICLE #1 CE TEST The article you have read qualifies for 1.5 contact hours of Continuing Education Credit from the Auburn University College of Veterinary Medicine. Choose the best answer to each of the following questions; then mark your answers on the postage-paid envelope inserted in Compendium. 1. HCM is characterized by a. systolic dysfunction and myocardial atrophy. b. LV dilation. c. diastolic dysfunction and myofibrillar disarray. d. diastolic dysfunction with decreased myocardial contractility. e. none of the above 2. In feline HCM, the LV diastolic diameter is commonly a. unchanged. b. increased. c. decreased. d. dependent on the cat s sleep wake cycle. e. none of the above 3. Myocardial ischemia plays a significant role in HCM because it a. may prevent the development of CHF. b. decreases the likelihood of arrhythmias. c. can lead to myocardial fibrosis and increased myocardial stiffness. d. decreases the fibrillation threshold and thus predisposes the patient to arrhythmias. e. both c and d 4. Pronounced hypertrophy of the IVS and SAM of the mitral valve may lead to a. an enlarged left atrium. b. increased forward cardiac output. c. a left to right shunt. d. LVOT obstruction and an intraventricular pressure gradient. e. both a and d 5. Diagnosis of feline HCM is usually confirmed by a. ruling out other causes for LV hypertrophy (e.g., hyperthyroidism, systemic hypertension, congenital or valvular heart diseases). b. radiography and electrocardiography. c. history and physical examination. d. echocardiography. e. all of the above 6. A low-grade heart murmur in a cat a. should be monitored by auscultation at yearly visits.

8 Compendium May 2002 Hypertrophic Cardiomyopathy 373 b. should be taken seriously and a cardiac evaluation recommended. c. can usually be ignored. d. can often be associated with advanced cardiac disease. e. both b and d 7. Significant left atrial enlargement a. will usually resolve with time. b. is uncommon with HCM. c. does not have any prognostic implications. d. predisposes the patient to thrombus formation with subsequent embolization. e. occurs in all cats with HCM. 8. The main echocardiographic criterion used to diagnose HCM is a. the thickness of the IVS and LV free wall during diastole. b. cardiac contractility. c. the size of the left atrium. d. the degree of mitral regurgitation. e. none of the above 9. ECG abnormalities a. are uncommon in HCM. b. are common in HCM. c. are usually supraventricular. d. often influence the type of therapy initiated. e. both b and d 10. Feline HCM is most commonly seen in a. young female cats. b. geriatric female cats. c. middle-aged male cats. d. association with vaccination. e. multicat households.