Hypertrophic cardiomyopathy (HCM) is a primary disorder of the myocardium characterized by concentric ventricular hypertrophy (predominantly of the left ventricle), in the absence of left ventricular dilatation and of underlying causes. The heart can undergo concentric hypertrophy following cardiovascular diseases that cause a pressure overload (aortic stenosis, systemic hypertension) or metabolic disorders (hyperthyroidism, acromegaly). HCM is the most common cardiovascular disease in cats, accounting for 67.6% of cardiac disorders in this species, with a prevalence ranging between 1.6 % and 8.3%.
HCM has been described in many breeds of cats and in the European Shorthair cat. Some breeds (Maine Coon, Persian, Norwegian Forest cat, Ragdoll, Sphynx, British Shorthair, Cornish Rex, Devon Rex) seem to be predisposed and a family history has been described in some cases. As in humans, the mode of transmission is autosomal dominant.
Autosomal dominant transmission refers to a disorder caused by a defect in the dominant allele of a gene in an autosome. For this reason the disease can be present in both males and females and can also be manifested by heterozygotes. Typical characteristics of the autosomal dominant mode of transmission are that several successive generations are affected, the proportions of males and females affected are the same, both males and females can transmit the disease, and at least one case of male to male transmission is known.
So far more than 400 mutations have been found to cause HCM in humans, with different mutations within the same family and even within a single individual. Genetic mutations underlying HCM have been identified in Maine Coon and Ragdoll cats, but it is thought that there are many more yet unidentified mutations, given the fact that subjects negative for the known mutations can develop the disease anyway, just as positive subjects, although being carriers of a mutation, do not necessarily develop the clinical phenotype of HCM.
A mutation of codon 31 of the gene coding for myosin binding protein C3 (MYBPC3) with an alanine to proline substitution has been identified in Maine Coon cats. The incidence of this mutation in the breed is 34%. A mutation in the same gene has also been found in Ragdoll cats, but in this case the mutation is in codon 820, and there is an arginine to tryptophan substitution.
PATHOPHYSIOLOGY
HCM is characterized primarily by diastolic dysfunction, although systolic dysfunction can also develop in the terminal stages. The left atrium becomes dilated as a result of the decreased ventricular compliance and increased ventricular diastolic pressures. In 42% of cats with HCM there is an obstructive form of cardiomyopathy characterized by dynamic stenosis of the outflow tract of the left ventricle caused by the septal movement of the anterior leaflet of the mitral valve (SAM) (Fig. 1).
Septal anterior motion (SAM) is the systolic movement of the anterior leaflet of the mitral valve towards the interventricular septum. There are numerous mechanisms involved in this motion. The main one is that ventricular hypertrophy alters the anatomy of the papillary muscles and the geometry of the mitral annulus, with consequent alterations to the movement of the valve leaflets. Furthermore, the Venturi effect which is created sucks the anterior leaflet of the mitral valve into the outflow tract of the left ventricle, thereby worsening the dynamic stenosis and consequent mitral valve regurgitation.
Atrial dilatation predisposes to pooling of blood and the formation of thrombi which can subsequently embolise.
Arterial thromboembolism occurs in about 50% of cats with HCM. The thrombus most commonly stops at the aortic trifurcation and the cat develops marked tenderness of the hind limbs and paraparesis. Arterial thromboembolism can, however, sometimes affect only one hind limb or one or both of the fore limbs; other sites have been described rarely (Fig. 2).
In the terminal stage of the disease, there is marked systolic dysfunction with thinning of the ventricular walls, volume overload and ventricular hypokinesia. The phenotype and echocardiographic findings of the terminal form resemble those of dilated cardiomyopathy. For this reason the diagnosis of terminal HCM can only be made in the presence of a prior echocardiographic diagnosis of HCM.
DIAGNOSIS
THE CAT WITH ASYMPTOMATIC HYPERTROPHIC CARDIOMYOPATHY
About 50% of cats with HCM have a heart murmur on examination, but no other clinical signs.
The murmur is an early or mid-systolic ejection murmur, generally located over the left parasternal region. The intensity of the murmur can vary with the heart rate (the intensity may increase or the heart murmur may only be audible at fast heart rates, particularly in the case of SAM). A gallop rhythm may be detectable.
Agallop rhythm is due to a third heart sound in addition to S1 and S2. The gallop rhythm during HCM is normally related to a strengthened S3, due to altered relaxation. In advanced stages an S4 can also be heard, due to reduced compliance, and a quadruple gallop rhythm is detectable during auscultation.
When making a diagnosis of HCM it is important to exclude systemic hypertension and hyperthyroidism which are possible causes of an ejection murmur.
The definitive diagnosis of HCM is made by echocardiography. Echocardiography enables the presence of HCM or other congenital or acquired disorders to be excluded or confirmed. The echocardiographic criteria for the diagnosis of HCM are controversial because of the wide phenotypic variability of this condition. There are subjects with borderline HCM from an echocardiographic point of view which can manifest the disease over time or remain with a non-classifiable cardiomyopathy with characteristics intermediate between those of the various recognized feline cardiomyopathies (Figs. 3 and 4).
Echocardiography must be carried out in several views in order to evaluate the morphology of the left ventricle and papillary muscles completely. Hypertrophy may, in fact, involve the whole ventricle or be segmental and measuring wall thickness at only one level could lead to a false diagnosis. Cut-off values for defining normal wall thicknesses have been established and accepted by most authors. Subjects are considered normal if the diastolic thickness of the free wall and of the interventricular septum is <5 mm. A diastolic wall thicknesses >6 mm in these sites is considered pathological. Thicknesses between 5 and 6 mm are considered border-line and should be monitored over time. Diastolic wall thicknesses should, however, be interpreted in the context of the findings of a full echocardiographic study. The atrial dimensions, the presence of SAM, any alterations in endocardiac echogenicity, hypertrophy of the papillary muscles and evaluation of diastolic function are indispensable for the diagnosis and staging of the disease in the subject under examination.
Genetic tests have recently become available for the detection of the two mutations in the gene coding for myosin binding protein C3 (MYBPC3) in Maine Coon and Ragdoll cats. The usefulness of these tests is, however, limited to the recognition of carriers of the specific mutations. Genetic tests, therefore, remain a monitoring instrument available for breeders, but not a useful strategy for the diagnosis of HCM, given that they are not able to exclude the development of the disease in subjects with a different mutation.
THE CAT WITH DYSPNOEIC HYPERTROPHIC CARDIOMYOPATHY
The main clinical sign in the stage of decompensation is dyspnoea secondary to pulmonary oedema and/or pleural effusion. Before starting with diagnostic investigations that are potentially stressful to the cat, it is important to stabilise the patient by administering humidified oxygen at 65 ml/kg/min. There are various ways to administer oxygen. In difficult to manage or severely dyspnoeic patients, an oxygen cage is the simplest system, allowing visual monitoring of the patient and minimising stress. Placement of a nasal tube, which in some subjects can require mild sedation, allows better administration with an appropriate and constant concentration of oxygen. Besides administering oxygen, it is advisable to carry out a thoracentesis in patients who are dyspnoeic because of a pleural effusion.
Thoracentesis is performed with the animal in lateral recumbency or sternal position, depending on which is less stressful for the animal. The part is shaven and prepared surgically. A butterfly needle (21 G), a three-way stopcock and a syringe are used. The access is made at the level of the seventh intercostal space, inserting the needle at two thirds of the distance between the costo-chondral junction and the spinal column. It is good practice to insert the needle first through the skin with the stopcock closed, subsequently moving the skin and needle to the level of the intercostal space. In this way the risk of allowing air to enter the thorax is reduced. The drainage is simplest if placed in a dependent area. If the first attempt is unsuccessful, the needle must be re-positioned. Complications of thoracentesis include iatrogenic pneumothorax, haemothorax and pyothorax.
Chest radiography is an easily performed examination, available in most clinics, and can provide useful information on the clinical condition of the patient. In the first place it enables dyspnoea of cardiac origin to be differentiated from that of pulmonary origin. In cats with HCM, chest X-rays show any enlargement of the cardiac shadow, the presence of pulmonary oedema, pleural or pericardial effusions, or changes in the pulmonary vessels (Figs. 5 and 6).
It has been suggested that levels of plasma B-type natriuretic protein (BNP) can be used to diagnose HCM. Unfortunately, from the data reported in the literature, it seems that although the plasma concentration of feline N-terminal pro-BNP (NTpro-BNP) has a high sensitivity and specificity for the diagnosis of severe HCM, it is not able to discriminate subjects with a mild or moderate form of HCM from healthy subjects. This limits the usefulness of BNP in making a clinical diagnosis of HCM.
Echocardiography in subjects with heart failure is the investigation that can confirm the diagnosis and stage the patient, after clinical stability has been achieved.
THE CAT WITH HYPERTROPHIC CARDIOMYOPATHY AND ARTERIAL THROMBOEMBOLISM
The five signs of thromboembolism are: absence of pulse, paresis, pain, pallor, and hypothermia. The diagnosis of thromboembolism is based on the findings of the clinical examination. The onset of the clinical signs is acute and the clinical picture depends on the area affected by the embolus. The hind limbs are involved most frequently but, rarely, the fore limbs may also be affected. The cat typically presents with an absent femoral pulse, cold limbs, cyanosis of the nail bed and hard, painful muscles in the area involved. Thrombi can also occlude the arterial circulation at the level of the renal arteries, causing acute renal failure, or mesenteric or pulmonary arteries, causing failure of the organs supplied by these vessels.
TREATMENT
Atenolol 6.25-12.5 mg every 12-24 hours per os
Diltiazem 15-30 mg every 12-24 hours per os
Benazepril 0.25-0.5 mg/kg every 24 hours per os
Enalapril 0.25-0.5 mg/kg every 24 hours per os
Ramipril 0.5 mg/kg every 24 hours per os
Spironolactone 6.25 mg every 24 hours per os
Pimobendan 0.625-1.25 mg every 24 hours per os
Dopamine 1.1-11 mcg/kg/min intravenously
Dobutamine 4.4-15.4 mcg/kg/min intravenously
Aspirin 81 mg every 3 days per os
Unfractionated heparin 100-500 IU/kg IV as acute treatment, followed by 50 IU/kg subcutaneously every 6-8 hours
Clopidogrel 18.75 mg every 24 hours
Tab. 1. Treatment. Recommended doses for cats (PlumbDC. Veterinary Drug Handbook. 4th edition, 2002, Ames, Iowa, Pharma Vet Publishing).
THE CAT WITH ASYMPTOMATIC HYPERTROPHIC CARDIOMYOPATHY
The management of asymptomatic subjects is controversial. Treatment with β-blockers, calcium antagonists, ACE inhibitors or spironolactone has beneficial effects on survival and cardiac remodelling in humans. However, although it is reasonable to expect that similar effects could also be obtained in cats, there are no double-blind, randomised studies demonstrating that these benefits do actually occur in felines.
THE CAT WITH SYMPTOMATIC HYPERTROPHIC CARDIOMYOPATHY
The treatment of the symptomatic patient is aimed at resolving the acute event and improving the quality of life of the animal.
The dyspnoeic patient is stabilised with the administration of oxygen. The use of intravenous diuretics is indicated for subjects with pulmonary oedema, while dyspnoea secondary to a pleural effusion improves rapidly following thoracentesis.
β-blockers (e.g., atenolol) are the drugs indicated to control heart rate, to reduce the dynamic component of the stenosis of the outflow tract of the left ventricle and to reduce myocardial oxygen consumption. However, given the negative inotropic effect of these drugs, they are indicated for chronic treatment, but not in the acute phase.
Calcium-antagonists are indicated for the control of heart rate and for their positive lusitropic property and vasodilatory effect on the coronary circulation.
In the case of systolic dysfunction, it may be necessary to use positive inotropes. Dopamine and dobutamine are indicated in the acute phase, administered by continuous intravenous infusion. The drugs advised for chronic treatment are digitalis and pimobendan; this latter is not currently registered for use in the cat, although it seems to be well tolerated in this species and appears to improve the clinical condition of the patients.
Anticoagulant or anti-aggregant drugs are used for the prevention of thromboembolism. It has not, however, been clearly established whether prophylactic treatment decreases the frequency and severity of thromboembolism in predisposed cats. The drugs used with a prophylactic purpose are aspirin, unfractionated heparin, low molecular weight heparin and clopidogrel. Warfarin is not recommended for long-term prophylaxis because it has an aspirin-like action but with a greater risk of causing spontaneous haemorrhage thus requiring close monitoring of the patient’s clotting parameters. The aim of the treatment of acute thromboembolism is to control the pain, through the administration of opioids, and to reduce the formation of further thrombi by administering anticoagulants (heparin, warfarin). The use of thrombolytic agents such as streptokinase or tissue type plasminogen activator (tPA) has been proposed; however, the currently available data do not encourage the use of these drugs rather than the traditional therapeutic approach.
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