Feline Cardiomyopathies

2. Feline Cardiomyopathies

Cardiomyopathy designates all the disorders of the myocardium not secondary to a disease of another part of the cardiovascular system (valvular disease, alteration of the pericardium or the conducting system). These disorders are described as primary when their cause is undetermined or poorly identified. They are secondary when their origin is identified (hormonal, dietary, toxic, infectious or infiltrative cause). The importance of cardiomyopathies in cats is linked to the fact that they represent more than 90% of acquired cardiopathies in this species and are found in around 10% of cats at post mortem (Fox, 1999).

Classification – Main Characteristics

Cardiomyopathies are very heterogenous and can be classified according to different criteria. The most commonly used classification in practice is one that combines morphological, functional and lesional characteristics. There are four main groups of cardiomyopathy: hypertrophic (HCM), dilated (DCM), restrictive (RCM) and ‘unclassified’ also known as intermediate.
- Hypertrophic forms (Figure 8) are characterized by myocardial hypertrophy, most often of the free wall of the left ventricle and/or the interventricular septum. This hypertrophy may be symmetrical, asymmetrical or localized in the subaortic region, at the mainstays or the apex, which is described as segmentary hypertrophy (Fox, 2003; Häggström, 2003). HCM includes the primary forms, some of which have been shown to be genetically determined. These are handled in the next section. There are also secondary HCM, especially associated with hyperthyroidism, SH (see chapter 2), acromegaly and inflammatory or cancerous myocardial infiltration (particularly lymphoma).

Figure 8. Example of hypertrophic cardiomyopathy in a cat. (© Unit of Pathologic Anatomy, ENVA).

- Dilated forms are rare compared with hypertrophic forms. They may be primary or secondary. Secondary forms are either due to the cardiotoxicity of adriamycin (now uncommon), a sequela of myocarditis or taurine deficiency. Taurine deficiency cardiomyopathy (Figure 9), which is now very rare due to the supplementation of taurine in commercial foods, is discussed further in the text (Pion et al., 1992 a,b). DCM is characterized by a drop in inotropism concerning the left ventricle only or both ventricles simultaneously. Dilated cardiomyopathies that affect only the right heart have also been described (Fox et al., 2000).

Figure 9. Example of taurine deficiency dilated cardiomyopathy. (© Paul Pion).

- Restrictive forms, of varying phenotypical expression, are characterized by a diastolic myocardial dysfunction caused by endocardial fibrosis or most often major endomyocardial fibrosis. The origin of these restrictive forms remains unclear (Fox, 2004). Fibrosis may be cicatricial, secondary to an immune process, a viral infection or inflammation.
- Intermediate cardiomyopathies cover all myocardial modifications not strictly dilated, hypertrophic or restrictive. They include primary cardiomyopathies associating hypertrophy and dilatation as well as various infiltrations (e.g., myocardial mineralization in the event of hypervitaminosis D or hyperparathyroidism).

One study (Gouni et al., 2006) has been conducted on acquired feline cardiovascular diseases (primary cardiomyopathies, SH and degenerative valve lesions) diagnosed by echo Doppler at the Cardiology Unit at Alfort (UCA) between 2001 and 2005. Primary HCM was by far the most common disease among the 305 cats in the study (197/305 or 65% of cases), representing more than 85% of all primary cardiomyopathies. The second cardiomyopathy was RCM, followed by DCM and ‘unclassified’ cardiomyopathies, accounting for only 9%, 2% and 1.3% of all 305 cardiopathies respectively.

Current Knowledge on Primary Hypertrophic Cardiomyopathy

Genetic Determinism

Breed predispositions to HCM have been described, especially the Maine Coon, American Shorthair and Persian. HCM on the other hand is fairly rare in the Siamese, Burmese and Abyssinian (Kittleson et al., 1998). A hereditary form of the disease was recently proven in a colony of Maine Coon cats in the United States (Meurs et al., 2005). The mutation is in the gene coding for myosin binding protein C (MYBPC3) and the described mode of transmission is dominant autosomal with variable expression. A different mutation of the same gene was recently found in the Ragdoll (Meurs et al., 2007).

The Maine Coon is predisposed to primary hypertrophic cardiomyopathy. (© Y. Lanceau/RC/Maine Coon).

Sex is also a factor in the expression of HCM. Most cats (up to 90% according to the studies) affected by HCM are toms. Age on the other hand does not appear to have so great an influence on the disease, which can affect cats aged 3 months to 17 years, with an average between 4 and 7 years (Fox, 2000).

Pathophysiological Consequences

Left myocardial hypertrophy characterizing HCM mainly causes alteration of the diastolic function, at least initially, both at the very start of diastole (relaxation phase or active phase necessitating energy) and in the second and final phase of diastole (compliance phase). Due to myocardial hypertrophy and especially the fibrotic lesions frequently associated with HCM, the elasticity of the myocardium is reduced and the compliance phase is altered. Furthermore, due to coronary alterations and myocardial ischemia connected with a ‘relative’ reduction in the coronary/myocardial mass ratio, the relaxation phase is also altered.

This diastolic myocardial dysfunction leads eventually to dilatation of the left atrium because of the problems of diastolic emptying of the atrium, followed by the development of left heart failure and finally to the terminal phase of overall heart failure. Left atrial dilatation is frequently accentuated by the presence of mitral layers that cause mitral systolic reflux, which in turn is aggravated by the abnormal movement of the mitral layers – mitral anterior systolic motion – accompanying the obstructive hypertrophies (the extremity of the mitral layers move in the left ventricular outflow tract during systole).

Recent studies using modern ultrasound imaging technology (tissue Doppler imaging (TDI)) have shown that systolic dysfunction associated with diastolic dysfunction occurs much earlier than previously thought. This may contribute to the earlier development of congestive heart failure (Carlos Sampedrano et al., 2006; Chetboul et al., 2006a;b).

Arterial thromboembolism, defined as the partial or total obliteration of an artery by a distally formed blood clot, constitutes another potential complication of HCM. According to a retrospective study of 100 cases of arterial thromboembolism in cats, the most common cause of this complication is HCM (Laste & Harpster, 1995). The primary thrombus forms most often in the left atrium (especially during atrial dilatation), sometimes in the left ventricle and much less frequently in the right cavities unless they are dilated themselves (Laste & Harpster, 1995; Smith et al., 2003). In the majority of cases (on average 90%), the embolized thrombus ends in the aortic trifurcation, causing ischemic neuropathy of the two posterior limbs. Other localizations are sometimes observed (brachial, cerebral, mesenteric, pulmonary and renal arteries). Congestive heart failure and cardiac arrhythmias (Smith et al., 2003) are commonly associated with arterial thromboembolism (more than 40% of cases for each).

Fatty Acid Metabolism

Fatty acids (FA) are the heart’s main source of energy. Abnormalities in the metabolism of FA are sometimes associated with some cardiopathies, including some forms of HCM in humans (Kelly & Strauss, 1994). A deficiency of CD36 has been described in human DCM. CD36 is a FA transporter that helps provide energy to the myocardium (Okamoto et al., 1998; Watanabe et al., 1998; Nakata et al., 1999; Hirooka et al., 2000).

In spontaneously hypertensive rats, in which SH is associated with insulin resistance and dyslipidemia, the administration of short- and medium-chain fatty acids (SMCFA) at 21.5 g/ 100 g diet permits restoration of normoglycemia and limits the consequences of hyperinsulinemia and cardiac hypertrophy (Hajri et al., 2001). These results suggest that insufficient provisioning of energy to the myocardial cells could contribute to the development of HCM.

Additional studies will be needed to confirm the positive role of SMCFA in cats with HCM.

Diagnosis

The first step in the diagnosis of HCM is a careful clinical examination, with special attention for auscultatory abnormalities (Figure 10): tachyarrhythmia, systolic murmur in the left apex, often also audible in the sternal region, systolic murmur in the left basal region during sub-valvular aortic obstruction, and a gallop rhythm. However, the absence of a heart murmur does not exclude the presence of HCM, as around 40% of cats are exempt (Rush et al., 2002). Almost half of cats with HCM have congestive heart failure characterized by restrictive dyspnea (pulmonary edema and pleural effusion), ascites or much more rarely coughing. Syncope is a rare expression of the disease, found in less than 5% of cases (Rush et al., 2002).

Figure 10. Auscultation (here a Maine Coon) is a fundamental part of the clinical cardiovascular examination, even in asymptomatic animals. (© Valérie Chetboul).

An echocardiographic examination permits the direct confirmation of myocardial hypertrophy (precise quantification and location) as well as its consequences for the cavities (dilatation of the left atrium) and hemodynamics (subvalvular aortic obstruction, pulmonary arterial hypertension). An earlier diagnosis of HCM can be obtained by tissue Doppler imaging (Figure 11), which may sometimes reveal a diastolic or systo-diastolic myocardial dysfunction even before parietal hypertrophy is detectable by conventional ultrasound imaging (Chetboul et al., 2005; Chetboul et al., 2006a, b). This technique can be especially useful for animals destined for breeding or "doubtful" cases, whose myocardial walls are at the higher end of the thickness limit.
Figure 11. Early screening for hypertrophic cardiomyopathy in a maine coon using echocardiography (Chetboul et al., 2006b).

A DNA test is now available to look for the gene mutation in the Maine Coon coding for MYBPC3. This test enables differentiation of wild homozygote animals from heterozygote animals or animals with mutated homozygotes. However, this genetic status does not predict myocardial disease (presence or absence, quantitative importance). Data collected over more than two years (unpublished UCA data) from complete clinical, ultrasound and TDI data in Maine Coons (more than 100) show that some heterozygote animals may remain asymptomatic for many years, when they undergo conventional ultrasound examinations or even normal TDI. Conversely, some rare cats genetically tested ‘normal’ (wild homozygotes) can present signs of HCM in an ultrasound examination and/or TDI, implying that HCM is not linked to a single gene, at least in this breed. In practice, if owners have the resources, the ideal scenario is a precautionary DNA test together with ultrasound imaging.

Prognosis and Therapeutic Principles

HCM is a serious cardiopathy due to the potential complications, which include congestive heart disease (46% of cases), arterial thromboembolic accidents (16.5%) and arrhythmia potentially causing sudden death (Rush et al., 2002). In a retrospective study by Rush et al. (2002), which included 260 cats with HCM, the median survival time in animals that survived more than 24 hours was 709 days with a large variability (2 - 4418 days). Animals whose disease was not clinically expressed had a better survival (median of 1129 days). Conversely, those presenting with an arterial thromboembolic accident had a lower survival rate (median of 184 days). The seriousness of thromboembolic complications in the cat is shown in other studies, including a study by Smith et al. (2003) that reported a median survival rate of 117 days, and only 77 days if associated with heart failure.

The treatment of HCM is based on the different classes of drugs (Table 3): angiotensin-converting enzyme inhibitors, calcium inhibitors of the benzothiazepine family and beta-blockers. In the event of congestive heart failure, angiotensin-converting enzyme inhibitors will be preferred due to preliminary results of the study by Fox et al. (Multicenter Feline Chronic Failure Study) (Fox, 2003). Studies are however necessary to improve understanding of the comparative position of each of these classes in the treatment of feline HCM.

Taurine Deficiency Cardiomyopathy

Until the end of the 1980s, dilated cardiomyopathy (DCM) was more common than HCM in the feline population (Fox, 1999). Improved knowledge of the taurine requirements of cats has since reduced its incidence considerably.

Taurine was discovered in 1827 as a constituent of ox bile (Bos taurus), which is where the name is derived from. It is a sulfur-containing amino acid.

(H+ 3 N - CH2 - CH2 - SO-3)

Taurine cannot be linked by peptide bonds and thus cannot be part of a protein. In its free form, it is mainly found in the striated muscles (including the myocardium), the central nervous system, the retina and the liver (Zelikovic et al., 1989). Taurine plays a membrane protection role in the myocardium and regulates contractile function. An inadequate taurine intake can thus cause myocardial dysfunction, which in turn may be complicated by congestive heart failure (Pion et al., 1992a,b).

Genetic Determinism

Taurine is primarily synthesized in the liver from sulfur-containing amino acids, methionine and cysteine (Figure 12), and the action of several enzymes, including cysteine dioxygenase and cysteine sulphinic acid decarboxylase. In cats, the biosynthesis of taurine from its precursors is inadequate to cover the needs, as the activity of the hepatic enzymes is very low (especially compared with dogs). A dietary intake of taurine is therefore essential.

Figure 12. General pathway of taurine synthesis in the liver from sulphur amino acids.

Moreover cats waste large amounts of taurine. Indeed, as dogs, they use only taurine for the conjugation of bile acids, whereas humans and rats can also use glycine (Morris et al., 1987). This represents a continual loss of taurine, as a substantial part is not recovered by the entero-hepatic circulation and is lost in the feces (Figure 13).

Figure 13. Enterohepatic circulation of taurine.

Why has the cat lost its ability to synthesize a nutrient as essential as taurine? Taurine is one of the most abundant amino acids in animal tissues, so cats are not at risk of taurine deficiency when on their natural diet. Under those circumstances producing taurine is a waste of energy whereas the deamination and desulfurization of cysteine is an alternative metabolic pathway that allows cats to produce energy rather than taurine from sulfur amino acid catabolism.

The requirement of taurine in cats is a unique example of a nutritional need that varies according to the influence of the diet on the intestinal flora (Backus et al., 2002). The measurement of breath hydrogen in cats (a measure of the level of intestinal fermentations) shows that wet food favors the proliferation of a flora that consumes larger quantities of taurine than the flora associated with dry expanded kibbles (Morris et al., 1994; Backus et al., 1994; Kim et al., 1996a,b). Taurine losses are linked to the level of protein in the diet as well as the heat processing applied in canning. This explains why wet food requires higher levels of taurine supplementation (1.7 g/kg DMB) compared to dry food (1 g/kg DMB).

Pathophysiological Consequences of Taurine Deficiency

When a cat is deficient, the body’s taurine concentrations fall in a few days to a few months depending on the tissue: the plasma is affected first, followed by the whole blood, then the muscles and lastly the retina and the nervous tissue (Pacioretty et al., 2001).

Taurine deficiency has been shown to be the main cause of DCM in cats (Pion et al., 1987). If identified in time, this disease can be reversed by the oral administration of taurine. Deficient cats present anatomical abnormalities of the heart but there are no histological lesions that would suggest an organic disease of the cardiac tissue. The pathophysiological mechanisms by which taurine deficiency affects cardiac function remain poorly understood. Taurine affects ionic flow of calcium and sodium in the myocardium and thus plays a role in regulating systolic and diastolic myocardial activity (Novotny et al., 1991). The interaction between taurine and calcium (characterized by the spontaneous release of calcium by the reticulum and increased sensitivity of the myofilaments to calcium) contributes to its positive inotrope effects.

Diagnosis

The role of taurine in feline DCM has been known for twenty years (Pion et al., 1987). Clinical signs vary widely depending on the individual. Experimental taurine deficiency often produces the simultaneous appearance of irreversible central retinal degeneration (Figure 14) (within six months and inducing total blindness within less than two years) and DCM of varying degrees within two to four years. Not all cats fed taurine deficient diets will develop ultrasonographic or clinical signs of DCM during this time frame.

Figure 14. Central retinal degeneration in a cat suffering from taurine deficiency. (© Paul Pion).

Taurine deficiency has been shown to be the main cause of DCM in cats (Pion et al., 1987).

When taurine-deficiency DCM develops, owners are often alerted by the sudden appearance of dyspnea caused by the development of congestive heart failure. Echocardiography shows a reduced shortening fraction (Figure 15) as well as an increased systolic diameter of the left ventricle. Later on a left ventricular dilatation that is both systolic and diastolic, associated with thinning of the cardiac walls occurs. In well-developed forms, all four heart chambers are dilated.
Figure 15. Echocardiograph of taurine-deficiency associated dilated cardiomyopathy (time-movement mode) before (on the left) and after (on the right) taurine supplementation. In this patient, the echocardiography shows a reduced shortening fraction and a dilatation of the left cavities (left picture). These alterations are reversible after taurine administration (right picture). (© Paul Pion).

In healthy cats, the plasma taurine concentration is greater than 50 nmol/mL (Pacioretty et al., 2001) but the plasma concentration reflects recent taurine intake only. It is affected by fasting and does not provide any information on the body’s reserves. The result may be artificially high in cats with systemic thromboembolism. As white blood cells and platelets contains high levels of taurine, plasma concentration will be affected by hemolysis or poor separation of the buffy coat.

Establishing a conclusive diagnosis of taurine deficiency requires measurement of the whole blood taurine level because it better reflects taurine concentrations in the myocardium and skeletal muscles. In healthy cats, the whole blood taurine concentration should be higher than 250 nmol/mL (Pacioretty et al., 2001). If lower, taurine deficiency is confirmed.

Treatment

In addition to feeding a diet containing adequate taurine, it is generally recommended to supplement the cat with 250 mg of taurine twice daily (Freeman, 2000). If the cat’s heart failure can be controlled initially the prognosis is good and clinical signs should clearly improve within one to two weeks. This delay corresponds to the recovery of a normal plasma concentration. Improvements in radiographic and echocardiographic signs will take at least 3 - 6 weeks. Even if clinical signs improve rapidly supplementation should be pursued for several months.

Some cases of taurine-deficiency associated DCM do not respond to the administration of taurine. The reason for this remains unclear. Nevertheless, taurine supplementation is still recommended for these "resistant" animals at 250 mg twice daily (Freeman, 2000).

Prevention

Prior to 1987 the taurine levels found in commercial wet cat foods were commonly inadequate to maintain plasma and whole blood concentrations. As the role of taurine in the pathogenesis of DCM has been better understood, manufacturers have increased taurine levels in their diets and the incidence of feline DCM is now very low (Pion et al., 1992a,b).

To maintain plasma and whole blood taurine concentrations within the physiological range, feline dry expanded diets must contain at least 1 g taurine/kg DMB and wet diets at least 1.7 g/kg DMB (NRC 2006). Taurine supplementation is very safe and no harmful effect on health has been found, even at doses in excess of 10 g/kg DMB in diets with energy concentrations around 4500 kcal/kg (NRC, 2006).