Hepatitis C virus infection and cardiomyopathies.

Cardiomyopathies may present as idiopathic dilated, hypertrophic, or restrictive disease, arrhythmogenic right ventricular cardiomyopathy (ARVC), and various other distinct disorders of the heart muscle.1 They constitute a heterogeneous group of myocardial diseases of multifactorial etiologies, including genetic anomalies and acquired immune factors, such as viral infections. The myocardium may be infected by a wide variety of viruses, although most commonly by enteroviruses, coxsackievirus B in particular. However, in many cases, when myocarditis has been diagnosed on the basis of clinical manifestations, a viral origin cannot be confirmed, despite extensive laboratory investigations. The clinical presentation of viral myocarditis is variable. When myocardial necrosis is diffuse, congestive heart failure develops, and growing evidence now links viral myocarditis with dilated cardiomyopathy.2,3 Localized myocardial lesions may result in thinning or aneurysms of the ventricular wall which, in the case of ARVC, are complicated by arrhythmias.4 When myocardial necrosis is limited to the subendocardium, restrictive cardiomyopathy may develop. Finally, although it has not been established that hypertrophic cardiomyopathy is a complication of viral myocarditis, asymmetrical septal hypertrophy has been observed in some patients with myocarditis.5 A high prevalence of hepatitis C virus (HCV) infection has recently been noted in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, and myocarditis (Figure 1).6–15 In this issue of Circulation Research, Omura et al16 report that mice transgenic for the HCV-core gene develop ventricular dilatation, cardiac dysfunction, and myocardial fibrosis at 12 months, similar to the pathological manifestations observed in human dilated cardiomyopathy. Although HCV infection may be the cause of several phenotypically different cardiomyopathies, mild inflammation with mononuclear cell infiltration has also been observed with HCV infection in humans.6,7,9 However, no lymphocytic infiltration was observed in these HCV-core transgenic mice. Furthermore, cardiomyocyte hypertrophy and disarray of the myofibers are typical characteristics of human hypertrophic cardiomyopathy, but the wall thickness of the HCV-core mice was not increased. Therefore, although the HCV-core mice did not have all the phenotypical manifestations of human cardiomyopathies, the observations made by Omura et al are nevertheless relevant, because they show that the expression of the HCV-core is associated with the long-term development of myocardial disease. They also found that the expression of atrial and brain natriuretic polypeptides was enhanced, and that activator protein-1 (AP-1) was activated in the heart. However, nuclear factorB (NFB) was not activated. The authors state that the activation of myocardial AP-1 by HCV-core is an important pathway toward cardiomyopathic changes, although it has not been shown that blocking this pathway changes the disease phenotype. Whereas AP-1 is activated in transgenic mice of HCV core protein,17 the latter interferes with the activation of AP-1 in human macrophages.18 Furthermore, HCV core protein inhibits AP-1,19 and activates extracellular signal-regulated kinase (ERK), C-jun N-terminal kinase (JNK), and p38 mitogen-activated protein (MAP) kinase.20 Although, HCV core protein is known to activate NFB,21 the authors found no changes in NFB. Therefore, further studies will be necessary to clarify the molecular pathogenetic changes observed in HCV-core transgenic mice.