Little Mice with Big Hearts: Finding the Molecular Basis for Dilated Cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is characterized by increased ventricular chamber size and dimension coupled with loss of contractile function, myofibril organization and 13-adrenergic responsiveness. [1] Typical microscopic features include high incidence of myocyte hypertrophy and apoptosis, [2–4] varying degrees of fibrosis and the presence of lymphocytes in the interstitial space [5]. Clinically, the disease displays heart failure symptoms consistent with New York Heart Association (NYHA) functional class III or IV at the time of diagnosis [6] and remains the principal indication for heart transplantation in both adults and pediatric cardiology [6–8]. The clinical treatment of human DCM is a substantial economic burden estimated to cost $10 to $40 billion annually in the United States alone [9]. First and foremost in terms of pathologic consequences, DCM is distinguished by a profound loss of myocardial contractile function. The degeneration of structure and function in cardiomyocytes observed in dilation is less amenable toin vitroanalysis compared to hypertrophie changes associated with enhanced contractile function and enlarged cardiomyocyte size that are readily apparent by analyses of cultured cells. Cardiomyocyte remodeling in dilation results from a combination of physical stresses and signal transduction leading to profound structural changes of the entire heart. This combinatorial environment is best reproducedin vivoas evidenced by the emergence of transgenic and gene targeted animal models that display the characteristic features of DCM. These models are useful to study the temporal progression of pathogenic alterations that occur at the molecular, cellular and organ levels. Many genetic mouse models of cardiomyopathy have emerged over the past decade, many of which display hypertrophie remodeling, whether or not in combination with features of DCM. The scope of this review, however, is to concentrate on those genetic models that display multiple characteristics of humanKeywordsSarcoplasmic ReticulumFocal Adhesion KinaseDilate CardiomyopathyCardiac HypertrophyHypertrophic ResponseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.