Molecular remodelling of dystrophin in patients with end-stage cardiomyopathies and reversal in patients on assistance-device therapy

Background Mutations that lead to disruption of cytoskeletal proteins have been recorded in patients with familial dilated cardiomyopathy. We postulated that changes in cytoskeletal and sarcolemmal proteins provide a final common pathway for dilation and contractile dysfuncton in dilated cardiomyopathy. In this study, we investigated the integrity of dystrophin in the myocardium of patients with end-stage heart failure due to ischaemic or dilated cardiomyopathy, and the response to treatment with left-ventricular assistance devices (LVAD). Methods We assessed the expression and integrity of dystrophin in myocardial biopsy samples by immunohistochemistry and westem-blot analysis using antibodies against the amino-terminal, carboxyl-terminal, and midrod domains. We took samples from the myocardia of ten controls, ten patients with dilated cardiomyopathy, ten with ischaemic heart disease, and six with dilated cardiomyopathy who underwent placement of a left-ventricular assistance device for progressive refractory heart failure. Findings Immunohistochemical staining identified a disruption to the amino-terminus of dystrophin in 18 of 20 patients with end-stage cardiomyopathy (dilated or ischaemic), whereas staining with antibodies against other domains of dystrophin was normal. Westem-blot analysis confirmed these observations, suggesting that remodelling of dystrophin is a common pathway for dysfunction of failing cardiomyocytes. Furthermore, this disruption was reversible in four patients after LVAD support. Interpretation Dystrophin remodelling is a useful indicator of left-ventricular function in patients with dilated and ischaemic cardiomyopathy. Our results lend support to the hypothesis that changes in cytoskeletal proteins and, in particular, dystrophin might provide a final common pathway for contractile dysfunction in heart failure and these changes might be reversible by reduction of mechanical stress.