Molecular Aspects and Gene Therapy Prospects for Diastolic Failure

Abnormal myocardial relaxation plays a major role in the pathogenesis of heart disease including hypertension, hypertrophic and dilated cardiomyopathies, and ischemic heart disease . In the latter two conditions, impairment of left ventricular (LV) diastolic function commonly occurs before systolic dysfunction . 16 The cause of abnormal muscle relaxation can be broadly attributed to increased chamber stiffness caused by combinations of passive and active factors. Passive factors include chronic changes in LV volume mass, chamber geometry, and composition of the LV wall including the collagen content, degree of fibrosis, and composition of the myofilaments . Active factors include dynamic changes that affect muscle relaxation, including abnormal sarcoplasmic reticulum Ca 2+ handling, and alterations of the myofilament Ca 2+ sensitivity. This article focuses on the active processes, in particular, the molecular mechanisms that regulate muscle relaxation during diastole , the possible molecular causes of impaired relaxation during ischemic, hypertrophic, and dilated cardiomyopathies, and newer gene therapy approaches that are attempting to address diastolic and the general contractile insufficiencies that accompany heart failure.