Myocyte deficiency as a target in the treatment of cardiomyopathy

Cardiomyopathy is a general term referring to any disorder of cardiac muscle function, and can result from a number of defined and unknown acquired and congenital disorders; the end result is generally reduced contractile function and heart failure. Heart failure may occur early or late in the course of cardiomyopathy depending on the etiology and the age of the patient. How cardiomyopathic disorders lead to heart failure is incompletely resolved, particularly for disorders associated with hypertrophy. A leading hypothesis is that heart failure is effectively a myocyte deficiency disorder, reflecting the view that cardiomyopathy leads to cell loss and thence to heart failure. Several approaches for addressing this deficiency have been studied, including gene therapy targeting specific molecular events, cell therapy using myocytes from various sources, and a combination of gene and cell therapy using gene-modified cell transplantation. The recent discovery of populations of self-renewing progenitor cells residing in the myocardium raises the possibility of enhancing endogenous repair and regeneration mechanisms, and suggests additional levels at which genetic disorders may lead to impairment of myocardial function. Here we will review the evidence for myocyte dropout as a functionally significant phenomenon in human myocardial disorders, briefly discuss mechanisms and effectors of myocyte death, and their potential as targets in the treatment of cardiomyopathy. Finally, we will consider ways in which cell replacement therapy may eventually provide a solution to myocyte deficiency disorders.