Function of the Cardiac Myocyte in the Conundrum of End-Stage, Dilated Human Heart Failure

Chronic heart failure is a phenotype that marks the final common pathway in a diversity of specific cardiovascular disease states, eg, severe coronary ischemia and myocardial infarction, and chronic hypertension, or it can be idiopathic in nature. A trilogy of clinical signs that includes reduced systolic myocardial function, increased diastolic filling pressure, and an increased likelihood for the occurrence of cardiac arrhythmias is eventually accompanied by a markedly dilated heart. The specific role of cardiac myocyte dysfunction in progressive cardiac dilatation that heralds the end stage of chronic heart failure is 1 facet of the conundrum of the end-stage dilated heart. In this issue of Circulation , Hasenfuss et al1 have studied cardiac muscle isolated from the left ventricle of end-stage, dilated cardiomyopathic hearts removed from patients and cardiac muscle from control, non–heart-failure organ donors in an attempt to discover mechanisms that may underlie cardiomyocyte dysfunction in chronic end-stage heart failure.See p 641As a platform for the discussion of their study, let us first acknowledge that a plethora of hypotheses, in addition to progressive myocyte dysfunction, have been put forth to explain the progressive functional demise and cardiac remodeling and dilatation that characterize end-stage heart failure. These hypotheses were originally cast from observations in heart failure in animal models, including those resulting from chronic experimental mechanical (pressure or volume) overload or chronic ischemia and those resulting from naturally occurring heart failure in specific genetic strains of rodents (eg, the Syrian hamster; the old, spontaneously hypertensive, obese, or diabetic rat; and more recently, heart failure in genetically manipulated mice). In most of these models, progressive cardiac dilatation and functional demise eventually occur. Studies that have attempted to understand the conundrum of the evolution to the progressively dilated phenotype have focused on a diverse array of specific changes in …