Connective tissue and the heart. Functional significance and regulatory mechanisms.

The heart has a three-dimensional extracellular fibrillar collagen scaffolding that normally serves a variety of functions important to tissue integrity and efficiency of muscular systolic pump and diastolic suction pump function (see article by Kovács). An adverse accumulation of extracellular matrix structural protein compromises tissue stiffness and adversely affects myocardial viscoelasticity, this leads to ventricular diastolic and systolic dysfunction. Hormonal factors, such as chronic, inappropriate (relative to dietary salt intake and intravascular volume) elevations in circulating angiotensin II and aldosterone, are accompanied by fibrosis of right and left sides of the heart. Hemodynamic factors regulate cardiac myocyte work and their adaptive hypertrophic growth. The relative contributions of hormonal and hemodynamic factors in regulating growth of muscular and nonmuscular compartments must form the basis for the selection of pharmacologic intervention that will optimize the management of symptomatic heart failure that accompanies hypertensive heart disease and ischemic cardiomyopathy. Cardioprotective strategies that prevent alteration of normal cardiac tissue structure by fibrosis and appearance of abnormal ventricular stiffness (viscoelasticity) are based on negating the generation of these hormones or interfering with their receptor-ligand binding. A regression of established cardiac fibrosis and improvement in abnormal ventricular stiffness is feasible. Experimental and clinical findings with lisinopril in hypertensive heart disease, where cardiac fibrosis and abnormal ventricular stiffness are present, indicate that such cardioreparation should be a targeted objective of pharmacologic intervention. Systematic analysis of this approach using a controlled clinical trial format is warranted. In recognizing the importance of viscoelastic elements in regulating the mechanical behavior of cardiac tissue, and in turn systolic and diastolic ventricular function, a broader tissue compartment based paradigm (ECM versus myocyte) for the management of heart failure emerges.