The Fuzzy Logic of Physiological Cardiac Hypertrophy

Abstract

Cardiac hypertrophy is defined as an abnormal increase in heart muscle mass and is functionally, mechanistically, and histologically distinguished from normal embryonic and postnatal myocardial growth by characteristic changes in cardiac myocyte shape and volume.1 Reactive hypertrophy, that is, hypertrophy that occurs in response to an extrinsic increase in cardiac work,2 is distinguished from genetic familial hypertrophic cardiomyopathy mutations3 in which the stimulus for hypertrophy is intrinsic to the cardiomyocyte. In the prototypical reactive hypertrophic response to pressure overload, decreased wall stress (estimated as the ratio of ventricular radius to wall thickness; Figure 1) resulting from “compensatory” cardiac hypertrophy provides mechanical advantages that help normalize ejection performance in the face of increased workload as originally described by Grossman et al4 (Figure 1). These mechanical benefits accrue whether the stimulus for hypertrophy is intermittent, as with exercise training that produces “physiological hypertrophy,” or sustained, as with hypertension or aortic stenosis that produce “pathological hypertrophy.” With sustained hemodynamic overload, however, progressive systolic dysfunction ultimately occurs that leads to heart failure (Figure 1). The realization that prolonged, continuous hemodynamic stress will ultimately lead to hypertrophy decompensation, together with accumulating information that the hypertrophied myocardium is transcriptionally and biochemically distinct from normal myocardium,5 lead Katz to derive the concept of a “cardiomyopathy of pressure overload,”6 which is a specific contextual application of the notion of pathological hypertrophy. Figure 1. Stimulus-specific hypertrophic responses of the heart and how they affect wall stress (c), which, at equal pressures, is proportional to the ratio of internal ventricular radius at end diastole (r) and ventricular wall thickness (h). Whether it is compensatory or decompensated, hypertrophy is associated with alterations in cardiac geometry (size and shape) collectively referred to as “ventricular remodeling.7 Importantly, although they are related to each other, cardiac architecture …