The fuzzy logic of physiological cardiac hypertrophy.

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. 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 (remodeled or not), function (failing or not), and mass (hypertrophied or not) are independent variables. For example, a concentrically hypertrophied (thick walled) pressureoverloaded ventricle can have normal or enlarged diastolic dimension with either normal or diminished ejection performance. Likewise, whereas eccentrically hypertrophied (normal wall thickness) volume-overloaded hearts are enlarged at end diastole and more spherical in shape, they can exhibit normal, supernormal, or diminished ejection performance. The standard approaches to categorize hypertrophy have tended to overlap with designations of cardiac architecture and function. For example, hypertrophy can be classified on the basis of chamber morphometrics as concentric or eccentric, on the basis of functional outcome as adaptive or maladaptive, and on the basis of whether it progresses to an outright disease state as physiological or pathological. Although each of these classification schemes has strengths and weaknesses,2 the label of “physiological” versus “pathological” generates confusion in part because the simplicity of the labels belies the complexity of the conditions. Certainly, it is an appealing notion that physiological hypertrophy should be distinguished from pathological forms strictly on the basis of it being a favorable adaptation.8 However, a useful operative definition of “physiological hypertrophy” has been difficult to achieve. As with Justice Potter Stewart’s explanation of obscenity for the 1964 United States Supreme Court (“I know it when I see it”), in a world of black and white, physiological hypertrophy can simply be considered as cardiac hypertrophy that is not pathological, that is, that does not cause or contribute to disease. This probabilistic approach relies on a binary or “crisp” presupposition that nonfailing hypertrophy and decompensated hypertrophy are precise and distinct, such that progression from one to the other can be determined with certainty. However, the distinctions are blurred in reality, where heart failure rarely exists without cardiac enlargement at the organ and cellular level2 and where a hypertrophied, pressure-overloaded heart with normal ejection performance characteristically exhibits abnormal contractile function measured at the cellular or myofibrillar level.9 Furthermore, it has been noted that the hypertrophy of cardiac conditioning may actually reverse heart failure.10,11 Thus, intermediate condition(s) between the ideals of normal and pathologically hypertrophied hearts are predominant and may best be characterized within a range of more or less physiological in nature (Figure 2). Here, an overview is presented to help the interested academic and clinician better understand the factors that contribute to hypertrophy being “more or less” physiological in nature, to recognize the adaptive and potentially maladaptive features of “physiological” hypertrophies, and to better appreciate the possibilities of harnessing various aspects of physiological hypertrophy as therapeutic modalities in heart failure.