Inhibition of Hypertrophy Is a Good Therapeutic Strategy in Ventricular Pressure Overload

Hypertrophic growth of ventricular myocytes is a hallmark feature of numerous forms of cardiovascular disease.1 The hypertrophic process is complex, involving a vast array of structural, signaling, transcriptional, electrophysiological, metabolic, and functional events within the growing cell.2,3 Other cellular elements within the ventricle, fibroblasts, vascular smooth muscle cells, and endothelium, also manifest intricate stress responses, resulting in fibrosis, inflammatory cell infiltration, endothelial dysfunction, and vascular stiffness. Current thinking holds that these events, the reaction of the heart to a host of pathological stresses, provide short-term benefit. However, if disease-related stress remains unchecked, these remodeling events become maladaptive and predispose to cardiovascular morbidity and mortality.Response by Crozatier and Ventura-Clapier on p 1447Among the risks conferred by disease-related ventricular hypertrophy are ventricular tachyarrhythmia, predisposing to sudden cardiac death, and transition to heart failure. Ultimately, these events derive from wholesale reprogramming and relative dedifferentiation of the cardiac myocyte, coupled with similar events in other cell types.Conventional thinking holds that hypertrophic growth of the myocardium is a compensatory response of the heart to increases in workload demand, serving to minimize wall stress and maintain contractile function. However, several lines of evidence, preclinical and epidemiological, highlight the maladaptive features of chronic ventricular hypertrophy. Indeed, in many instances, suppression of load-induced growth is well tolerated.4 Furthermore, left ventricular hypertrophy is among the most robust markers of increased risk for developing chronic heart failure.5 Therefore, we submit that suppression of load-induced ventricular hypertrophy warrants careful consideration as a therapeutic strategy.Although evidence suggests that a small fraction of cells within the ventricle are capable of re-entering the cell cycle,6–8 the majority of cardiomyocytes are postmitotic and, hence, do not retain the ability to divide. Rather, they respond to stress by growing, shrinking, or dying. In …