Proteasomal regulation of cardiac hypertrophy: is demolition necessary for building?

Left ventricular hypertrophy (LVH) is a common adaptive response of the heart to the increased workload associated with hypertension.1 Essential hypertension is characterized by an increase in total peripheral resistance.2 Mechanical modeling of the cardiovascular system suggests that a necessary consequence of increased downstream resistance to flow is increased pressure to maintain end organ perfusion. Energetically, increased pressure generation requires greater work to be performed by the existing cardiac mass or an increase in cardiac mass to normalize workload per unit of mass. The result of LVH is to normalize wall tension and workload. According to the law of Laplace, increased wall tension is induced by the increased pressure and may also be induced by an increase in the fluidcontaining volume of the left ventricle because of the partially elastic expansion of the ventricle under greater pressure loads.3 Without hypertrophy, increased workload by the existing cardiac mass would require greater perfusion of the myocardium or decreased cardiac reserve. Increased wall tension has the potential to decrease myocardial compliance, thereby limiting myocardial perfusion. In this scenario, it is not surprising that inhibition of cardiac hypertrophy in response to increased peripheral resistance is detrimental. Indeed, Meguro et al4 found that inhibition of LVH due to pressure overload in mice resulted in an increase in death due to heart failure. Inhibition of postinfarction cardiac hypertrophy has also been shown to cause left ventricular dilation and diminishment of cardiac function.5 This topic is well reviewed by Morisco et al.6