Statins and the myocardium

Abstract

Cardiac hypertrophy and heart failure are leading causes of morbidity and mortality worldwide. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have been shown to inhibit cardiac hypertrophy and improve symptoms of heart failure by cholesterol-independent mechanisms. Statins block the isoprenylation and function of members of the Rho GTPase family, such as Rac1 and RhoA. Because Rac1 is a requisite component of NADPH oxidase, which is a major source of reactive oxygen species in cardiovascular cells, the ability of statins to inhibit Rac1-mediated oxidative stress contributes importantly to their inhibitory effects on cardiac hypertrophy. Furthermore, inhibition of RhoA by statins leads to the activation of protein kinase B/Akt and upregulation of Type 3 nitric oxide synthase in the endothelium and the heart. This activation and upregulation results in increased angiogenesis and myocardial perfusion, decreased myocardial apoptosis, and improvement in endothelial and cardiac function. Because these effects of statins occur independent of cholesterol lowering, statins may have therapeutic benefits in nonhyperlipidemic patients with cardiac hypertrophy and heart failure.

Figure 1

Cholesterol biosynthesis. HMG-CoA indicates 3-hydroxy-3-methylglutaryl coenzyme A. HMG-CoA reductase is a rate-limiting enzyme, and this blockade (statins) leads to the reduction of other isoprenoid intermediates such as mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate, as well as intracellular cholesterol.

Figure 2

Effect of statins in HF. The line graph shows serial changes in left ventricular (LV) shortening fraction in (A) untreated heart failure and (B) statin-treated cardiomyopathic hamsters. *p<0.05 from baseline; ^‡ p<0.01 from HF. HF, heart failure; Ham, hamster.

Figure 3

Effect of statins on angiogenesis and eNOS. (A) Left ventricular myocardial capillary density (i.e., the number of capillaries per three high-power fields) in the statom-treated cardiomyopathic hamsters (open bar) compared with controls (solid bar) and untreated cardiomyopathic hamsters (hatched bar) (n = 6 in each group). ^†p<0.01 from controls; ^‡p<0.01 from untreated HF hamsters. (B) Representative microscopic images of myocardial sections stained for eNOS in the three groups of hamsters are shown. The brown staining (red arrows) represents eNOS staining of capillaries. HF, heart failure; Sim, simvastatin; eNOS, endothelial nitric oxide synthase.