The Pleiotropic Effects of Statins - From Coronary Artery Disease and Stroke to Atrial Fibrillation and Ventricular Tachyarrhythmia

Abstract

Statins, 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, have been used for decades for the prevention of coronary artery disease and stroke. They act primarily by lowering serum cholesterol through the inhibition of cholesterol synthesis in the liver, which results in the upregulation of low-density lipoprotein receptors in the liver. This results in the removal of low-density lipoproteincholesterol. Studies have suggested that statins may demonstrate additional effects that are independent of their effects on low-density lipoprotein-cholesterol. These have been termed "pleiotropic" effects. Pleiotropic effects may be due to the inhibition of isoprenoid intermediates by statins. Isoprenoid inhibition has effects on the small guanosine triphosphate binding proteins Rac and Rho which in turn effects nicotinamide adenine dinucleotide phosphate oxidases. Therefore, there are changes in endothelial nitric oxide synthase expression, atherosclerotic plaque stability, pro-inflammatory cytokines and reactive oxygen species production, platelet reactivity, and cardiac fibrosis and hypetrophy development. Recently, statins have been compared to the ezetimibe and the recently published outcomes data on the proprotein convertase subtilisin kexin type 9 inhibitors has allowed for a reexamination of statin pleiotropy. As a result of these diverse effects, it has been suggested that statins also have anti-arrhythmic effects. This review focuses on the mechanisms of statin pleiotropy and discusses evidence from the statin clinical trials as well as examining the possible anti-arrhythmic effects atrial fibrillation and ventricular tachyarrhythmias.

Keywords: Statins; atrial fibrillation; cholesterol; coronary artery disease; low density lipoprotein; pleiotropy; stroke..

Fig. (1).

Statin Mechanism of Action. Rock – Rho Kinase; NADPH – nicotinamide adenine dinucleotide phosphate.

Fig. (2).

Effects of Statins by Different Tissues and Cell Types: There is interplay between the pleiotropic effects of statins and the reduction in atherosclerosis also plays a role in the possible reduction of atrial fibrillation or ventricular tachyarrhythmias that may be seen with statin use. SMC – smooth muscle cell, IL- interleukin, ROCK – rho kinase, PF – platelet factor, eNOS – endothelial nitric oxide synthase.