Endothelium-ameliorating effects of statin therapy and coenzyme Q₁₀ reductions in chronic heart failure

Abstract

Although not currently indicated for chronic heart failure (CHF), statins have been associated with improved outcome in retrospective analysis. However, statin therapy reduces plasma levels of coenzyme Q₁₀ (ubiquinone), which may have adverse effects on heart failure states. We hypothesized that atorvastatin treatment improves endothelial function in patients with chronic heart failure independent of LDL-cholesterol alterations. Furthermore, we assessed how reductions in coenzyme Q₁₀ levels impact on potentially improved endothelial function. Twenty-four patients with stable, symptomatic heart failure (New York Heart Association Class II or III) and a left ventricular ejection fraction <40% were randomised to 40 mg atorvastatin or placebo for 6 weeks and crossed over to the other treatment arm for a further 6 weeks, after a 2-week wash out. Forearm resistance vessel function was assessed by venous occlusion plethysmography during infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and N^G–monomethyl-l-arginine (l-NMMA) into the brachial artery. Atorvastatin treatment lowered triglycerides, LDL-cholesterol and coenzyme Q₁₀ levels (all p < 0.001) and improved endothelium-dependent vasodilatation during acetylcholine infusion (p = 0.015). Endothelium-dependent forearm blood flow improvements correlated with reductions in coenzyme Q₁₀ levels (p = 0.011), but not with LDL-cholesterol levels (p = 0.084). Coenzyme Q₁₀ remained the significant variable predicting improvement in NO dependent endothelial function after adjusting for LDL-cholesterol levels (p = 0.041). In conclusion, short-term atorvastatin therapy improved endothelial function in chronic heart failure patients. Further studies are required to determine whether coenzyme Q₁₀ reductions are limiting the maximum favourable effects of statin therapy on the microcirculation.

Introduction

Chronic heart failure (CHF) is associated with endothelial dysfunction [1], [2]. The endothelial nitric oxide pathway has been found defective in patients with heart failure [1], [2] and the degree of endothelial impairment is related to the severity of heart failure [3]. A multitude of studies have demonstrated that 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibition can profoundly improve both coronary and peripheral endothelial function [4], [5], [6] even in young, healthy and normocholesteremic males. Endothelial function enhancing properties of statins could explain why well-established reductions in cardiovascular mortality in patients with or without CAD [7], [8] are independent of baseline cholesterol levels [8] and not fully explicable by their lipid lowering properties [9], [10]. The improvement in tissue perfusion is an important goal in patients with CHF, in terms of both the peripheral and coronary circulation [11]. Although not currently indicated for chronic heart failure, statin therapy could result in substantial clinical benefits through its endothelium enhancing properties and other pleiotropic effects. In a retrospective analysis of large statin trials, statin therapy was associated with improved cardiovascular outcome in subgroups with heart failure [12]. However, statin therapy may potentially be unfavourable in CHF patients due to its coenzyme Q₁₀ (ubiquinone) reducing properties [13], [14], [15], [16]. Coenzyme Q₁₀ deficiency has been implicated in chronic heart failure [17] and the severity of heart failure is correlated with the degree of coenzyme Q₁₀ depletion [18]. In this double blind, placebo controlled, cross-over study we investigated if HMG CoA reductase inhibition can improve endothelial function in patients with chronic heart failure and whether this effect is independent of reductions in LDL-cholesterol and coenzyme Q₁₀ levels.