Several trials have shown that statins significantly lower cardiovascular mortality in high-risk patients, notably those with documented coronary artery disease. There is no evidence regarding their benefit/risk profile in heart failure as this condition was a noninclusion criterion in the trials concerned. Extrapolation of their effects to the heart failure syndrome can only be arbitrary, given the specificity of the biological milieu involved, illustrated by the many failures littering the history of clinical drug research in the heart failure syndrome. However, the literature suggests potential advantages and disadvantages of statins in heart failure.
â¢ Given that coronary artery disease (CAD) is the main cause of heart failure, prevention of the one should prevent the other. Retrospective analysis of the Scandinavian Simvastatin Survival Study (4S) showed that statins indeed prevented the emergence of congestive heart failure in CAD patients without heart failure at entry.
â¢ Recent evidence suggests that statins do more than lower cholesterol. Inhibition of P-hydroxy-|3-methyl-glutaryl coenzyme A (HMG-CoA) reductase may not only affect cholesterol, but interfere with the synthesis of anti-inflammatory components by decreasing the synthesis of mevalonate-derived compounds. This would downregulate the increased cytokine and chemokine production seen in all-cause heart failure.
â¢ Statins could also improve the endothelial function, which is largely compromised in all-cause heart failure and plays a key role in multiorgan failure.
â¢ Recent experimental data suggest that statins combat the adverse effects of angiotensin II on left ventricular remodeling, independently of lowering cholesterol.
â¢ High cholesterol levels may be beneficial in heart failure. Cholesterol-rich lipoprotein modulates inflammatory immune function by binding and detoxifying bacterial lipopolysaccharide (LPS), whose production is increased in heart failure (the endo-toxin-lipoprotein hypothesis). LPS is a potent trigger of the proinflammatory cytokine release responsible for heart failure progression.
â¢ By inhibiting mevalonate synthesis, statins lower the production of ubiquinone, a central compound in the mitochondrial respiratory chain. Impairment of mitochondrial respiration would impair cardiac and skeletal muscle function (mitochondrial dysfunction may be responsible for toxic myopathy, the main adverse effect of the statins).
Only retrospective, nonrandomized, underpowered subanalyses have been performed on the conflicting data. The Losartan Heart Failure Survival Study (ELITE-2) found that mortality was lower in patients with all-cause heart failure receiving statins (nonrandomized comparison). In the 897 patients with left ventricular (LV) dysfunction or heart failure enrolled in the statin arm of the Gruppo Italiano per lo Studio della Soprawivenza nell’Infarto miocardico (GISSI) Prevention trial, no safety problems were observed in those allocated to pravastatin, and the trend in overall mortality reduction was similar in patients with and without LV dysfunction/failure. Despite the absence of direct evidence from randomized clinical trials, these data provide good grounds for a formal study of statins in heart failure.