Rosuvastatin for Reduction of Myocardial Damage and Systemic Inflammation During Coronary Angioplasty - The REMEDY Study

Myocardial necrosis, assessed by creatine kinase-MB (CK-MB) elevation, is relatively frequent after percutaneous coronary intervention (PCI), occurring in up to 40% of cases. Although most patients remain asymptomatic and with no changes in cardiac function, even a mild release of CK-MB is associated with higher mortality during the follow-up. A number of treatment strategies have been proposed to limit myocardial damage during PCI, but procedural ischemic myocardial injury remains the most frequent complication after coronary angioplasty.

Several randomized studies have demonstrated the beneficial effects of therapy with HMG-CoA reductase inhibitors (statins) in patients with already established coronary artery disease or in normal subjects with hypercholesterolemia in primary prevention, and retrospective observational studies have suggested that pre-treatment with statins might reduce the incidence of myocardial infarction after coronary intervention. This benefit was confirmed in patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS) undergoing PCI, who received 80 mg atorvastatin 12 h before PCI, with a further 40-mg pre-procedure, as compared with placebo.

The mechanisms underlying the beneficial effects of statins in ischemic conditions are not completely clear. Previous studies have suggested that the anti-inflammatory effect of statins may play a role, showing that the benefit was higher in patients with high C-reactive protein. Since an inflammatory status before angioplasty, as detected by high levels of C-reactive protein, is associated with a higher risk of peri-procedural myocardial necrosis and adverse cardiac events during the follow-up, the anti-inflammatory effects of statins might contribute to reduce myocardial necrosis, by reducing to the microembolization occurring during coronary intervention. Statin administration also rapidly improves endothelial function. Thus, even short-term treatment with statins (unable to provide LDL reduction persistent enough to decrease the atherosclerotic burden) may have important effects on endothelial function and inflammation. In patients undergoing PCI, reduction of peri-procedural myocardial injury after pre-treatment with statins is paralleled by a concomitant attenuation of post-procedural increase of intercellular cell adhesion molecule-1 (ICAM-1) and E-selectin plasma levels, thus reinforcing the concept that a reduction of endothelial inflammatory response may explain peri-procedural protective effect of statins.

Statins induce heme oxygenase-1 (HO-1) expression in vitro and are reported to have pleiotropic benefits that reduce oxidative stress in the vasculature and in various extravascular tissues Two anti-inflammatory cytokines, interleukin-10 (IL-10) and transforming growth factor-beta, play a critical role in the modulation of immunoinflammatory cell infiltration in the atherosclerotic intima and the mechanism underlying the protective effects of IL-10 against inflammatory cell infiltration involves heme oxygenase-1 (HO-1). Moreover, statins can efficiently increase levels of endothelial progenitor cells (EPCs), contributing to vascular repair, in patients with coronary heart disease and in patients with chronic heart failure, and augment EPC proliferative capacity, in a way similar to vascular endothelial growth factor (VEGF).

Therefore, this study is directed at: