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:
documenting whether the immediate pre-procedural administration of a statin at a high
dosage may reduce the extent of peri-procedural MI compared with placebo on the
background of the best current medical therapy;
proving that treatment with rosuvastatin, a hydrophilic statin, at the proposed dosage,
is at least comparable (and possibly superior) to atorvastatin at the proposed dosage on
top of standard treatment in inducing a significant reduction of peri-procedural damage
previously documented with atorvastatin in the presence of a 1-week pre-treatment at 40
mg/day (12);
characterizing the relevance of HMG-CoA reductase inhibition (vs largely HMGCoA
reductase-independent cholesterol lowering) in this phenomenon;
providing a mechanistic explanation for such effects, investigating the role of 1) HO-1
and 2) EPCs in the context of peri-PCI myocardial damage.