EDITORIAL COMMENT
Recapturing the MagicRevisiting the Pleiotropic Effects of Statins in Percutaneous Coronary Revascularization*
Stephen G. Ellis, MD* and
Saif Anwaruddin, MD
Section of Interventional Cardiology, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
* Reprint requests and correspondence: Dr. Stephen G. Ellis, Cleveland Clinic Foundation, Department of Cardiovascular Medicine, Desk J2-3, 9500 Euclid Avenue, Cleveland, Ohio 44195-0001 (Email: elliss{at}ccf.org).
Key Words: coronary artery disease • atorvastatin • percutaneous coronary intervention • myocardial infarction
Attenuation of injury and inflammation associated with percutaneous coronary intervention (PCI) is an important concept in cardiovascular medicine. Vascular injury and inflammation occurring in the context of PCI leading to periprocedural infarction is likely the result of either jailing of side-branch vessels or embolization of particulate matter into the microcirculation. Numerous studies have demonstrated an association between elevated inflammatory states and adverse events following PCI (1,2). It is perhaps no surprise, then, that attempts to suppress inflammation have led to favorable outcomes (3). One might ponder why treatments focusing on this idea have not more quickly gained traction.
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) were shown to reduce infarct size in numerous animal models of both coronary and cerebral ischemia in the early to mid-1990s. In the context of PCI, these were followed by observational studies published in the earlier part of this decade suggesting both a reduction in periprocedural myocardial infarction (4) and a survival benefit (5,6). Di Sciascio et al. (7,8) followed with randomized trials confirming a reduction in periprocedural myocardial infarction for patients both with stable and unstable angina.
The premise for the acute benefit of statin therapy initiated shortly before PCI is based primarily on effects independent of lipid lowering. Statins alter numerous pathways involved in injury and inflammation including those affecting cytokine production and adhesion molecule expression (9,10). Lipid-lowering independent effects of statin therapy, or pleiotropic effects, have gained increasing attention given potential benefits of statins on endothelial function, heart failure, and Alzheimer's disease.
Although the pleiotropic effects of statins are often defined as any lipid-lowering independent effects of statins, we will address these effects specifically as those leading to a reduction in isoprenoid (farnesyl pyrophosphate and geranyl-geranyl pyrophosphate) formation by inhibiting the metabolism of mevalonic acid into cholesterol. The binding of isoprenoids to G proteins such as Rho and Ras leads to activation of nuclear transcription factors involved in pro-inflammatory actions and in the down-regulation of endothelial nitric oxide synthetase. The importance of this pathway is confirmed by the abrogation of infarct size reduction by N -nitro-L-arginine methylester (11). Statins attenuate reperfusion injury via their effect on the phosphatidyl inositol 3-kinase (PI3K) and the serine/threonine kinase (Akt) pathway (12,13). The Akt pathway is inhibited by the actions of the G protein Rho-A. Protection from reperfusion-induced cell death is blocked by the PI3K inhibitor wortmannin (14).
However advantageous the pleiotropic effects of statin therapy may be, it has been suggested that over the long term, there is an attenuation of these benefits, particularly those associated with the PI3K/Akt pathway (15). It is believed that the antiapoptotic effects of the PI3K/Akt cascade can be oncogenic (16) and are inhibited by the effects of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Mensah et al. (17) previously demonstrated in an animal model that cardioprotection against ischemia/reperfusion injury with atorvastatin was lost over a period of time and was likely mediated by increasing PTEN activity. Furthermore, they suggested that this benefit could be "recaptured" by the dosing of high levels of atorvastatin acutely. The accompanying editorial (18) called upon future clinical studies to determine whether this idea of acute statin treatment on top of chronic therapy would be clinically meaningful.
The investigators of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) trial have previously addressed the issue of periprocedural benefits of statin use in both patients with chronic stable angina and with non–ST-segment elevation acute coronary syndrome. In this 383-patient study by Di Sciascio et al. (19) appearing in this issue of the Journal, the authors test the hypothesis of whether acute reloading of atorvastatin in those chronically on statin therapy would improve cardioprotection in the setting of PCI. An acute load of 80 mg of atorvastatin 12 h before angiography and 40 mg in the 2 h before the procedure versus placebo resulted in a reduction in major adverse cardiac events at 30 days (3.7% vs. 9.4%, p = 0.037) that was primarily driven by a reduction in periprocedural myocardial infarction. Although no mortality benefit was observed in this study, it was possibly due to the combination of a small study population and short follow-up period. Many of the studies demonstrating a benefit in cardiovascular mortality with statins in PCI included many more patients and noted benefit at 6 months to 1 year.
Interestingly, the ARMYDA-RECAPTURE investigators make note of the fact that the mean absolute increase in C-reactive protein in the atorvastatin reload arm was not statistically different from placebo, although it tended to be lower (p = 0.12). This would tend to support an underlying pleiotropic mechanism as high-dose statins have been shown to put forth differential effects upon G protein Rho associated pathways versus those involving C-reactive protein and low-density lipoprotein cholesterol (20).
Based upon the body of evidence, supported by the ARMYDA-RECAPTURE study results, it would seem virtually indisputable that pre-treatment with statins benefits patients undergoing PCI. Likely, reloading is also beneficial, although the modest size of the present study precludes firm conclusions. Clinicians perhaps can be excused for being slow to embrace this concept because of the assumption that all patients with coronary disease should already be on statins and because of lingering doubts regarding the significance of low levels of enzyme rise associated with PCI (21,22).
Where should our focus turn to from here? Recent data suggest that cyclooxygenase-2 inhibitors (23) and caffeine may blunt the cardioprotective effect of statins, and that patients unable to take higher doses of statins perhaps might benefit from low-dose statin therapy plus periprocedural sildenafil (24) or cilostazol (25). These pre-clinical observations also deserve testing in the clinical arena. Further, the suggested benefit of statins in the setting of cerebral ischemia should be formally tested in patients undergoing carotid stenting procedures. Finally, the ARMYDA investigators should be congratulated on their efforts to bring this information to the clinical setting.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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