Associate editor: B. McDermott
Statins and cardioprotection — More than just lipid lowering?

https://doi.org/10.1016/j.pharmthera.2009.01.002Get rights and content

Abstract

Lipid-lowering using HMG-CoA reductase inhibitors or statin therapy forms the cornerstone of medical therapy in the primary and secondary prevention of cardiovascular disease. In addition, to the improvements in lipid profile, the beneficial effects elicited by this class of drugs may be attributed to their diverse variety of non-lipid lowering pleiotropic effects, including improved endothelial function, reduced oxidative stress, less platelet adhesion, and increased atherosclerotic plaque stability. A less appreciated effect of statin therapy that has been reported in experimental studies is its cardioprotective effect with respect to its ability to directly protect the myocardium from the detrimental effects of acute ischaemia–reperfusion injury. In the current article we review the cardioprotective effects of statin therapy beyond serum lipid lowering, the underlying mechanisms involved and the potential implications for patients with coronary heart disease.

Introduction

Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide. HMG-CoA reductase inhibitors (henceforth referred to as ‘statins’) have become standard medical therapy in the armamentarium available for the prevention and treatment of cardiovascular disease. Large randomised controlled clinical trials have established their role as effective medical therapy for the primary (Shepherd et al., 1995, Downs et al., 1998) and secondary (Pedersen et al., 2005, Heart Protection Study Collaborative Group, 2002) prevention of cardiovascular events. HMG-CoA reductase inhibitors competitively inhibit the conversion of acetyl coenzyme A and acetoacetyl coenzyme A to mevalonate in the formation of cholesterol and prevent the formation of the isoprenoids (Istvan, 2002) (see Fig. 1). Statins were first developed in order to lower total serum cholesterol and improve the lipid profile but have subsequently been shown to exert a variety of beneficial, ‘pleiotropic’ effects, particularly relevant to cardiovascular disease, including improved endothelial function, reduced oxidative stress, less platelet adhesion, and atherosclerotic plaque stabilisation (Ray & Cannon, 2005).

It is well-established that statin therapy offers widespread beneficial effects on the cardiovascular system through both its lipid lowering and non-lipid lowering effects described above. However, in this article, we will focus on a less appreciated non-lipid lowering effect of statin therapy, namely its potential to directly protect the myocardium from the detrimental effects of acute ischaemia–reperfusion injury, a feature which has been widely documented in the experimental literature. The mechanisms underlying this cardioprotective effect and the implications for clinical therapy of patients with CHD will be covered.

Section snippets

Experimental cardioprotection using statin therapy

In the late 1990s, the finding that statin therapy was beneficial in terms of improving cardiovascular outcomes resulted in a search for the mechanisms underlying this cardioprotective effect. Using experimental animal models of acute myocardial ischaemia–reperfusion injury, it is possible to examine the effects of statin therapy at different time-points in the course of the acute ischaemia–reperfusion insult. In this section we review the experimental evidence for acute cardioprotection

Potential mechanisms underlying statin-induced cardioprotection

Nitric oxide has been implicated as a crucial signalling molecule in the mechanism of cardioprotection and the other pleiotropic effects of statin therapy (Fig. 2). Experimental studies have demonstrated that statins stabilise eNOS mRNA, upregulate and activate eNOS and increase NO production (Laufs et al., 1997, Laufs et al., 1998, Scalia et al., 2001). The mechanism through which statins actually activate the nitric oxide signalling pathway is still the subject of investigation but it may be

Clinical cardioprotection using statin therapy

The experimental animal studies suggest that statin therapy has the ability to protect the myocardium against the detrimental effects of acute ischaemia–reperfusion injury irrespective of whether it is administered prior to the index ischaemic event or at the onset of myocardial reperfusion. As such it could be argued that statin therapy may theoretically confer cardioprotection in a range of clinical settings including those in which the index ischaemic event can be readily anticipated such as

Conclusion

Statins are established as playing a major role in cardiovascular disease in almost all categories of patient risk. The ‘pleiotropic’ effects of statins continue to reveal further potential benefits in a diverse range of interventional settings. The benefit of using statins acutely prior to scenarios where myocardial injury may be expected and in emergent situations is slowly being realised. The potential benefits of limiting myocardial injury in these settings are evident and further work is

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