Patients who survive an acute coronary syndrome are at much higher risk of a recurrent event within the following month than patients with stable coronary syndromes. Statin therapy lowers the risk of recurrent events for many years but also reduces the risk of another event within the weeks to months following the initial acute coronary syndrome. The mechanisms that contribute to this benefit are likely related to improved endothelial function, decreased vascular inflammation, and reduced prothrombotic factors. Observation studies show an early reduction in mortality with statin therapy started before discharge from the hospital after an acute coronary syndrome.
Recent research has shown that inflammation plays a key role in coronary artery disease (CAD) and other manifestations of atherosclerosis. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit an acute coronary syndrome (ACS). Atherosclerosis, the main cause of CAD, is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the arterial tree. A decade ago, the treatment of hypercholesterolemia and hypertension was expected to eliminate CAD by the end of the 20th century. Lately, however, that optimistic prediction has needed revision. Cardiovascular diseases are expected to be the main cause of death globally within the next 15 years owing to a rapidly increasing prevalence in developing countries and eastern Europe and the rising incidence of obesity and diabetes mellitus in the Western world.1 These facts force us to revisit cardiovascular disease and to consider new strategies for prediction, prevention, and treatment.2
Large clinical trials have demonstrated that statin treatment reduces the risk of coronary events and total mortality in patients with stable CAD. After an acute coronary event, an enhanced incidence of new events occurs during a prolonged period; as a consequence, there is higher mortality. Compared with patients with stable disease, patients after an acute coronary event have a 2- to 6-fold higher incidence of recurrent events.3 Recently, the early introduction of statin treatment during the acute phase of a coronary event has been highlighted as a possible therapeutic approach for improving the outcome in patients with unstable disease. However, clinical, biochemical, and histologic features have indicated that these 2 clinically distinct forms of CAD (ie, unstable and stable forms) are derived from different pathogenetic backgrounds. Several clinical investigations have been undertaken to clarify the mechanisms by which lipid-lowering treatment can minimize the risk of recurrence after an initial coronary event. Statin therapy positively affects the equilibrium between atherogenic and antiatherogenic lipoproteins, favoring reverse cholesterol transport and leading to beneficial changes in the composition, structure, and stability of atherosclerotic plaques.4 Furthermore, a wide spectrum of statin-mediated actions on inflammation, thrombo-genesis, and arterial vasomotor properties may contribute to the potential benefit of such therapy in patients with ACS. Such multiple actions have been termed collectively .5 They may result from (1) action dependent on lipid lowering; (2) action independent of lipid lowering but dependent on inhibition of 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reductase, such as that resulting from cellular mevalonate depletion; (3) actions independent of HMG-CoA reductase inhibition; and (4) distinct combinations of these actions.6
Statin-Mediated Effects on Inflammation
Statins inhibit lymphocyte adhesion to intercellular adhesion molecule 1 and impair T-cell stimulation by directly binding to the lymphocyte function—associated antigen 1 site by a mechanism independent of HMG-CoA reductase inhibition. By inhibiting HMG-CoA reductase, statins inhibit the mevalonate pathway and, consequently, reduce the intracellular pool of isoprenoids, thereby down-regulating the prenylation process. In turn, reduced prenylation of the protein Rho down-regulates activation of nuclear factor–kB and increases the transcription of nitric oxide (NO) synthase, which (in combination with increased stability of NO synthase messenger RNA) induces elevation in the endothelial production of NO. Statins reduce plasma low-density lipoprotein (LDL) levels, thereby decreasing substrate available for generation of oxidized LDL; oxidized LDL can inactivate NO and equally down-regulate endothelial NO synthase expression. By reduction of LDL substrate and by a direct mechanism, statin treatment increases NO bioavailability and decreases monocyte adhesion to endothelial cells (
Statin treatment may modify plaque composition, reducing inflammatory activity and favoring lesion stability in patients with low-grade chronic inflammation, such as patients with stable atherosclerotic disease. However, during the acute phase of coronary syndromes, an intense augmentation of inflammation is observed, and it is closely related to the incidence of recurrent events.7 By consequence, the anti-inflammatory effect of statins in patients with ACS and the augmented inflammatory activity warrant specific consideration.6
Overall, enhanced thrombogenicity has been observed in patients who develop an acute coronary event compared with those who display a stable evolution.4 Such increased tissue or blood thrombogenicity could result from interaction between inflammatory, lipid, and genetic factors, representing a key element in the clinical outcome of patients with ACS. Overall blood thrombogenicity has been estimated in an ex vivo model in which a patient’s blood passes through a perfusion system that includes a small segment of arterial wall.8 In this model, a significant reduction in thrombus formation was observed after 3 months of treatment with pravastatin sodium or simvastatin, even in patients already treated with aspirin.8,9 Tissue thrombogenesis mainly results from plaque tissue factor expression, and statin treatment attenuates such expression. Therefore, statin therapy affects the process of thrombus formation by a combination of actions on blood and tissue thrombogenicity (
Statin Action on Endothelial Dysfunction
During acute coronary events, several stimuli (such as thrombin, platelet-released serotonin, and adenosine diphosphate) and low intracoronary blood pressure may cause paradoxical vasoconstriction of the dysfunctional endothelium, which intensifies ischemic injury. Statin-mediated reduction in atherogenic lipoprotein levels and elevation in antiatherogenic high-density lipoprotein, in addition to effects independent of lipid lowering, result in amelioration of endothelial function. By consequence, the coronary artery responds to those stimuli with an adaptive dilation, thereby attenuating the ischemic insult (
Statin-Mediated Myocardial Protection
Rapid and effective reperfusion is a key factor minimizing myocardial injury after an acute coronary event. However, reperfusion itself may promote an inflammatory response and enhance myocardial injury.10,11 In an animal model, reperfusion injury and ventricular dysfunction were significantly reduced in rats treated with statins 18 hours before the induction of myocardial ischemia.12 In addition, the researchers found lower adherence of polymorphonuclear leukocytes to vascular endothelium and decreased infiltration in the ischemic myocardium from the statin-treated rats. This attenuation in neutrophil-endothelium interaction seems to be the consequence of a reduction in the expression of adhesion molecules from endothelial cells and an inhibition of neutrophil activation after statin treatment. The myocardial protective effect of statins is also detectable in the absence of neutrophils. The addition of the active form of simvastatin to the perfusion medium of isolated rat hearts reduces ischemia and reperfusion injury.13 In addition, statin treatment partially prevents endothelial NO synthase reduction induced by ischemia and reperfusion injury; this cardioprotective effect of statins is completely abolished by simultaneous treatment with an NO synthase inhibitor. These findings in animal models suggest that acute treatment with statins could potentially attenuate ischemia and reperfusion injury by a lipid-lowering independent mechanism. Despite the relevance of these findings, further studies are awaited to clarify this statin-mediated mechanism.6
Statins are potent inhibitors of cholesterol biosynthesis and exert beneficial effects in the primary and secondary prevention of CAD. However, the overall benefits observed with statins appear to occur much earlier and to a greater extent than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent findings indicate that some of the cholesterol-independent or pleiotropic effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of the small guanosine triphosphate—binding proteins Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins.14
Blood cholesterol lowering with statins has been regarded as a long-term strategy to reduce death and ischemic cardiovascular events in patients with stable coronary heart disease, with significant effects evident after approximately 2 years of treatment. However, it is within the early period after an ACS that patients experience the highest rates of death and recurrent ischemic events. Recent findings indicate that statins have salutary physiologic effects within weeks. In conjunction with lowering total and LDL cholesterol, statins may improve endothelial function,15 decrease platelet aggregability and thrombus deposition,16,17 and reduce vascular inflammation.18 Each of these mechanisms might be expected to have a favorable effect in the early period following an ACS.
Although statins improve dyslipidemia and cardiovascular risk over the long term, efforts to identify new ACS treatments are focusing on the ability of statins to modify the arterial wall—blood interface and to reduce the risk of early recurrent ischemic events. Statins have been shown to reduce circulating markers of inflammation within days of an acute ischemic event. Short-term statin therapy has been associated with improvement in coronary endothelial function, reversal of prothrombotic states, and reduction in atherosclerotic plaque volume. The very early benefits of statin therapy appear to be correlated with C-reactive protein reductions, which may relate to the intensity of the pleiotropic effects of statins.
Acute coronary syndrome is associated with a poor prognosis and, despite the availability of several treatment strategies, the incidence of subsequent serious complications following an acute event remains high. Large long-term clinical trials have established the benefits of statin therapy in the prevention of cardiovascular events and mortality, but patients with recent ACS were excluded from these studies.20-23 Data from observational studies and a randomized controlled trial support the routine use of statins in ACS and highlight the association between early initiation of therapy and reductions in recurrent coronary events and mortality. Preclinical and clinical evidence indicates that, in addition to their lipid-lowering effects, statins may reduce inflammation, improve endothelial function, and increase plaque stability. Ongoing clinical trials with efficacious statins are expected to provide valuable information about the most appropriate agents and dosages to improve the treatment of patients with ACS.19