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HMG-CoA reductase inhibitors ('statins') represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of statins, the patient population suitable for long-term statin treatment is expected to further expand. An overall positive safety and tolerability profile of statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical. The purpose of this review is to summarize the factors that increase the risk of statin-related myopathy. Data from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects were reviewed. Briefly, the epidemiology, clinical spectrum and molecular mechanisms of statin-associated myopathy are discussed. We further analyse in detail the risk factors that precipitate or increase the likelihood of statin-related myopathy. Individual demographic features, genetic factors and co-morbidities that may account for the significant interindividual variability in the myopathic risk are presented. Physicochemical properties of statins have been implicated in the differential risk of currently marketed statins. Pharmacokinetic interactions with concomitant medications that interfere with statin metabolism and alter their systemic bioavailability are reviewed. Of particular clinical interest in cases of resistant dyslipidaemia is the interaction of statins with other classes of lipid-lowering agents; current data on the relative safety of available combinations are summarized. Finally, we provide an update of current guidelines for the prevention and management of statin myopathy. The identification of patients with an increased proclivity to statin-induced myopathy could allow more cost-effective approaches of monitoring and screening, facilitate targeted prevention of potential complications, and further improve the already overwhelmingly positive benefit-risk ratio of statins.

The heterogeneity of plaque formation, the vascular remodelling response to plaque formation, and the consequent phenotype of plaque instability attest to the extraordinarily complex pathobiology of plaque development and progression, culminating in different clinical coronary syndromes. Atherosclerotic plaques predominantly form in regions of low endothelial shear stress (ESS), whereas regions of moderate/physiological and high ESS are generally protected. Low ESS-induced compensatory expansive remodelling plays an important role in preserving lumen dimensions during plaque progression, but when the expansive remodelling becomes excessive promotes continued influx of lipids into the vessel wall, vulnerable plaque formation and potential precipitation of an acute coronary syndrome. Advanced plaques which start to encroach into the lumen experience high ESS at their most stenotic region, which appears to promote plaque destabilization. This review describes the role of ESS from early atherogenesis to early plaque formation, plaque progression to advanced high-risk stenotic or non-stenotic plaque, and plaque destabilization. The critical implication of the vascular remodelling response to plaque growth is also discussed. Current developments in technology to characterize local ESS and vascular remodelling in vivo may provide a rationale for innovative diagnostic and therapeutic strategies for coronary patients that aim to prevent clinical coronary syndromes.

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Restenosis and thrombosis are potentially fatal complications of coronary stenting with a recognized multifactorial etiology. The effect of documented risk factors, however, cannot explain the preponderance of certain lesion types, stent designs, and implantation configurations for the development of these complications. Local hemodynamic factors, low endothelial shear stress (ESS) in particular, are long known to critically affect the natural history of atherosclerosis. Increasing evidence now suggests that ESS may also contribute to the development of restenosis and thrombosis upon stenting of atherosclerotic plaques, in conjunction with well-appreciated risk factors. In this review, we present in vivo and mechanistic evidence associating ESS with the localization and progression of neointimal hyperplasia and in-stent clotting. Clinical studies have associated stent design features with the risk of restenosis. Importantly, computational simulations extend these observations by directly linking specific stent geometry and positioning characteristics with the post-stenting hemodynamic milieu and with the stent's thrombogenicity and pro-restenotic potential, thereby indicating ways to clinical translation. An enhanced understanding of the pathophysiologic role of ESS in restenosis and thrombosis might dictate hemodynamically favorable stent designs and deployment configurations to reduce the potential for late lumen loss and thrombotic obstruction. Recent methodologies for in vivo ESS profiling at a clinical level might allow for early identification of patients at high risk for the development of restenosis or thrombosis and might thereby guide individualized, risk-tailored treatment strategies to prevent devastating complications of endovascular interventions.