The Use of Statins in Atherosclerotic Cardiovascular Disease

Over the last decade, therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has evolved as much as the context in which these agents have developed. Advances in knowledge of molecular mechanisms of disease have led to major paradigm shifts in our understanding of atherosclerosis, whereas results of major clinical trials have provided invaluable lessons for the use of statins in clinical practice. The notion of culprit lesion, the importance of endothelial dysfunction, and the contribution of inflammation and oxidation to atherogenesis have become the focus of attention, raising new questions about the beneficial cardiovascular attributes of statins. In fact, the target for statin therapy is gradually evolving from low-density lipoprotein cholesterol alone toward atherosclerosis at large-another paradigm shift.

With time, it has become evident not only that statins act effectively on anatomical and functional atherogenic changes but that they may also have desirable effects throughout the lifetime evolution of the atherosclerotic process.[1] Along with improved methodology to study the natural history of atherosclerosis, insightful probing techniques to tease out novel effects of statins on the vessel wall and on the myocardium have evolved. There is, for instance direct evidence of the antiinflammatory effect of statins in human coronary arteries[2] and clear demonstration of their ability to stabilize carotid artery plaques in humans.[3] [4] Clearly, these multiple or “pleiotropic” effects of statins in concert with their powerful low-density lipoprotein cholesterol lowering properties provide a strong support for the view that statins are cardio- and vasculoprotective.[5] The widespread use of statins and the exploration of their emerging properties has been greatly influenced by such changes in emphasis and advances in technology, resulting in a rapidly growing knowledge base.

This expanding field has prompted the editors of Seminars in Vascular Medicine to publish this series of articles on the use of statins in atherosclerotic cardiovascular disease. These articles are authored by major contributors to this area of research. They provide insight into the scope and magnitude of this new information, the need to organize and establish links between its components, and the many questions that remain to be answered before the full clinical relevance of these numerous effects are established. Many of the pleiotropic effects of statins stem from the ability of these agents to block the isoprenoid half of the mevalonate pathway in addition to the squalene half that leads to cholesterol synthesis. The resulting reduction in isoprenoid intermediates causes changes in levels of several bioactive proteins and signaling molecules, influencing many different systems. Although this focuses the attention on a common link-isoprenylation of small guanosine triphosphate-binding proteins such as Rho, Rac, and Ras-other effects are clearly independent of isoprenylation and unrelated to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase,[6] raising a new interest for the nonpharmacophore moiety of the statin molecule as well as new avenues of research.[7]

What stands out from the contributions to this issue of Seminars in Vascular Medicine is that statins have beneficial cardiovascular effects in vivo that had never been anticipated at the outset, when these drugs were discovered or developed. The authors also emphasize that many of the emerging pleiotropic effects are clinically relevant. These include, among others, reduction of myocardial hypertrophy and of the prevalence of congestive heart failure (see Mital and Liao), a blood pressure-lowering effect (Pellat and Balligand), a beneficial effect on fibrinolysis (Colli et al) and on the immune system (Steffens and Mach), mobilization of endothelial progenitor cells and improvement of their function and integrity with a potential for myocardial repair (Walter et al), and favorable effects on angiogenesis (Skaletz-Rorowski et al) and on plaque stability (Aikawa and Libby). The immunomodulatory properties of statins have led to their indication postcardiac transplantation to improve survival and reduce allograft rejection (Kobashigawa). The endothelium is at the center of many of the statin effects and has served as a model in attempts to separate the lipid- and non-lipid-mediated effects of statins. This is exhaustively reviewed by Larose and Ganz, while the direct effect of statins on smooth muscle cells is discussed by Bellosta et al. We are reminded also that statins have a place in children and adolescents if cardiovascular disease prevention is to be implemented (Rodenburg et al) and that they constitute a key agent for the prevention of macrovascular disease in diabetes (Carmena and Betteridge).

I thank the authors for their outstanding contributions and hope that the reader will find them as informative and useful as I have.

REFERENCES

• 1 Grobbee D E, Bots M L. Statin treatment and progression of atherosclerotic plaque burden.  Drugs. 2003;  63 893-911
• 2 Stefanadis C, Toutouzas K, Vavuranakis M et al.. Statin treatment is associated with reduced thermal heterogeneity in human atherosclerotic plaques.  Eur Heart J. 2002;  23 1664-1669
• 3 Crisby M, Nordin-Fredriksson G, Shah P K, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques-implications for plaque stabilization.  Circulation. 2001;  103 926-933
• 4 Cipollone F, Fazia M, Iezzi A et al.. Suppression of the functionally coupled cyclooxygenase-2/prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans.  Circulation. 2003;  107 1479-1485
• 5 Davignon J. The cardioprotective effects of statins.  Curr Atheroscler Rep. 2004;  6 27-35
• 6 Weitz-Schmidt G. Statins as anti-inflammatory agents.  Trends Pharmacol Sci. 2002;  23 482-486
• 7 Wan M X, Schramm R, Klintman D, Welzenbach K, Weitz-Schmidt G, Thorlacius H. A statin-based inhibitor of lymphocyte function antigen-1 protects against ischemia/reperfusion-induced leukocyte adhesion in the colon.  Br J Pharmacol. 2003;  140 395-401