Bonetti, Piero O.

Lipid-independent effects of statins. Today, there is growing evidence that 3-hydroxy-3-methylglutaryl(HMG) CoA reductase inhibitors or statins are not only potent plasma lipid-lowering drugs, but also exert various effects upon the cardiovascular system which are independent of their impact on plasma lipid levels. Moreover, it has become clear that many of these so-called pleiotropic effects (e.g. anti-oxidant, anti-inflammatory, anti-proliferative, anti-thrombotic, and endothelial-protective) are unrelated to the statinmediated lowering of intracellular cholesterol. Because most of these nonlipid effects of statins have been demonstrated in vitro or in animal models, they cannot be directly translated to the situation in humans. Thus, the clinical relevance of the variety of lipid-independent effects of these compounds is still unclear. However, several recently published articles demonstrated the existence of such lipid-independent statin effects in humans. This article, by reviewing the current literature about the presence of nonlipid effects of statins in humans, tries to determine how relevant these properties are in clinical practice. Furthermore, the current evidence regarding possible new indications for this interesting class of drugs is discussed. Viele dieser in letzter Zeit nachgewiesenen sogenannten pleiotropen Effekte (z.B. antioxidative, antiinflammatorische, antiproliferative und antithrombotische Wirkungen sowie Verbesserung der Endothelfunktion) scheinen unabhiingig vom Einfluss der Statine auf die zelluliire Cholesterin-Synthese zu sein. Aufgrund der Tatsache, dass diese lipidunabhiingigen Effekte mehrheitlich in vitro bzw. in Tiermodellen nachgewiesen wurden, stellt sichjedoch die Frage nach der klinischen Relevanz dieser Eigenschaften. Einige in letzter Zeit publizierte Studien haben aber gezeigt, dass zumindest gewisse der experimentell nachgewiesenen lipidunabhiingigen Effekte auch beim Menschen vorhanden sind. Die vorliegende Ubersichtsarbeit versucht anhand der derzeit vorliegenden Resultate klinischer Studien die Frage zu beantworten, wie relevant lipidunabhiingige Statin-Effekte im klinischen Alltag sind und ob bereits genug Evidenz vorhanden ist, um die Indikationsstellung for Sta tine uber die Therapie der Hyperlipidiimie hinaus auszuweiten. . Today, there is growing evidence that 3-hydroxy-3-methylglutaryl(HMG) CoA reductase inhibitors or statins are not only potent plasma lipid-lowering drugs, but also exert various effects upon the cardiovascular system which are independent of their impact on plasma lipid levels. Moreover, it has become clear that many of these so-called pleiotropic effects (e.g. anti-oxidant, anti-inflammatory, anti-proliferative, anti-thrombotic, and endothelial-protective) are unrelated to the statinmediated lowering of intracellular cholesterol. Because most of these nonlipid effects of statins have been demonstrated in vitro or in animal models, they cannot be directly translated to the situation in humans. Thus, the clinical relevance of the variety of lipid-independent effects of these compounds is still unclear. However, several recently published articles demonstrated the existence of such lipid-independent statin effects in humans. This article, by reviewing the current literature about the presence of nonlipid effects of statins in humans, tries to determine how relevant these properties are in clinical practice. Furthermore, the current evidence regarding possible new indications for this interesting class of drugs is discussed. Viele dieser in letzter Zeit nachgewiesenen sogenannten pleiotropen Effekte (z.B. antioxidative, antiinflammatorische, antiproliferative und antithrombotische Wirkungen sowie Verbesserung der Endothelfunktion) scheinen unabhiingig vom Einfluss der Statine auf die zelluliire Cholesterin-Synthese zu sein. Aufgrund der Tatsache, dass diese lipidunabhiingigen Effekte mehrheitlich in vitro bzw. in Tiermodellen nachgewiesen wurden, stellt sichjedoch die Frage nach der klinischen Relevanz dieser Eigenschaften. Einige in letzter Zeit publizierte Studien haben aber gezeigt, dass zumindest gewisse der experimentell nachgewiesenen lipidunabhiingigen Effekte auch beim Menschen vorhanden sind. Die vorliegende Ubersichtsarbeit versucht anhand der derzeit vorliegenden Resultate klinischer Studien die Frage zu beantworten, wie relevant lipidunabhiingige Statin-Effekte im klinischen Alltag sind und ob bereits genug Evidenz vorhanden ist, um die Indikationsstellung for Sta tine uber die Therapie der Hyperlipidiimie hinaus auszuweiten.

Background— Stroke, mainly attributable to atherothrombotic disease, represents a leading cause of disability and death in the Western world. Endothelial dysfunction, which is considered a key factor in atherogenesis, is associated with an increased risk of cardiovascular events. However, the magnitude of the association between coronary endothelial dysfunction (CED) and cerebrovascular events is unknown. This study was performed to investigate the association between CED and cerebrovascular events. Methods and Results— We studied 503 patients without obstructive coronary artery disease (CAD) who underwent coronary endothelial function testing by intracoronary acetylcholine infusion. Patients were divided according to the presence (n=305) or absence (n=198) of CED, and medical records were examined for the occurrence of ischemic or hemorrhagic stroke or transient ischemic attack either before (prevalent) or after (incident) coronary endothelial function testing. Among the study population, a total of 25 cerebrovascular events were documented, 22 in patients with CED (15 prevalent) and 3 in patients without (all prevalent) ( P =0.008). Multivariable logistic regression, which included traditional cerebrovascular disease–related risk factors, identified the presence of CED as the single strongest factor associated with cerebrovascular events (OR, 4.32; 95% CI, 1.26 to 14.83). Kaplan-Meier analysis indicated that patients with CED had a significantly higher cumulative cerebrovascular event rate than those without ( P =0.04). Conclusions— Presence of CED in patients without obstructive CAD is independently associated with an increased risk of cerebrovascular events. Thus, detection of this early stage of atherosclerosis may provide important information to identify patients who benefit from aggressive preventive strategies.

Endothelial dysfunction is a systemic disorder and a key variable in the pathogenesis of atherosclerosis and its complications. Current evidence suggests that endothelial status is not determined solely by the individual risk factor burden but rather, may be regarded as an integrated index of all atherogenic and atheroprotective factors present in an individual, including known as well as yet-unknown variables and genetic predisposition. Endothelial dysfunction reflects a vascular phenotype prone to atherogenesis and may therefore serve as a marker of the inherent atherosclerotic risk in an individual. In line with this hypothesis, dysfunction of either the coronary or peripheral vascular endothelium was shown to constitute an independent predictor of cardiovascular events, providing valuable prognostic information additional to that derived from conventional risk factor assessment. Interventions like risk factor modification and treatment with various drugs, including statins and angiotensin-converting enzyme inhibitors, may improve endothelial function and thereby, potentially prognosis. Hence, given its reversibility and granted the availability of a diagnostic tool to identify patients at risk and to control the efficacy of therapy in clinical practice, endothelial dysfunction may be an attractive primary target in the effort to optimize individualized therapeutic strategies to reduce cardiovascular morbidity and mortality.