Statin therapy: new therapy for cardiac microvascular dysfunction.

Cardiac syndrome-X is a clinical entity characterized by angina-like chest discomfort that is often prolonged in duration, normal coronary arteries as assessed by arteriography, non-inducible coronary vasospasm with ergonovine provocation and ST segment depression on treadmill exercise testing. The pathogenesis of cardiac syndrome-X has been ascribed to myocardial ischaemia that may be caused by microvascular dysfunction and increased sensitivity to intracardiac pain. Support for impaired myocardial perfusion in the aetiology of chest pain was provided in a case-control study of 20 patients with established syndrome-X and 10 matched controls that underwent cardiac magnetic resonance imaging at rest and after adenosine infusion. In syndrome-X patients, adenosine infusion reduced the subendocardial to subepicardial myocardial perfusion index and provoked chest pain in 19 of 20 patients. The mechanisms that may contribute to microvascular dysfunction in syndrome-X include endothelial dysfunction, and abnormal vasoconstrictive responses of the microvasculature to nitric oxide and endothelin. Several lines of evidence support impaired nitric oxide production or endothelial release by coronary vessels of syndrome-X patients. Intracoronary infusions of acetylcholine induce a diminished vasodilator response in syndrome-X patients compared to controls or may induce myocardial ischemia in the absence of vasospasm in epicardial coronary arteries. The acetylcholine-induced ischaemia may result from a vasoconstrictor effect of acetylcholine on vascular smooth muscle cells. In contrast, intracoronary infusions of L-arginine, the precursor of nitric oxide, enhance coronary vasodilation in response to acetylcholine. Further, levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide, are increased in syndrome-X patients. Therapeutic approaches for patients with syndrome-X include short-term symptom relief with sublingual nitrates, and potentially longer-term use of beta adrenergic blockers or calcium channel antagonists. Beta blockers and calcium antagonists have been shown to reduce the frequency and lessen the severity of chest pain and improve exercise tolerance. Estrogenreplacement therapy has been shown to reduce the frequency of anginal episodes in postmenopausal women presumably by improving endothelium-dependent coronary vasodilatation. In this issue of the Journal, Kayikcioglu and colleagues present the results of a clinical trial in syndrome-X patients that investigated whether statin therapy changed endothelial function as measured by flow-mediated dilatation of the brachial artery, and exercise-induced ischemia. Forty patients with well-characterized features of syndrome-X were randomly assigned to pravastatin (40 mg daily) or placebo for 3 months. The study patients included predominantly middle-aged women with LDL cholesterol levels <4.2 mmol/l and fasting triglycerides <2.3 mmol/l. It is important to consider that these patients would not be considered for cholesterol lowering therapy according to expert guidelines for cholesterol management. After 3 months, pravastatin-treated patients had a modest 16% lowering of LDL cholesterol (3.1±0.65 mmol/l to 2.6±0.47 mmol/l). There were no significant changes in other plasma lipids. Statin therapy resulted in significant improvements in flow-mediated vasodilatation, exercise duration and time to 1 mm ST segment depression. Ischemic episodes were completely resolved in 26% of statin-treated patients. Total exercise duration correlated with the reduction in LDL cholesterol (rs=0.65). Unfortunately, there was no measurement of myocardial ischaemia such as by cardiac magnetic resonance imaging. Other biochemical parameters that improved with pravastatin therapy include fibrinogen and highsensitivity CRP. Statin therapy has shown consistent benefits in reducing ischaemic cardiac events in patients with * Corresponding author. Tel.: +1-312-695-0013; fax: +1-312-695-0047 E-mail address: [email protected] (R.S. Rosenson). European Heart Journal (2003) 24, 1993–1994