Peter Ganz

Paradoxical Vasoconstriction Induced by Acetylcholine in Atherosclerotic Coronary Arteries

Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, acetylcholine constricts blood vessels. We tested the hypothesis that muscarinic cholinergic vasodilation is impaired in coronary atherosclerosis. Graded concentrations of acetylcholine and, for comparison, the nonendothelial-dependent vasodilator nitroglycerin were infused into the left anterior descending artery of eight patients with advanced coronary stenoses (greater than 50 percent narrowing), four subjects with angiographically normal coronary arteries, and six patients with mild coronary atherosclerosis (less than 20 percent narrowing). Vascular responses were evaluated by quantitative angiography. In several segments each of four normal coronary arteries, acetylcholine caused a dose-dependent dilation from a control diameter of 1.94 +/- 0.16 mm to 2.16 +/- 0.15 mm with the maximal acetylcholine dose (P less than 0.01). In contrast, all eight of the arteries with advanced stenoses showed dose-dependent constriction, from 1.05 +/- 0.05 to 0.32 +/- 0.16 mm at the highest concentration of acetylcholine (P less than 0.01), with temporary occlusion in five. Five of six vessels with minimal disease also constricted in response to acetylcholine. All vessels dilated in response to nitroglycerin, however. We conclude that paradoxical vasoconstriction induced by acetylcholine occurs early as well as late in the course of coronary atherosclerosis. Our preliminary findings suggest that the abnormal vascular response to acetylcholine may represent a defect in endothelial vasodilator function, and may be important in the pathogenesis of coronary vasospasm.

Anticoagulant effects of Hirulog, a novel thrombin inhibitor, in patients with coronary artery disease

Selective thrombin inhibitors are a new class of antithrombotic drugs that, unlike heparin, can effectively inhibit clot-bound thrombin and escape neutralization by activated platelets. Hirulog is a 20 amino acid hirudin-based synthetic peptide that has shown promise in experimental models of thrombosis. Little information is available about the effects of hirulog in patients with coronary artery disease. Forty-five patients undergoing cardiac catheterization, who were taking aspirin, were randomized to receive either (1) hirulog, 0.05 mg/kg intravenous bolus followed by 0.2 mg/kg/hour intravenous infusion until the end of the catheterization; (2) hirulog, 0.15 mg/kg intravenous bolus followed by 0.6 mg/kg/hour intravenous infusion; or (3) heparin; 5,000 U intravenous bolus. Serial activated partial thromboplastin time (APTT), prothrombin time, activated clotting time and fibrinopeptide A were measured. Hirulog produced a dose-dependent prolongation of all coagulation parameters; the 0.6 mg/kg/hour dose prolonged the APTT to 218 +/- 50% of baseline after 2 minutes and 248 +/- 50% of baseline after 15 minutes. The half-life of the effect on APTT was 40 minutes. The hirulog blood level correlated well with the APTT, prothrombin time and activated clotting time (r = 0.77, 0.73, and 0.82 respectively, all p < 0.001). Both doses of hirulog potently suppressed the generation of fibrinopeptide A (p < 0.05). There were no major hemorrhagic, thrombotic or allergic complications in patients treated with hirulog or heparin. Thus, hirulog, a direct thrombin inhibitor, provides a predictable level of anticoagulation and appears to have a potent yet well-tolerated anticoagulant profile in patients with coronary artery disease.

Imaging atherosclerosis: lesion vs. lumen

Conventional coronary imaging, in the form of coronary angiography, does not directly image the atherosclerotic lesion. Despite a marked reduction in acute coronary events with lipid-lowering (“regression”) therapy, angiography has failed to detect significant improvement in the coronary lumen. Recent clinical and pathobiologic data point to features within the atherosclerotic plaque, such as the fibrous cap, lipid pool, inflammatory cell infiltrate, and extracellular matrix, that are critical to plaque disruption and acute coronary events. Lipid-lowering therapy may ameliorate these structural and biologic features of the vulnerable atherosclerotic plaque. Advanced imaging techniques capable of identifying features of the vulnerable atherosclerotic lesion are needed to elucidate further the mechanisms of atherosclerosis progression, to identify patients at risk for acute coronary events, and to provide a means to study novel plaque stabilizing therapies. Ultrasound, nuclear scintigraphy, x-ray, magnetic resonance, and light-based imaging techniques all have the potential to image plaque components and provide more direct information about atherosclerotic lesion vulnerability.

The Role of Nitric Oxide in Coronary Disease

The vascular endothelium is capable of modulating many biological responses through the release of locally derived vasoactive factors.’ One of the most important is nitric oxide, the endothelium-derived relaxing factor (EDRF).2 Nitric oxide is synthesized by endothelial cells from the essential amino acid I-arginine by nitric oxide synthase (NOS). Three forms of nitric oxide synthase have been sequenced: a constitutive form from vascular endothelium; a constitutive form from the central nervous system; and an inducible enzyme derived from macrophages in response to cytokines.5 Together, these enzymes, through the release of nitric oxide, control a great variety of processes, in both health and disease. Nitric oxide is important as an inhibitor of platelet aggregation, smooth muscle cell proliferation and endothelial-leukocyte interaction.6,7,8 However, one of the most important actions of nitric oxide is in the regulation of both basal and stimulated arterial tone.9,10 In response to a number of pharmacological and physiological stimuli, the activation of constitutive nitric oxide synthase releases nitric oxide, leading to vasodilation. However, in patients with atherosclerosis or cardiac risk factors, vasodilation is attenuated and this may be important in the pathogenesis disturbances in regional and coronary blood flow leading to coronary ischemia.11 Although many other locally produced vasoactive substances including prostacyclin, endothelium-derived hyperpolarizing factor, endothelin, and thromboxane, are important in controlling vascular tone, nitric oxide plays a key role (Figure 7.1). This chapter will thus focus, on the role of endothelium-derived nitric oxide in the control of coronary conduit vessel vasomo-tion and coronary blood flow and the abnormalities in this system which are seen with atherosclerosis and related conditions.

Endothelial Role in Coronary Vasospasm and Atherosclerosis

A large body of evidence indicates that abnormal constriction or spasm of the coronary arteries contributes to the pathogenesis of myocardial ischemia not only in variant angina but also in patients with stable and unstable angina (12–14, 22, 29, 30, 34, 49–51, 82). Although proposed as a mechanism of ischemia shortly after the turn of the century (99), it was not until the reasoned observations of Prinzmetal (103) that this concept gained broader acceptance. The systematic studies of variant (Prinzmetal) angina that followed (80, 81) provided the impetus to examine the relative contribution of “dynamic” and “fixed” components of resistance associated with atherosclerotic epicardial coronary lesions, which are more commonly known to precipitate myocardial ischemia and angina. As a consequence the accepted dogma, that myocardia ischemia develops whenever a fixed coronary stenosis acts to prevent coronary blood flow from increasing to meet the prevailing myocardial demand, is now considered incomplete.