View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 920 JACC Vol. 30, No. 4 October 1997:920–6 Nitric Oxide-Mediated Flow-Dependent Dilation Is Impaired in Coronary Arteries in Patients With Coronary Spastic Angina KIYOTAKA KUGIYAMA, MD, MASAMICHI OHGUSHI, MD, TAKESHI MOTOYAMA, MD, SEIGO SUGIYAMA, MD, HISAO OGAWA, MD, MICHIHIRO YOSHIMURA, MD, YOSHITO INOBE, MD, OSAMU HIRASHIMA, MD, HIROAKI KAWANO, MD, HIROFUMI SOEJIMA, MD, HIROFUMI YASUE, MD Kumamoto City, Japan Objectives. This study sought to examine whether flow- Results. Flow-dependent dilation of the proximal LAD was dependent dilation is impaired at the site of coronary artery found to be less in spasm arteries than in control arteries. G spasm in patients with coronary spastic angina. Infusion of N -monomethyl-L-arginine (L-NMMA) in the proxi- Background. Physiologic stimuli such as exercise and exposure mal LAD suppressed flow-dependent dilation in control arteries to cold have been shown to cause an increase in coronary blood but had no significant effect on spasm arteries. The dilator flow, leading to flow-dependent dilation of coronary arteries in response to nitroglycerin was not impaired in spasm coronary normal subjects, but cause coronary constriction in patients with arteries. coronary spastic angina. Conclusions. Our results indicate that flow-dependent coronary Methods. A maximal increase in blood flow was induced dilation is impaired in spasm arteries, partly due to a deficiency in selectively in the left anterior descending coronary artery (LAD) endothelial nitric oxide bioactivity, which in turn may contribute by infusion of adenosine through a Doppler flow catheter tip in the to the increase in coronary tone during physiologic stimuli in midportion of the LAD in 10 patients with coronary spastic patients with coronary spastic angina. angina, all with angiographically demonstrated spasm of the LAD, (J Am Coll Cardiol 1997;30:920–6) and in 11 control patients. Coronary artery diameter at the ©1997 by the American College of Cardiology proximal site of the LAD (exposed to increased flow but not to adenosine) was measured by quantitative angiography. Coronary artery spasm has been shown (1,2) to play an continuously generates NO, which has been shown (8–14) to important role not only in the pathogenesis of variant angina, maintain basal vascular tone in animals and humans. We but also of ischemic heart disease in general, including other recently showed (14) that there is a deficiency in endothelial forms of angina pectoris, acute myocardial infarction and NO bioactivity at the sites of coronary artery spasm and that sudden death. However, the precise mechanism by which this deficiency plays an important role in the pathogenesis of coronary spasm occurs remains unknown. Nitric oxide (NO) is coronary spasm. Flow-dependent vasodilation is well known to an important vasodilator and is produced from L-arginine by have an important role in the regulation of arterial tone way of the enzyme NO synthase (NOS) (3–7). Analogues of (15–19). Physiological stimuli, such as exercise and the cold G L-arginine, such as N -monomethyl-L-arginine (L-NMMA), pressor test, which induce an increase in coronary blood flow, competitively inhibit NO production and have been widely have been shown (20–23) to dilate coronary arteries in normal used to examine the NO pathway in animals and humans subjects. However, we and others have shown (1,2,24,25) that (6–13). The constitutive NOS in the arterial endothelium spastic coronary arteries have increased basal tone and do not dilate but constrict during exercise and exposure to cold. An increase in blood flow or shear stress has been shown (3– From the Division of Cardiology, Kumamoto University School of Medicine, Kumamoto City, Japan. This study was supported in part by Grant-in-Aid for 13,26,27) to produce endothelial release of NO, which causes Scientific Research C05670622 from the Ministry of Education, Science and flow-dependent vasodilation. Thus, the present study aimed to Culture and a Smoking Research Foundation Grant for Biochemical Research, examine whether flow-dependent dilation is impaired at the Tokyo, Japan. Manuscript received February 12, 1997; revised manuscript received May 27, sites of coronary artery spasm in patients with coronary spastic 1997, accepted June 20, 1997. angina and to determine the possible relevance of deficient NO Address for correspondence: Dr. Kiyotaka Kugiyama, Division of Cardiol- ogy, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto City, bioactivity to the abnormal response of coronary tone to blood 860 Japan. E-mail: [email protected]. flow in spasm coronary arteries. ©1997 by the American College of Cardiology 0735-1097/97/$17.00 Published by Elsevier Science Inc. PII S0735-1097(97)00236-2 JACC Vol. 30, No. 4 KUGIYAMA ET AL. 921 October 1997:920–6 FLOW-INDUCED DILATION IN SPASM CORONARY ARTERY Table 1. Clinical Characteristics of Study Patients* Abbreviations and Acronyms Patients Control ACh 5 acetylcholine With CSA Patients ECG 5 electrocardiogram (n 5 10) (n 5 11) LAD 5 left anterior descending coronary artery Age (yr) 59 11 57 10 LCx 5 left circumflex coronary artery 6 6 G Women/men 4/6 3/8 L-NMMA 5 N -monomethyl-L-arginine NO 5 nitric oxide Total serum cholesterol (mg/dl) 181 6 36 191 6 33 NOS 5 nitric oxide synthase HDL cholesterol (mg/dl) 39 6 846614 Serum triglyceride (mg/dl) 127 6 69 140 6 41 Hypercholesterolemia† 0 1 Hypertension‡ 3 2 Diabetes mellitus§ 0 2 Methods Current smokeri 24 *p 5 NS for all comparisons. †Total serum cholesterol $240 mg/dl. ‡Blood Study patients. The study included 10 patients with coro- pressure $140/90 mm Hg or taking antihypertensive medication. §Fasting blood nary spastic angina (mean age 59 years, range 43 to 71; six men, glucose $140 mg/dl or taking antidiabetic medication. i$10 cigarettes/day for four women) who fulfilled the following inclusion criteria: 1) $10 years. Data presented are mean value 6 SD or number of patients. CSA 5 spontaneous chest pain in association with ST segment eleva- coronary spastic angina. tion or depression on the 12-lead electrocardiogram (ECG) or the ambulatory ECG at rest, usually in the middle of the night or early morning and more than two times a day during the spasm (,50% decrease in coronary diameter from baseline) study; 2) coronary spasm (total or subtotal occlusion) of the after intracoronary injection of ACh. Neither nitrates nor left anterior descending coronary artery (LAD) demonstrated calcium channel blockers were effective in relieving chest pain angiographically during chest pain, with ST segment changes in any control patient. after intracoronary injection of acetylcholine (ACh), as previ- The clinical characteristics of the study patients are shown ously reported (28,29); 3) no organic coronary artery stenosis in Table 1. All medications except sublingual nitroglycerin on angiography. Five patients had transient ST segment ele- were withdrawn at least 3 days before the study, and no patient vation and five ST segment depression during the spontaneous had taken nitroglycerin within6hofthestudy. No patient had attacks. All 10 patients with coronary spastic angina performed a previous myocardial infarction, congestive heart failure or treadmill exercise and hyperventilation tests. Anginal attacks other serious diseases. Written informed consent was obtained of chest pain with ST segment changes occurred in two patients from all patients before the study. The study was approved by during the treadmill test (ST segment elevation in one, ST the ethics committee of our institution. segment depression in the other) and in four during the Study protocol. Coronary angiography was performed with hyperventilation test (ST segment elevation in three, ST seg- the Judkins technique using contrast material (Ioxaglate, ment depression in one). The spontaneous attacks were Guerbet S.A.) in the morning when the patients were fasting. promptly resolved by the administration of sublingual nitro- After heart rate and blood pressure measurements, control glycerin and were almost completely prevented by calcium angiography of the left main and right coronary arteries was channel blocking agents in all 10 patients with coronary spastic performed. Thereafter, incremental doses of ACh were in- angina. In patients with coronary spastic angina, the proximal jected into the left main coronary artery (20, 50 and 100 mg) LAD diameter at baseline angiography was .1.5 mm, so the and subsequently into the right coronary artery (20 and 50 mg). Doppler catheter was allowed to avoid catheter-induced coro- The method of injecting ACh for provocation of coronary nary spasm in these patients. All study patients had ambulatory spasm has been detailed elsewhere (28,29). Coronary spasm ECG monitoring for at least 48 h. ST segment changes on resolved spontaneously without the use of nitroglycerin in all 12-lead and ambulatory electrocardiography were considered patients with coronary spastic angina in this study. significant if transient ST segment elevation (.0.2 mV) or Flow-dependent dilation in human coronary arteries in vivo depression (.0.1 mV) versus baseline levels occurred at 60 to was assessed similar to previously reported methods (18,19). In 80 ms after the J point. brief, 15 min after completion of the intracoronary injection of This study also included 11 control patients who underwent ACh, when systemic hemodynamic variables and angiographic diagnostic cardiac catheterization for evaluation of atypical coronary artery diameters had returned to baseline levels, an chest pain (mean age 57 years, range 39 to 70; eight men, three additional 5,000 U of heparin was given intravenously, and an women) and were matched for coronary artery disease risk 8F guiding catheter was positioned in the ostium of the left factors to patients with coronary spastic angina.