Review Article Acta Cardiol Sin 2013;29:1-10 Coronary Vasospastic Angina: Current Understanding and the Role of Inflammation Ming-Jui Hung and Wen-Jin Cherng Coronary vasospastic angina (CVsA) plays an important role in myocardial ischemia including stable angina, acute coronary syndromes, and sudden cardiac death. Inflammation status from either endothelium or adventitia can cause endothelial dysfunction. Thereafter, the endothelial dysfunction further induces vascular smooth muscle hypercontraction through the enhanced rho-kinase with the resultant clinical event. With better understanding of the interactions between inflammation, endothelium, and smooth muscle cells, we and other investigators have provided new insights into the basic pathophysiology of CVsA. Apart from calcium channel blockers, nitrates, and the rho-kinase inhibitor fasudil, anti-inflammatory treatment is helpful in some patients with refractory CVsA. Additional studies are needed to clarify the mechanisms of recurrent CVsA. Key Words: Angina · Coronary vasospasm · Inflammation HISTORY OF CORONARY VASOSPASM (CVsp) angina (CVsA)”.4 Recently, many investigators found that much of the underlying cause of CVsA is associated with In 1959, Prinzmetal and his colleagues described a ST-segment depression rather than ST-segment elevation.5,6 syndrome characterized by angina at rest with transient Therefore, the term “variant angina” is usually denoted ST-segment elevation in patients with diseased coronary as angina with transient ST-segment elevation. arteries, which is different from that seen in classic an- gina.1 In these circumstances where the heart burden is not increased, the angina must be due to a reduction in CLINICAL CHARACTERISTICS OF CVsA coronary blood flow. Prinzmetal proposed the term “vari- ant angina” and suggested that it was caused by spasm of CVsA is different from typical atherosclerotic angina in a major coronary artery, because it was relieved promptly the pathophysiologies. CVsp, however, might be induced by administration of nitroglycerin. With the advent of by exercise, particularly in the morning in some patients coronary angiography, it became apparent that variant with variant angina,7 and might cause exercise-induced angina was caused by CVsp and it may occur at the site of angina with ST-segment depression in some patients with a coronary stenosis2 or in normal coronary arteries, the stable effort angina5 (Figure 1). The authors postulated that so-called “variant of the variant”3 or “coronary vasospastic the spastic arteries are not normal, in that the spastic ar- teries cannot dilate fully in response to exercise as in nor- mal coronary arteries. There are daily, weekly, monthly, Received: June 28, 2012 Accepted: September 19, 2012 and circadian variations in the incidence of CVsA.8 Department of Cardiology and Medical Research Center, Chang Gung Memorial Hospital, Keelung, Chang Gung University College of Medicine, Taiwan. Circadian variation in the incidence of attacks in Address correspondence and reprint requests to: Dr. Ming-Jui Hung, patients with CVsA Department of Cardiology, Chang Gung Memorial Hospital, No. 222, Maijin Road, Keelung 20401, Taiwan. Tel: 886-2-2431-3131 ext. CVsA occurs usually at rest, particularly from mid- 9 10 3168; Fax: 886-2-2433-5342; E-mail: [email protected] night to early morning. Yasue et al. compared coro- 1 Acta Cardiol Sin 2013;29:1-10 Ming-Jui Hung et al. AB C D Figure 1. Treadmill exercise electrocardiograms (upper panels) and the coronary angiograms (lower panels) of a patient who had stable angina pectoris. Resting (A) and peak exercise (B) status of 12-lead electrocardiograms show positive for stress-induced ischemia in the V3-6, I, and aVL leads. The coronary angiograms reveal intracoronary methylergonovine-induced diffuse diameter reduction > 70% in the mid-to-distal portion of left ante- rior descending coronary artery (C, arrows), which is relieved after intracoronary nitroglycerin 100 mg administration (D, arrows). nary arteriograms recorded in the early morning with grams and the coronary arteriograms taken after nitro- those recorded in the afternoon in patients with variant glycerin administration. The percentage increase in di- angina. In the early morning, the tone of the major cor- ameter of the major coronary artery after nitroglycerin onary artery was increased and its diameter was small. administration was significantly greater in the early Under such conditions, mild exercise could induce CVsp morning than in the afternoon. This may be one of the resulting in attacks; the administration of nitroglycerin reasons that there is a circadian variation in the exercise dilated the artery markedly. In contrast, in the after- capacity of most patients with variant angina. A pathol- noon, the major coronary artery was usually already di- ogy study illustrated the complexity of the local neural lated, and its tone was low on the control coronary ar- events that modulate the tone of the coronary arter- teriograms. Under such conditions, exercise could in- ies.11 The occurrence of CVsA in the early morning has duce little coronary vasoconstriction and no attacks been noted to be associated with rapid eye move- usually occurred except in patients with severe organic ment.12 Therefore, a rapid elevation of sympathetic ac- stenosis, in whom only a mild spasm could occlude the tivity during augmented parasympathetic activity has artery and result in angina attacks. To record quantita- been suggested to be related to the occurrence of CVsA tively the difference in the tone in the major coronary in the early morning. arteries observed in the early morning and in the after- noon, Yasue et al.10 measured the diameter of the major Acute coronary syndrome coronary artery on both the control coronary arterio- There is general consensus in the medical commu- Acta Cardiol Sin 2013;29:1-10 2 Inflammation and Coronary Vasospasm nity that intracoronary thrombus plays a major role in several agents or procedures, including ergonovine the pathogenesis of acute myocardial infarction. Yasue maleate, methylergonovine maleate, acetylcholine or et al.13 found that CVsp was presumed to be responsible hyperventilation reported that induce CVsp in patients for the acute myocardial infarction because the culprit with CVsA. Intracoronary ergonovine administration has artery was patent without delay of visualization in been a popular method to induce CVsp during angio- 17.9% of patients in the early phase of acute myocardial graphic study because of its high sensitivity and specific- infarction. Our report also found that the responsible ity.18 This test was administrated using a step-wise dose coronary arteries were patent in 12% of patients with of ergonovine (1, 5, 10, and 30 mg) every 3 minutes; acute myocardial infarction (Figure 2).14 There was in- farct-related CVsp involvement in 95% in these patients. This may be explained by the spontaneous resolution of either spasm or thrombus, or both. Oshima et al.15 re- ported that CVsp causes intracoronary thrombus forma- tion, supporting the concept that CVsp is one of the pri- mary factors contributing to acute myocardial infarc- A B tion. Therefore, CVsp appears to play a role in the pro- duction of acute myocardial infarction in these patients. Most of the patients with CVsA present as angina with ST-segment depression and/or T-wave inversion on electrocardiogram, which is an acute coronary syn- C D drome. If there is no cardiac enzyme elevation, we de- fine the cardiac event as an unstable angina because most of the CVsA occurs at rest. Angiographically normal or near-normal coronary arteries occurs in 25% of pa- tients with acute coronary syndrome irrespective of the 16,17 provocative agents. The CVsp can be induced in E F 50-60% of these patients. After initial management (i.e. oxygen, aspirin, nitroglycerin, and/or morphine) for acute coronary syndrome, follow-up electrocardiograms areimportanttoindicatetheroleofCVspfortheacute coronary syndrome. If there is a normalized ST-segment after the initial management, the CVsp may play a role G H in acute coronary syndrome. Figure 2. A serial 12-lead electrocardiograms and the coronary angiograpms of a patient who had coronary vasospasm-induced acute Intracoronary administration of methylergonovine myocardial infarction. The patient had normal coronary angiograms 1 year before acute myocardial infarction. Initial resting 12-lead electro- Provocative testing for CVsp is required to clarify its cardiograms at emergency department showed complete atrioven- role in the pathogenesis of angina pectoris, especially in tricular block with ST-elevation in the II, III, aVF and V1-4 (A) and right patients without significant obstructive coronary artery ventricular infarction (B). The emergency coronary angiogram revealed disease (CAD). To ensure a valid provocative test, vasodi- total occlusion of right coronary artery since the orifice (C, arrow) inititally. After intra-aortic nitroglycerin 200 mg administration, patent lators (calcium antagonists and nitrates) must be with- proximal and mid-portion of right coronary artery with thrombi-oc- drawn for at least 24 hours, except sublingual nitroglyc- cluded (D, arrow) in the distal portion of right coronary artery was erin if necessary. The nitroglycerin solution must be well noted. A thrombuster-catheter (E, arrow) was used to aspirate thrombi. prepared before starting intracoronary methylergo- After thrombi suction and further intracoronary 200 mg nitroglycerin