CLINICAL RESEARCH: CORONARY SPASM
Provoked Coronary Spasm Predicts Adverse Outcome in Patients With Acute Myocardial InfarctionA Novel Predictor of Prognosis After Acute Myocardial Infarction
Kohei Wakabayashi, MD, PhD*,
Hiroshi Suzuki, MD, PhD*,*,
Yuki Honda, MD*,
Daisuke Wakatsuki, MD*,
Keisuke Kawachi, MD*,
Kei Ota, MD*,
Shinji Koba, MD, PhD ,
Nobuyuki Shimizu, MD, PhD*,
Fuyuki Asano, MD, PhD*,
Tokutada Sato, MD, PhD* and
Youichi Takeyama, MD, PhD*
* Division of Cardiology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan
Third Department of Internal Medicine, Showa University, School of Medicine, Tokyo, Japan.
Manuscript received November 12, 2007;
revised manuscript received January 22, 2008,
accepted January 27, 2008.
* Reprint requests and correspondence: Dr. Hiroshi Suzuki, 1-30 Fujigaoka, Yokohama City, Yokohama 227-8501, Japan. (Email: hrsuzuki{at}med.showa-u.ac.jp).
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Abstract
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Objectives: This study was conducted to examine the relationship between provoked coronary spasm and clinical course in patients with acute myocardial infarction (AMI).
Background: Coronary spasm has a pathogenetic role in the occurrence of AMI and progressive atherosclerosis. There is no report that focused on the prognostic significance of provoked coronary spasm in AMI patients.
Methods: Our group investigated 240 consecutive patients who underwent spasm-provocation tests using acetylcholine after AMI. Coronary spasm was defined as a transient total or subtotal occlusion of the luminal diameter. The patients were divided into 2 groups (positive group: n = 174, negative group: n = 66).
Results: The clinical courses of the 2 groups were compared at long-term follow up (mean, 43 months). Major adverse cardiac events (death, acute coronary syndrome, or revascularization) occurred in 82 patients (47.1%) in the positive group and 18 patients (27.3%) in the negative group (p = 0.0055). The frequency of major adverse cardiac event–free survival was significantly lower in the positive group than in the negative group (p = 0.0018). Provoked coronary spasm was a significant independent predictor of poor prognosis.
Conclusions: Provoked coronary spasm predicts adverse outcome in AMI patients.
Key Words: acetylcholine • provoked coronary spasm • acute myocardial infarction • prognosis
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Abbreviations and Acronyms
| | ACh = acetylcholine | | ACS = acute coronary syndrome | | AMI = acute myocardial infarction | | IRA = infarct-related artery | | MACE = major adverse cardiac event(s) | | PCI = percutaneous coronary intervention | | TVR = target vessel revascularization | | VSA = vasospastic angina |
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Coronary spasm is well known to play an important role in acute myocardial infarction (AMI) patients (1–3). In vasospastic angina (VSA) patients, AMI occurs not only in significant atherosclerotic coronary artery disease but also in the absence of coronary stenosis (4). A previous study (5) has identified aggravated VSA as a risk factor for AMI and cardiac death. It has been reported that coronary spasm is a trigger of coronary thrombus and subsequent AMI (6). On the other hand, it has been reported that persistent vasospastic activity is closely associated with progressive atherosclerosis in VSA patients (7). Coronary spasm is an important factor behind the progression of coronary atherosclerosis and subsequent AMI.
Provocation testing frequently provokes coronary spasms in AMI patients (2). Pristipino et al. (3) reported that Japanese AMI patients show a 3-fold greater incidence of acetylcholine (ACh)-induced spasms than Caucasians. It thus seems that coronary spasms are particularly important triggers of AMI in Japanese patients (8).
Although many reports have been published on the prognosis of VSA patients (4,5,7,8), none have focused on the prognostic significance of provoked coronary spasm in AMI patients. For further insight, our group investigated whether ACh-provoked coronary spasms are associated with adverse outcomes in Japanese AMI patients. This study is the first single-center registry conducted chiefly to evaluate the significance of provoked coronary spasms for long-term prognosis after AMI.
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Methods
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Patients and follow-up protocol.
In the population of patients admitted to Showa University Fujigaoka Hospital with a diagnosis of AMI between January 1, 1999, and September 30, 2004, emergent PCI was successfully administered within 24 h from onset in 373 consecutive patients. Of those 373 patients, 130 met 1 or more of the following exclusion criteria and were thus excluded: in-hospital death, cardiopulmonary arrest, coronary artery bypass graft, cardiogenic shock, stroke, subacute thrombosis, or renal failure. Patients with residual stenosis received additional percutaneous coronary intervention (PCI) at the discretion of attending physicians. The remaining 243 patients underwent spasm provocation tests using ACh, and the clinical courses of 240 of them could be followed up through charts and interviews. A major adverse cardiac event (MACE) was defined as death, acute coronary syndrome (ACS), or revascularization. Cardiovascular death was defined as death caused by either cardiovascular disease or stroke, or documented as sudden cardiac death.
The study protocol was approved by the ethics committee of Showa University, and informed consent was obtained from every patient.
Provocative protocol.
The patients underwent provocation tests using ACh from 10 to 20 days after the onset of AMI. Calcium-channel blockers and nitrates were discontinued for at least 24 h before the tests were performed.
The provocative protocol has been previously described (3). After coronary angiography to obtain control data, ACh was injected in incremental doses of 20 and 50 µg into the right coronary artery and 50 and 100 µg into the left coronary artery, with support of temporary right ventricular pacing. Coronary angiography was repeated thereafter. After injection of isosorbide dinitrate, coronary angiography was repeated. Coronary spasm was defined as a transient total or subtotal reduction of the luminal diameter with electrocardiographic changes (significant ST-segment elevation [>0.1 mV] or ST-segment depression [horizontal or sagging <–0.1 mV, upsloping <–2.0 mV] in  2 leads) and/or typical chest oppression.
Statistical analysis.
Continuous variables were presented as mean ± SD and compared using the Student t test. Categorical variables were presented as counts and percentages, and compared using the Fisher exact probability test. A multivariate Cox regression analysis was performed to identify independent predictors of MACE. The cumulative incidence of MACE was estimated using the Kaplan-Meier method. For patients who experienced multiple events, survival analysis was restricted to the first event. Statistical significance was assumed if the null hypothesis could be rejected at the level of p = 0.05.
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Results
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Vascular responses to ACh.
In total, 701 coronary arteries (240 infarct-related arteries [IRAs] and 461 non-IRAs) were examined by coronary provocation test after excluding 17 total or subtotal occlusive coronary arteries and 2 hypoplastic right coronary arteries, because it was difficult to assess transient ischemia induced spasm. Coronary spasm was positive in IRA and/or non-IRA in 174 of 240 patients (72.5%, positive group) and negative in both IRA and non-IRA in 66 of 240 patients (27.5%, negative group) (Table 1). Coronary spasms were provoked in 400 of 701 arteries examined by provocation test. Provoked coronary spasms were identified in 170 of 240 IRAs (70.8%) and in 230 of 461 non-IRAs (49.9%).
Baseline characteristics.
Distributions of demographic parameters across the 2 groups are listed in Table 1. All patients were followed up for at least 6 months or until death (follow-up period: 6 to 82 months; mean 42.6 ± 23.2 months; median 42 months). Men (p < 0.001) and current smokers (p < 0.0001) were significantly more frequent in the positive group than in the negative group, and none of the other characteristics differed between the groups. In the comparison of medications, the positive group received significantly more calcium-channel blockers (p < 0.05) and fewer beta-blockers (p < 0.05) than the negative group. All patients were given aspirin (100 to 200 mg/day) during the follow-up period.
Clinical determinants of prognosis.
One hundred patients experienced MACE, and 14 patients died during follow-up. The causes of death were cardiovascular disease in 4 patients, cancer in 7, infection in 2, and acute pancreatitis in 1. Table 2
compares the incidence of MACE between the 2 groups; MACE was significantly more frequent in the positive group than in the negative group (p < 0.01). Revascularization and ACS were significantly more frequent in the positive group than in the negative group (p < 0.05).
The Fisher exact probability test for MACE was performed among the following variables: spasm provocation test, age, gender, hypertension, diabetes mellitus, hyperlipidemia, smoking, prior myocardial infarction, left ventricular ejection fraction, 3-vessel disease, and medications at discharge (angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers, calcium-channel blockers, beta-blockers, and nitrates). Significant differences were found in provoked coronary spasm, hypertension, 3-vessel disease, and nitrates (Table 3). A multivariate Cox regression analysis was performed to identify independent predictors of MACE among the factors related to provoked spasm (gender and smoking) (Table 1), and the significant factors related to MACE (provoked coronary spasm, hypertension, 3-vessel disease, and nitrates) (Table 3). Table 4
presents the results of a multivariate Cox regression analysis of MACE. Provoked coronary spasm was the strongest predictor of MACE in the multivariate analysis.
Figure 1
compares the cumulative proportions of patients without MACE in the positive and the negative groups. The frequency of MACE-free survival was significantly lower in the positive group than in the negative group (p = 0.0018).
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Figure 1 Kaplan-Meier Curves for MACE-Free Survival
Kaplan-Meier curves for MACE-free survival in the positive and negative groups. The frequency of MACE-free survival was significantly lower in the positive group than in the negative group (p = 0.0018). ACh = acetylcholine; MACE = major adverse cardiac events.
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Relationship between the spasm-positive artery and the advance of coronary lesions.
The incidences of target vessel revascularization (TVR), de novo lesions, and ACS were compared between the spasm-positive arteries and spasm-negative arteries.
In 199 spasm-positive arteries and 99 spasm-negative arteries during the first hospitalization, PCIs were performed for culprit lesions of AMI and residual stenosis. More frequently, TVR was performed in the spasm-positive arteries (63 of 199, 31.7%) than in the spasm-negative arteries (18 of 99, 18.2%) (p < 0.05) (Fig. 2A). In the spasm-positive arteries, ACS was observed more frequently (10 of 400 [4 IRAs and 6 non-IRAs], 2.5%) than in the spasm-negative arteries (0 of 301, 0%) (p < 0.01) (Fig. 2B). Revascularized de novo lesions including ACS were more frequent in the spasm-positive arteries (25 in 400, 6.3%) than in the spasm-negative arteries (3 in 301, 0%) (p < 0.001) (Fig. 2C).
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Figure 2 Relationship Between the Spasm-Positive Artery and the Advance of Coronary Lesions
Target vessel revascularization was more frequent in the spasm-positive arteries (PAs) (31.7%) than in the spasm-negative arteries (NAs) (18.2%, p = 0.014). De novo lesions, including acute coronary syndrome lesions, were observed in 25 of 400 PAs and in 3 NAs (p = 0.00044). Acute coronary syndrome (ACS) was observed in 10 of 400 PAs and in 0 of 301 NAs (p = 0.0057).
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Discussion
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This is the first report to show that provoked coronary spasms are closely associated with the prognosis of AMI patients. The incidence of provoked coronary spasms in the present study was similar to that in the previous study on Japanese AMI patients (3). The MACE-free survival was less frequent in the positive group than in the negative group. The incidences of ACS and revascularization were significantly higher in the positive group than in the negative group. In the analyses of advance of coronary lesions, TVR and de novo lesions were more frequent in the spasm-positive arteries than in the spasm-negative arteries. Also, ACS was more frequent in the spasm-positive arteries than in the spasm-negative arteries, suggesting that provoked coronary spasms may be predictive of ACS.
In the present study, TVR, ACS, and de novo lesions were more frequent in the spasm-positive arteries than in the spasm-negative arteries. The first possible explanation for the results is the involvement of inflammation and fibrosis in coronary arteries. Repeated episodes of coronary spasm may provoke vascular injury, and thus lead to neointimal hyperplasia and progressive atherosclerosis. Previous studies have shown the presence of various inflammatory cells and mast cells in the adventitia of coronary arteries of patients with spasms (9). The second possible explanation is the involvement of hemorrhaging of the coronary arteries. Reports in swine models have shown that strong coronary spasms induce histological intramural hemorrhaging and intimal thickening, conditions that frequently progress to the rapid advance of coronary atherosclerosis (10). Ogawa et al. (6) reported high plasma levels of fibrinopeptide A, a sensitive marker of thrombin production that appears in the coronary circulation after coronary spasm attacks in VSA patients. Coronary spasms trigger coronary thrombus and subsequent AMI.
The previous experimental studies (10,11) and clinical studies (7,12) have suggested a causal link between repeated coronary spasms and atherogenesis. Intravascular ultrasound studies by Hong et al. (13) revealed intimal plaque at sites of focal coronary spasms in VSA patients. Those plaques were mostly hypoechoic and highly eccentric, with no calcification and only mild reference vessel disease. These findings indicate that coronary spasm is associated with mild atherosclerosis in the early stage and may induce vulnerable plaque as a precursor to ACS.
The patients in our positive group received beta-blockers less frequently and calcium-channel blockers more frequently compared with the patients in the negative group. This trend may be attributable to the previous studies regarding these agents (14,15). Because various kinds and doses of agents including calcium-channel blockers and beta-blockers were used, the assessment of such agents may be limited in the present study.
Although we defined a coronary spasm as a transient total or subtotal reduction of the luminal diameter with significant ischemia, provoked spasm and abnormal vasoconstriction related to endothelial dysfunction cannot be distinguished in the present study. When a coronary artery had total or subtotal spasm in the ostium, it was difficult to assess the distal part of the artery. Furthermore, if the culprit lesion of AMI is ostium, we had no way to assess the proximal part of the IRA. Thus, lacking any means to examine the characteristics of provoked coronary spasm (focal, diffuse, proximal, or distal of the IRA) accurately, we limited our assessments of the spasms to analysis in separate arteries.
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Conclusions
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The provocation test frequently induces potent coronary spasms, and the spasm affects outcome in AMI patients. In coronary arteries with provoked spasms, TVR, ACS, and de novo lesions were observed more frequently.
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References
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1. Maseri A, L'Abbate A, Baroldi G, et al. Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the study of "preinfarction" angina. N Engl J Med 1978;299:1271-1277.[Abstract]2. Bertrand ME, Lablanche JM, Tilmant PY, Thieuleux FA, Delforge MG, Chahine RA. The provocation of coronary arterial spasm in patients with recent transmural myocardial infarction Eur Heart J 1983;4:532-535.[Abstract/Free Full Text] 3. Pristipino C, Beltrame JF, Finocchiaro ML, et al. Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction Circulation 2000;101:1102-1108.[Abstract/Free Full Text] 4. Bott-Silverman C, Heupler Jr FA. Natural history of pure coronary artery spasm in patients treated medically J Am Coll Cardiol 1983;2:200-205.[Abstract] 5. Nakamura M, Takeshita A, Nose Y. Clinical characteristics associated with myocardial infarction, arrhythmias, and sudden death in patients with vasospastic angina Circulation 1987;75:1110-1116.[Abstract/Free Full Text] 6. Ogawa H, Yasue H, Oshima S, Okumura K, Matsuyama K, Obata K. Circadian variation of plasma fibrinopeptide A level in patients with variant angina Circulation 1989;80:1617-1626.[Abstract/Free Full Text] 7. Ozaki Y, Keane D, Serruys PW. Progression and regression of coronary stenosis in the long-term follow-up of vasospastic angina Circulation 1995;92:2446-2456.[Abstract/Free Full Text] 8. Beltrame JF, Sasayama S, Maseri A. Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients J Am Coll Cardiol 1999;33:1442-1452.[Abstract/Free Full Text] 9. Forman MB, Oates JA, Robertson D, Robertson RM, Roberts 2nd LJ, Virmani R. Increased adventitial mast cells in a patient with coronary spasm N Engl J Med 1985;313:1138-1141.[Web of Science][Medline] 10. Nagasawa K, Tomoike H, Hayashi Y, Yamada A, Yamamoto T, Nakamura M. Intramural hemorrhage and endothelial changes in atherosclerotic coronary artery after repetitive episodes of spasm in x-ray-irradiated hypercholesterolemic pigs Circ Res 1989;65:272-282.[Abstract/Free Full Text] 11. Shimokawa H, Tomoike H, Nabeyama S, et al. Coronary artery spasm induced in atherosclerotic miniature swine Science 1983;221:560-562.[Abstract/Free Full Text] 12. Nobuyoshi M, Tanaka M, Nosaka H, et al. Progression of coronary atherosclerosis: is coronary spasm related to progression? J Am Coll Cardiol 1991;18:904-910.[Abstract] 13. Hong MK, Park SW, Lee CW, et al. Intravascular ultrasound findings of negative arterial remodeling at sites of focal coronary spasm in patients with vasospastic angina Am Heart J 2000;140:395-401.[CrossRef][Web of Science][Medline] 14. Yasue H, Touyama M, Shimamoto M, Kato H, Tanaka S. Role of autonomic nervous system in the pathogenesis of Prinzmetal's variant form of angina Circulation 1974;50:534-539.[Abstract/Free Full Text] 15. Chahine RA, Feldman RL, Giles TD, et al. Amlodipine Study 160 Group Randomized placebo-controlled trial of amlodipine in vasospastic angina J Am Coll Cardiol 1993;21:1365-1370.[Abstract]
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Abstract
Methods