日本循環器学会．循環器病の診断と治療に関するガイドライン（2012年度合同研究班報告）：冠攣縮性狭心症の診断と治療に関するガイドライン（2013年改訂版）．https://www.j-circ.or.jp/cms/wpcontent/uploads/2020/02/JCS2013_ogawah_h.pdf.
Pristipino C, Beltrame JF, Finocchiaro ML, Hattori R, Fujita M, Mongiardo R, Cianflone D, Sanna T, Sasayama S, Maseri A.
Major racial differences in coronary constrictor response between japanese and caucasians with recent myocardial infarction.
Circulation. 2000 Mar 14;101(10):1102-8. doi: 10.1161/01.cir.101.10.1102.
Abstract/Text
BACKGROUND: Enhanced coronary vasomotion may contribute to acute coronary occlusion during the acute phase of myocardial infarction (AMI). Japanese have a higher incidence of variant angina than Caucasian patients, but racial differences in vasomotor reactivity early after AMI are controversial.
METHODS AND RESULTS: The same team studied 15 Japanese and 19 Caucasian patients within 14 days of AMI by acetylcholine injection into non-infarct-related (NIRA) and infarct-related (IRA) coronary arteries followed by nitroglycerin. Incidence of vasodilation, vasoconstriction, spasm, and basal tone were assessed in proximal, middle, and distal segments after each drug bolus by quantitative angiography. Japanese patients had much lower cholesterol levels than Caucasians (183+/-59 versus 247+/-53 mg/dL, P<0.006) but showed a lower incidence of vasodilation (2% versus 9% of coronary segments) and a greater incidence of spasm after acetylcholine (47% versus 15% of arteries, P<0.00001). Incidence of spasm was higher in IRAs than in NIRAs in both populations (67% versus 39% and 23% versus 11%, respectively). Multivessel spasm was more common (64% versus 17%, P<0.02) and vasoconstriction of nonspastic segments was greater in Japanese patients (-23.4+/-14.9% versus -20.1+/-15.7%, P<0.02) in the presence of similar average basal coronary tone with respect to post-nitroglycerin dilation and of nonsignificant differences of coronary atherosclerotic score.
CONCLUSIONS: Soon after AMI, Japanese patients exhibited a 3-fold-greater incidence of spasm and greater vasoconstriction of nonspastic segments after acetylcholine than Caucasians. The causes of such differences warrant further investigation because they may have relevant pathophysiological and therapeutic implications.
Sugiishi M, Takatsu F.
Cigarette smoking is a major risk factor for coronary spasm.
Circulation. 1993 Jan;87(1):76-9. doi: 10.1161/01.cir.87.1.76.
Abstract/Text
BACKGROUND: Although there have been many studies on the risk factors for coronary artery disease, the etiology of coronary artery spasm has not yet been determined.
METHODS AND RESULTS: After diagnosis by coronary arteriography, various risk factors were compared between two groups of subjects using logistic regression analysis. The vasospasm group included 175 patients with angiographically determined coronary artery spasm but no coronary artery narrowing exceeding 25% of the luminal diameter. The control group comprised 176 subjects with completely normal coronary arteries and a negative response to ergonovine maleate. The adjusted odds ratio and 95% confidence interval for smoking as a risk factor for vasospasm was 2.41 and 1.53-3.82, respectively (p < 0.05). The adjusted odds ratios for total cholesterol, low density lipoprotein, high density lipoprotein, triglycerides, diabetes mellitus, and body mass index, calculated by multivariate logistic regression analysis, were not statistically nonsignificant.
CONCLUSIONS: Smoking appears to be a major risk factor for vasospastic angina without significant coronary narrowing. The other risk factors for coronary artery disease may not contribute to coronary vasospasm.
Yoshimura M, Yasue H, Nakayama M, Shimasaki Y, Sumida H, Sugiyama S, Kugiyama K, Ogawa H, Ogawa Y, Saito Y, Miyamoto Y, Nakao K.
A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese.
Hum Genet. 1998 Jul;103(1):65-9. doi: 10.1007/s004390050785.
Abstract/Text
Coronary spasm plays an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general. However, the precise mechanism(s) by which coronary spasm occurs remains to be elucidated. Coronary spasm may arise from interactions between environmental and genetic factors. Endothelial-derived nitric oxide (NO) has been implicated in the control of vascular tone. We have recently shown that both basal and acetylcholine (ACh)-induced NO activities are impaired in the coronary arteries of patients with coronary spasm. The purpose of this study has been to elucidate the possible variants that occur in the coding region of the endothelial nitric oxide synthase (eNOS) gene and that may be associated with coronary spasm. After initial screening in the entire 26 coding regions of the eNOS gene, we found a missense Glu298Asp variant in exon 7 in patients with coronary spasm. We subsequently performed a larger scale study involving 113 patients with coronary spasm and 100 control subjects, who were all diagnosed by intracoronary injection of ACh. The analysis revealed a significant difference in the distribution of the variant between the coronary spasm group (21.2%) and control group (9.0%; P=0.014 for dominant effect). Thus, we have found the missense Glu298Asp variant in the eNOS gene by the analysis of its entire 26 coding regions. The variant is significantly associated with coronary spasm.
Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H, Motoyama T, Saito Y, Ogawa Y, Miyamoto Y, Nakao K.
T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm.
Circulation. 1999 Jun 8;99(22):2864-70. doi: 10.1161/01.cir.99.22.2864.
Abstract/Text
BACKGROUND: Coronary spasm plays an important role in the pathogenesis of ischemic heart diseases in general. However, the precise mechanism(s) responsible for coronary spasm remains to be elucidated, and we examined the molecular genetics of coronary spasm.
METHODS AND RESULTS: We searched for the possible mutations in the endothelial nitric oxide synthase (eNOS) gene in patients with coronary spasm. In this study, we demonstrate the existence of 3 linked mutations in the 5'-flanking region of the eNOS gene (T-786-->C, A-922-->G, and T-1468-->A). The incidence of the mutations was significantly greater in patients with coronary spasm than in the control group (P<0.0001). Multiple logistic regression analysis with forward stepwise selection using the environmental risk factors and the eNOS gene variant revealed that the most predictive independent risk factor for coronary spasm was the mutant allele (P<0.0001). As assessed by luciferase reporter gene assays, the T-786-->C mutation resulted in a significant reduction in eNOS gene promoter activity (P<0.05), whereas neither the A-922-->G nor the T-1468-->A mutation had any affect.
CONCLUSIONS: Taken together, these findings strongly suggest that the T-786-->C mutation in the eNOS gene reduces the endothelial NO synthesis and predisposes the patients with the mutation to coronary spasm.
Mizuno Y, Harada E, Morita S, Kinoshita K, Hayashida M, Shono M, Morikawa Y, Murohara T, Nakayama M, Yoshimura M, Yasue H.
East asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome.
Circulation. 2015 May 12;131(19):1665-73. doi: 10.1161/CIRCULATIONAHA.114.013120. Epub 2015 Mar 10.
Abstract/Text
BACKGROUND: Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese.
METHODS AND RESULTS: The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower (P<0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA (P<0.001 and P=0.024, respectively).
CONCLUSIONS: East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA.
© 2015 American Heart Association, Inc.
Nakamura M, Takeshita A, Nose Y.
Clinical characteristics associated with myocardial infarction, arrhythmias, and sudden death in patients with vasospastic angina.
Circulation. 1987 Jun;75(6):1110-6. doi: 10.1161/01.cir.75.6.1110.
Abstract/Text
A total of 349 patients with vasospastic angina were followed in eight centers in Japan for a period of 3.4 +/- 0.1 years (mean +/- SE). Ninety-eight percent of patients were treated with calcium blockers. Twenty-one episodes of myocardial infarction occurred in 18 patients (5%), including two fatal myocardial infarctions. The rate of myocardial infarction was higher (p less than .01) in patients with a fixed stenosis of 90% or greater than in patients with a fixed stenosis of less than 90% or normal coronary arteries. Myocardial infarctions occurred predominantly during hospital stays or at a time when the frequency of vasospastic angina increased. There were five sudden deaths (2%). Only one patient suffering sudden death had a fixed stenosis of 75% or greater. Serious arrhythmias were noted in 49 patients (14%). The risk of arrhythmias did not depend on the presence of a fixed stenosis of 75% or greater. These results suggest that cardiac events are rather infrequent in Japanese patients with vasospastic angina who are receiving treatment with calcium blockers and that the presence of a severe fixed stenosis markedly increases the risk of myocardial infarction but not the risk of arrhythmias.
Yasue H, Takizawa A, Nagao M, Nishida S, Horie M, Kubota J, Omote S, Takaoka K, Okumura K.
Long-term prognosis for patients with variant angina and influential factors.
Circulation. 1988 Jul;78(1):1-9. doi: 10.1161/01.cir.78.1.1.
Abstract/Text
Two hundred forty-five patients with variant angina were followed for an average of 80.5 months (range, 36-184 months). Survival rate at 1, 3, 5, and 10 years was 98%, 97%, 97%, and 93%, respectively. Survival rate without myocardial infarction at 1, 3, 5, and 10 years was 86%, 85%, 83%, and 81%, respectively. By univarite analysis, ST segment elevation in both the anterior and inferior electrocardiographic leads was the most important factor influencing survival, followed by use of calcium antagonists, left ventricular function, smoking, and alcohol intake. The variables that significantly correlated with survival without myocardial infarction were use of calcium antagonists, left ventricular function, extent and severity of coronary artery disease, coronary artery bypass surgery, and disease activity. Multivariate analysis using the Cox proportional hazards model showed that intake of calcium antagonists, extent and severity of coronary artery disease, and ST segment elevation in both the anterior and inferior leads were significant independent predictors of survival without myocardial infarction. We conclude that long-term prognosis for patients with variant angina is relatively good and that use of calcium antagonists improves it.
Kugiyama K, Yasue H, Okumura K, Ogawa H, Fujimoto K, Nakao K, Yoshimura M, Motoyama T, Inobe Y, Kawano H.
Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina.
Circulation. 1996 Aug 1;94(3):266-71. doi: 10.1161/01.cir.94.3.266.
Abstract/Text
BACKGROUND: Coronary spasm can be induced by acetylcholine, serotonin, ergonovine, or histamine, all of which cause vasodilation when the endothelium is intact by releasing nitric oxide (NO). Coronary spasm is promptly relieved by nitroglycerin, which vasodilates through its conversion to NO. It is thus possible that NO release may be deficient in the spasm arteries in patients with coronary spastic angina (CSA). The aim of this study was to determine whether NO release is deficient in coronary arteries of patients with CSA.
METHODS AND RESULTS: NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, was infused into coronary arteries in 21 patients with coronary spastic angina (CSA) and in 28 control patients. Coronary spasm was induced by intracoronary injection of acetylcholine and was documented angiographically in all patients with CSA. L-NMMA dose-dependently decreased basal luminal diameter of coronary arteries in control patients, whereas it had no effect on basal diameter of the spasm arteries in patients with CSA. L-NMMA abolished the dilator response to acetylcholine and enhanced the constrictor response to acetylcholine in control arteries, whereas it had no effect on the constrictor response to acetylcholine in spasm arteries. Intracoronary infusion of L-arginine did not affect the diameter of spasm or control arteries. The dilator response to nitroglycerin was increased markedly in spasm arteries compared with control arteries, whereas response to diltiazem did not differ between them.
CONCLUSIONS: There is a deficiency in endothelial NO activity in spasm arteries, which leads to the supersensitivity of the artery to the vasodilator effect of nitroglycerin and to the vasoconstrictor effect of acetylcholine in patients with CSA. This deficient endothelial NO activity plays an important role in the pathogenesis of coronary spasm.
Katsumata N, Shimokawa H, Seto M, Kozai T, Yamawaki T, Kuwata K, Egashira K, Ikegaki I, Asano T, Sasaki Y, Takeshita A.
Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1beta.
Circulation. 1997 Dec 16;96(12):4357-63. doi: 10.1161/01.cir.96.12.4357.
Abstract/Text
BACKGROUND: Although coronary artery spasm plays an important role in a wide variety of ischemic heart diseases, the intracellular mechanism for the spasm remains to be clarified. We examined the role of myosin light chain (MLC) phosphorylations, a key mechanism for contraction of vascular smooth muscle, in our swine model with interleukin-1beta (IL-1beta).
METHODS AND RESULTS: IL-1beta was applied chronically to the porcine coronary arteries from the adventitia to induce an inflammatory/proliferative lesion. Two weeks after the operation, intracoronary serotonin repeatedly induced coronary hyperconstrictions at the IL-1beta-treated site both in vivo and in vitro, which were markedly inhibited by fasudil, an inhibitor of protein kinases, including protein kinase C and MLC kinase. Western blot analysis showed that during serotonin-induced contractions, MLC monophosphorylation was significantly increased and sustained in the spastic segment compared with the control segment, whereas MLC diphosphorylation was noted only in the spastic segment. A significant correlation was noted between the serotonin-induced contractions and MLC phosphorylations. Both types of MLC phosphorylation were markedly inhibited by fasudil. In addition, MLC diphosphorylation was never induced by a simple endothelium removal in the normal coronary artery, whereas enhanced MLC phosphorylations in the spastic segment were noted regardless of the presence or absence of the endothelium.
CONCLUSIONS: These results indicate that enhanced MLC phosphorylations in the vascular smooth muscle play a central role in the pathogenesis of coronary spasm in our swine model.
Mohri M, Koyanagi M, Egashira K, Tagawa H, Ichiki T, Shimokawa H, Takeshita A.
Angina pectoris caused by coronary microvascular spasm.
Lancet. 1998 Apr 18;351(9110):1165-9. doi: 10.1016/S0140-6736(97)07329-7.
Abstract/Text
BACKGROUND: Microvascular angina can occur during exercise and at rest. Reduced vasodilator capacity of the coronary microvessels is implicated as a cause of angina during exercise, but the mechanism of angina at rest is not known. Our aim was to test the hypothesis that primary hyperconstriction (spasm) of coronary microvessels causes myocardial ischaemia at rest.
METHODS: Acetylcholine induces coronary artery spasm in patients with variant angina. We tested the effects of intracoronary acetylcholine at graded doses in 117 consecutive patients with chest pain (at rest, during exertion, or both) and no flow-limiting (>50%) organic stenosis in the large epicardial coronary arteries. We also assessed the metabolism of myocardial lactate during acetylcholine administration in 36 of the patients by measurement of lactate in paired blood samples from the coronary artery and coronary sinus vein.
FINDINGS: Of the 117 patients, 63 (54%) had large-artery spasm, 29 (25%) had microvascular spasm, and 25 (21%) had atypical chest pain. The 29 patients with microvascular spasm developed angina-like chest pain, ischaemic electrocardiogram (ECG) changes, or both spontaneously (two patients) or after administration of acetylcholine (27 patients) without spasm of the large epicardial coronary arteries. Testing of paired samples of arterial and coronary sinus venous blood showed that lactate was produced during angina attack in nine of 11 patients with microvascular spasm. There was more women (p<0.01) and fewer coronary risk factors (p<0.01) in patients with microvascular spasm than in those with large-artery spasm.
INTERPRETATION: Coronary microvascular spasm and resultant myocardial ischaemia may be the cause of chest pain in a subgroup of patients with microvascular angina.
Sun H, Mohri M, Shimokawa H, Usui M, Urakami L, Takeshita A.
Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina.
J Am Coll Cardiol. 2002 Mar 6;39(5):847-51. doi: 10.1016/s0735-1097(02)01690-x.
Abstract/Text
OBJECTIVES: We aimed to test the hypothesis that coronary microvascular spasm (MVS) alone causes myocardial ischemia in patients with angina attributable to epicardial coronary spasm, and to determine whether there is a difference in clinical characteristics between those with and without microvascular spasm.
BACKGROUND: Patients with "vasospastic angina" have epicardial coronary artery spasm, but it is unknown whether coronary microvessel disease also contributes to the occurrence of angina in these patients.
METHODS: We studied 55 consecutive patients with angina in whom epicardial coronary spasm was provoked by intracoronary acetylcholine (ACH).
RESULTS: In 14 patients (25.5%, Group 1), submaximal dose of ACH induced myocardial ischemia (chest pain, ischemic electrocardiogram changes, lactate production) without large epicardial spasm, suggesting the occurrence of coronary microvascular spasm. By contrast, the remaining 41 patients (Group 2) had evidence of myocardial ischemia only when epicardial spasm was angiographically demonstrated. The Group 1 patients were predominantly women (p < 0.05) and had a history of prolonged (>30 min) chest pain (p < 0.05), whereas the Group 2 patients were more likely men and smokers (p < 0.01).
CONCLUSIONS: Myocardial ischemia most probably due to coronary MVS was demonstrated in a sizable portion of patients with epicardial vasospasm, preferentially in women having both typical and prolonged anginal pain. The result suggests that coronary microvascular disease may also contribute to angina in patients with "vasospastic angina."
Maseri A, Lanza GA.
Angina pectoris caused by microvascular spasm.
Lancet. 1998 Jul 18;352(9123):237-8. doi: 10.1016/S0140-6736(05)77842-9.
Abstract/Text
Crea F, Bairey Merz CN, Beltrame JF, Berry C, Camici PG, Kaski JC, Ong P, Pepine CJ, Sechtem U, Shimokawa H.
Mechanisms and diagnostic evaluation of persistent or recurrent angina following percutaneous coronary revascularization.
Eur Heart J. 2019 Aug 1;40(29):2455-2462. doi: 10.1093/eurheartj/ehy857.
Abstract/Text
Persistence or recurrence of angina after a percutaneous coronary intervention (PCI) may affect about 20-40% of patients during short-medium-term follow-up. This appears to be true even when PCI is 'optimized' using physiology-guided approaches and drug-eluting stents. Importantly, persistent or recurrent angina post-PCI is associated with a significant economic burden. Healthcare costs may be almost two-fold higher among patients with persistent or recurrent angina post-PCI vs. those who become symptom-free. However, practice guideline recommendations regarding the management of patients with angina post-PCI are unclear. Gaps in evidence into the mechanisms of post-PCI angina are relevant, and more research seems warranted. The purpose of this document is to review potential mechanisms for the persistence or recurrence of angina post-PCI, propose a practical diagnostic algorithm, and summarize current knowledge gaps.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
Hoshino S, Tsuda E, Miyazaki A.
Vasospastic angina and asymptomatic moyamoya disease in a 14-year-old girl.
Pediatr Int. 2018 Mar;60(3):296-297. doi: 10.1111/ped.13499. Epub 2018 Feb 26.
Abstract/Text
Fukuda N, Kurokawa S, Maeda K, Iseki S, Takahasi M, Niwano H, Nakazato K, Niwano S, Kurosawa T, Izumi T.
A young girl with vasospastic angina associated with mutation in endothelial nitric oxide synthase gene--a case report.
Angiology. 2003 Mar-Apr;54(2):233-7. doi: 10.1177/000331970305400214.
Abstract/Text
A 13-year-old girl was successfully recuperated from cardiopulmonary arrest shortly after running 80 m in a competition. The electrocardiogram, echocardiogram and 123I-MIBG myocardial scintigraphic imaging indicated myocardial ischemia in the anteroseptal wall of the left ventricle. Coronary angiography during the recovery phase revealed no stenotic lesions, and spasms of the left anterior descending artery and the left circumflex artery could be provoked by acetylcholine. The endothelial nitric oxide synthase gene abnormality associated with coronary spasms was examined. The patient had the T-786 --> C, A-922 --> G, and T-1468 --> A mutations in the 5'-flanking region on one allele of the endothelial nitric oxide synthase gene. To the authors' knowledge, she represents the first case of life-threatening coronary spasms in childhood associated with mutations in the endothelial nitric oxide synthase gene.
池田翔，石井卓，細川奨，他．Reactive Hyperemia-Peripheral Arterial Tonometry（ RH-PAT）により血管内皮機能障害が示唆された冠攣縮性狭心症の10歳男児例．日小循誌 2021; 37:220-226.
小川俊一．小児における冠攣縮性狭心症に対する侵襲的診断法の重要性と問題点．日小循誌2009; 28: 65-66.
Shimokawa H, Nagasawa K, Irie T, Egashira S, Egashira K, Sagara T, Kikuchi Y, Nakamura M.
Clinical characteristics and long-term prognosis of patients with variant angina. A comparative study between western and Japanese populations.
Int J Cardiol. 1988 Mar;18(3):331-49. doi: 10.1016/0167-5273(88)90052-6.
Abstract/Text
To determine the factors influencing the prognosis of variant angina, the clinical characteristics and long-term prognosis of 158 consecutive Japanese patients were examined and compared with those in previous major western studies (Pisa, Montreal, and Duke studies). The Japanese patients were characterized by relatively low prevalences of coronary risk factors, significant coronary stenoses and previous myocardial infarction. Survival and survival without myocardial infarction for the entire group or for the subpopulation with significant coronary artery disease were significantly better in the Japanese population than in the western populations; however, in the subpopulation without significant coronary artery disease, the prognosis was excellent in all four studies. If the prevalence of coronary artery disease was corrected for the Japanese population, there would be no difference in the prognosis between the Japanese and the western populations. It is concluded: (1) the overall prognosis of variant angina may be better in Japanese patients, and (2) coronary artery disease appears to be the strongest prognostic factor for assessing the differences in the prognosis between the Japanese and the western populations.
Yasue H, Kugiyama K.
Coronary spasm: clinical features and pathogenesis.
Intern Med. 1997 Nov;36(11):760-5. doi: 10.2169/internalmedicine.36.760.
Abstract/Text
Coronary artery spasm (coronary spasm) is an abnormal contraction of an epicardial coronary artery resulting in myocardial ischemia and its incidence is relatively high in Japanese as compared with Caucasians. Coronary spasm occurs most often from midnight to early morning when the patient is at rest and it is usually not induced by exercise in the daytime. Coronary spasm can be induced by acetylcholine, an endothelium-dependent vasodilator which causes vasodilatation in the normal coronary artery. Spasm artery is hyperresponsive to the vasodilator effect of nitroglycerin, an nitric oxide (NO) donor and is deficient in NO activity. The major risk factor for coronary spasm is cigarette smoking. Coronary spasm can be a cause of not only variant angina but also ischemic heart disease in general, including unstable angina, acute myocardial infarction and sudden ischemic death.
日本循環器学会．2023年JCS/CVIT/JCC ガイドライン フォーカスアップデート版 冠攣縮性狭心症と冠微小循環障害の診断と治療（日本循環器学会/ 日本心血管インターベンション治療学会/ 日本心臓病学会合同ガイドライン）．https://www.j-circ.or.jp/cms/wp-ontent/uploads/2023/03/JCS2023_hokimoto.pdf.
Nakao K, Ohgushi M, Yoshimura M, Morooka K, Okumura K, Ogawa H, Kugiyama K, Oike Y, Fujimoto K, Yasue H.
Hyperventilation as a specific test for diagnosis of coronary artery spasm.
Am J Cardiol. 1997 Sep 1;80(5):545-9. doi: 10.1016/s0002-9149(97)00419-0.
Abstract/Text
The hyperventilation test has been used as a clinical tool to induce coronary spasm. However, its diagnostic and prognostic values have not been fully elucidated. This study was designed to establish the sensitivity and specificity of the hyperventilation test and to clarify the characteristics of hyperventilation test-positive patients. We examined 206 patients in whom coronary spasm was documented by angiography (spasm group), and 183 patients without angina at rest in whom acetylcholine failed to induce spasm (nonspasm group). All patients performed vigorous hyperventilation for 6 minutes in the early morning. Of the spasm group patients, 127 showed positive responses to the test, including ST elevation (n = 111), ST depression (n = 15) and negative U wave (n = 1). None in the nonspasm group showed any ischemic electrocardiographic change. Thus, the sensitivity and specificity of this test for diagnosis of coronary spasm were 62% and 100%, respectively. In the spasm group, there were no significant differences between hyperventilation test-positive and test-negative patients in age, sex, the prevalence of hypertension, diabetes mellitus, obesity, smoking, and the number of diseased vessels. When clinical characteristics were compared, the proportions of the patients with high disease activity (> or =5 attacks a week), with severe arrhythmias (second- or third-degree atrioventricular block and/or ventricular tachycardia) during attacks, and with multivessel spasm were significantly higher in the hyperventilation test-positive patients than in the negative patients (69% vs 20%, p <0.0001; 31% vs 11%, p <0.005; and 58% vs 34%, p <0.01, respectively). These findings imply that hyperventilation is a highly specific test for the diagnosis of coronary artery spasm, and that hyperventilation test-positive patients are likely to have life-threatening arrhythmias during attacks and multivessel spasm.
Okumura K, Yasue H, Matsuyama K, Goto K, Miyagi H, Ogawa H, Matsuyama K.
Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm.
J Am Coll Cardiol. 1988 Oct;12(4):883-8. doi: 10.1016/0735-1097(88)90449-4.
Abstract/Text
Intracoronary injection of acetylcholine has been shown to induce coronary spasm in patients with variant angina. To examine its sensitivity and specificity, incremental doses of acetylcholine (20, 50 and 100 micrograms into the left coronary artery and 20 and 50 micrograms into the right coronary artery) were injected into the coronary artery or arteries in 70 patients with variant angina (Group 1) (mean age 57 years) and 93 patients without variant angina or angina at rest (Group 2) (mean age 54 years). Forty patients of the latter group had atypical chest pain, 16 cardiomyopathy, 14 arrhythmia, 11 valvular disease, 7 stable effort angina due to advanced coronary artery disease, 3 congenital heart disease and 2 hypertension. A temporary cardiac pacemaker set at 40 to 50 beats/min was positioned in the right ventricle. Coronary spasm was defined as total occlusion or severe vasoconstriction associated with chest pain or ischemic ST changes on the electrocardiogram or both. In Group 1, acetylcholine induced spasm in 63 (90%) of the 70 patients in the artery or arteries predicted to be responsible for spontaneous attacks. In Group 2, acetylcholine induced coronary spasm only in one patient with effort angina and advanced coronary artery disease although lesser degrees of vasoconstriction (less than or equal to 75% of the luminal diameter) occurred in most patients after acetylcholine (specificity of acetylcholine thus was 99%). In conclusion, intracoronary injection of acetylcholine is sensitive and reliable for the induction of coronary spasm.
Sueda S, Ochi N, Kawada H, Matsuda S, Hayashi Y, Tsuruoka T, Uraoka T.
Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine.
Am J Cardiol. 1999 Apr 15;83(8):1186-90. doi: 10.1016/s0002-9149(99)00057-0.
Abstract/Text
This study examines the incidence of spasm by intracoronary injection of acetylcholine in Japanese patients who underwent coronary angiography. The subjects were 685 consecutive patients (477 men, mean age 63.2 +/- 7.5 years) who were studied with an acetylcholine test. Acetylcholine was injected in incremental doses of 20, 50, and 80 microg into the right coronary artery and 20, 50, and 100 microg into the left coronary artery. Spasm was defined as total or subtotal occlusion. Coronary vasospasm was determined in 221 patients (32.3%). Spasm occurred often during effort and rest in patients with angina (25 of 51, 49.0%), exertional angina (25 of 74, 33.8%), recent myocardial infarction (30 of 80, 37.5%), healed myocardial infarction (14 of 37, 37.8%), and especially in patients with rest angina (83 of 124, 66.9%), whereas spasm was relatively uncommon in patients with nonischemic heart disease (23 of 252, 9.1%). Spasm was superimposed on significant atherosclerotic lesions in 35.9% of patients as well as on nonfixed atherosclerotic lesions in 30.8% of patients. We conclude that >9% of Japanese patients may have coronary vasospasm with intracoronary injection of acetylcholine and recommend the provocation test for evaluating coronary vasospasm if coronary angiography is undertaken.
Okumura K, Yasue H, Matsuyama K, Ogawa H, Morikami Y, Obata K, Sakaino N.
Effect of acetylcholine on the highly stenotic coronary artery: difference between the constrictor response of the infarct-related coronary artery and that of the noninfarct-related artery.
J Am Coll Cardiol. 1992 Mar 15;19(4):752-8. doi: 10.1016/0735-1097(92)90513-m.
Abstract/Text
To examine the constrictor response of the infarct-related stenotic coronary artery in comparison with that of noninfarct-related stenotic arteries, acetylcholine in maximal doses of 100 micrograms for the left and 50 micrograms for the right coronary artery was injected into the 16 infarct-related coronary arteries of 16 patients with previous myocardial infarction (group 1) and into 19 stenotic coronary arteries of 16 patients with stable angina without myocardial infarction (group 2). Acetylcholine's effects on lumen diameter and area were quantitatively analyzed at the stenotic segment and its proximal segment without significant stenosis. Acetylcholine decreased lumen diameter and area at the stenotic segments from 0.72 +/- 0.18 to 0.18 +/- 0.33 mm and from 0.45 +/- 0.22 to 0.10 +/- 0.22 mm2, respectively, in group 1 (both p less than 0.01) and from 0.75 +/- 0.22 to 0.49 +/- 0.30 mm and 0.48 +/- 0.29 to 0.26 +/- 0.23 mm2, respectively, in group 2 (both p less than 0.01). Acetylcholine decreased the diameter and area at the proximal segment from 2.71 +/- 0.75 to 2.38 +/- 0.6 mm and from 6.18 +/- 3.4 to 4.71 +/- 2.23 mm2, respectively, in group 1 (both p less than 0.01) and from 2.31 +/- 0.67 to 1.95 +/- 0.59 mm and from 4.5 +/- 2.97 to 3.22 +/- 1.96 mm2, respectively, in group 2 (both p less than 0.01). The changes in diameter and area at the stenotic segment in group 1 were significantly greater than those in group 2 (both p less than 0.01); there were no significant differences between groups in the changes at the proximal segment.(ABSTRACT TRUNCATED AT 250 WORDS)
Sueda S, Izoe Y, Kohno H, Fukuda H, Uraoka T.
Need for documentation of guidelines for coronary artery spasm: an investigation by questionnaire in Japan.
Circ J. 2005 Nov;69(11):1333-7. doi: 10.1253/circj.69.1333.
Abstract/Text
BACKGROUND: Because there are no guidelines concerning coronary spasm in Japan, the present study examined the current status of the spasm provocation test.
METHODS AND RESULTS: Questionnaires concerning the number of cases of coronary angiography, percutaneous coronary intervention, and invasive/non-invasive spasm provocation tests over 3 years (2001-2003) and the status of spasm provocation tests were sent to members of the Japanese Circulation Society in 120 cardiology hospitals in the Chugoku and Shikoku areas. Completed surveys were returned from 45 hospitals, giving a collection rate of 38%. As a spasm provocation agent, acetylcholine tests were performed in 29 hospitals, and ergonovine tests in 18 hospitals. Non-invasive spasm provocation tests were performed in only 9 hospitals (20%). In total, 5,267 patients underwent acetylcholine spasm provocation test (2,387 patients) or ergonovine spasm provocation test (2,880 patients) and vasospastic angina was diagnosed in 1,663 (2.4%) patients. Invasive spasm provocation tests were performed in 7.8% of patients with diagnostic catheterization and the spasm-positive rate was 31.6%. The difference among hospitals concerning the number of invasive spasm provocation tests was remarkable, and the angiographic spasm-positive standard and acetylcholine/ergonovine dose varied among the hospitals.
CONCLUSIONS: Guidelines on coronary spasm in Japan are essential to overcome the current differences between institutions.
Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, Shimokawa H, Bairey Merz CN; Coronary Vasomotion Disorders International Study Group (COVADIS).
International standardization of diagnostic criteria for vasospastic angina.
Eur Heart J. 2017 Sep 1;38(33):2565-2568. doi: 10.1093/eurheartj/ehv351.
Abstract/Text
The Coronary Vasomotion Disorders International Study Group (COVADIS) was established to develop international standards for the diagnostic criteria of coronary vasomotor disorders. The first symposium held on the 4-5 September 2013 addressed the criteria for vasospastic angina, which included the following (i) nitrate-responsive angina, (ii) transient ischaemic electrocardiogram changes, and (iii) documented coronary artery spasm. Adoption of these diagnostic criteria will improve the clinical diagnosis of this condition and facilitate research in this field.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
日本循環器学会．循環器病の診断と治療に関するガイドライン（2006-2007年度合同研究班報告）：冠攣縮性狭心症の診断と治療に関するガイドライン．Circ J. 2008; 72:suppl. IV: 1195-1238.
日本循環器学会．慢性冠動脈疾患診断ガイドライン（2018年改訂版）．https://www.j-circ.or.jp/cms/wp-content/uploads/2020/02/JCS2018_yamagishi_tamaki.pdf.
Hokimoto S, Kaikita K, Yasuda S, Tsujita K, Ishihara M, Matoba T, Matsuzawa Y, Mitsutake Y, Mitani Y, Murohara T, Noda T, Node K, Noguchi T, Suzuki H, Takahashi J, Tanabe Y, Tanaka A, Tanaka N, Teragawa H, Yasu T, Yoshimura M, Asaumi Y, Godo S, Ikenaga H, Imanaka T, Ishibashi K, Ishii M, Ishihara T, Matsuura Y, Miura H, Nakano Y, Ogawa T, Shiroto T, Soejima H, Takagi R, Tanaka A, Tanaka A, Taruya A, Tsuda E, Wakabayashi K, Yokoi K, Minamino T, Nakagawa Y, Sueda S, Shimokawa H, Ogawa H; Japanese Circulation Society and Japanese Association of Cardiovascular Intervention and Therapeutics and Japanese College of Cardiology Joint Working Group.
JCS/CVIT/JCC 2023 Guideline Focused Update on Diagnosis and Treatment of Vasospastic Angina (Coronary Spastic Angina) and Coronary Microvascular Dysfunction.
Circ J. 2023 May 25;87(6):879-936. doi: 10.1253/circj.CJ-22-0779. Epub 2023 Apr 6.
Abstract/Text
Walling A, Waters DD, Miller DD, Roy D, Pelletier GB, Théroux P.
Long-term prognosis of patients with variant angina.
Circulation. 1987 Nov;76(5):990-7. doi: 10.1161/01.cir.76.5.990.
Abstract/Text
The long-term prognosis of variant angina and the factors influencing it were assessed in 217 consecutive patients hospitalized in our coronary care unit and followed for a mean of 65 months (range 2 to 123). Cardiac death occurred in 30 patients and an additional 54 experienced a nonfatal myocardial infarction. Survival at 1 and 5 years was 95% and 89%, respectively; survival without infarction was 83% and 69%. Coronary disease and the degree of disease activity were strong predictors of survival by Cox analysis. Survival at 1 year was 99%, and that at 5 years was 95% and 94%, respectively, for patients with one-vessel disease (n = 81) and for those without stenoses of 70% or greater (n = 87). Survival at 1 and 5 years was only 87% and 77% for those with multivessel disease (n = 40). The Cox analysis selected left ventricular function, initial treatment, extent score, duration of angina at rest, and disease activity as multivariate predictors of survival without infarction. Coronary disease was a strong predictor (p less than .0001) of survival without infarction by univariate analysis. Treatment with nifedipine, diltiazem, or verapamil improved survival without infarction compared with other medical treatment (p = .002). Myocardial infarction occurred most commonly soon after diagnosis in patients with a short history of angina at rest. Late coronary events were almost never preceded by resting angina.
Chahine RA, Feldman RL, Giles TD, Nicod P, Raizner AE, Weiss RJ, Vanov SK.
Randomized placebo-controlled trial of amlodipine in vasospastic angina. Amlodipine Study 160 Group.
J Am Coll Cardiol. 1993 May;21(6):1365-70. doi: 10.1016/0735-1097(93)90310-w.
Abstract/Text
OBJECTIVES: This study was designed to assess the efficacy and safety of amlodipine, a long-acting calcium channel blocker, in patients with vasospastic angina.
BACKGROUND: Previous studies have established the value of short-acting calcium channel blockers in the treatment of coronary spasm.
METHODS: Fifty-two patients with well documented vasospastic angina were entered into the present study. After a single-blind placebo run-in period, patients were randomized (in a double-blind protocol) to receive either amlodipine (10 mg) or placebo every morning for 4 weeks. Twenty-four patients received amlodipine and 28 received placebo. All patients were given diaries in which to record both the frequency, severity, duration and circumstances of anginal episodes and their intake of sublingual nitroglycerin tablets.
RESULTS: The rate of anginal episodes decreased significantly (p = 0.009) with amlodipine treatment compared with placebo and the intake of nitroglycerin tablets showed a similar trend. Peripheral edema was the only adverse event seen more frequently in amlodipine-treated patients. No patient was withdrawn from the double-blind phase of the study because of an adverse event. Patients who completed the double-blind phase as responders to amlodipine or as nonresponders to placebo were offered the option of receiving amlodipine in a long-term, open label extension phase. During the extension, the daily dose of amlodipine was adjusted to 5 or 15 mg if needed and the rate of both anginal episodes and nitroglycerin tablet consumption showed statistically significant decreases between baseline and final assessment.
CONCLUSION: This study suggests that amlodipine given once daily is efficacious and safe in the treatment of vasospastic angina.
Takaoka K, Yoshimura M, Ogawa H, Kugiyama K, Nakayama M, Shimasaki Y, Mizuno Y, Sakamoto T, Yasue H.
Comparison of the risk factors for coronary artery spasm with those for organic stenosis in a Japanese population: role of cigarette smoking.
Int J Cardiol. 2000 Jan 15;72(2):121-6. doi: 10.1016/s0167-5273(99)00172-2.
Abstract/Text
We compared the risk factors for coronary spasm with those for coronary atherosclerosis in 183 patients with coronary spasm, 132 patients with coronary organic stenosis, and 224 control subjects with chest pain syndrome. Our findings confirmed that, when compared with controls, age, gender, total cholesterol, LDL-cholesterol, hypertension, diabetes mellitus, and cigarette smoking are all significant risk factors for coronary organic stenosis. On the other hand, only cigarette smoking proved to be a significant risk factor for coronary spasm. Also, when compared between coronary spasm group and coronary organic stenosis group, the incidence of cigarette smoking in males was significantly higher in the coronary spasm group than in the coronary organic stenosis group. We conclude that cigarette smoking is a crucial risk factor for coronary spasm. On the other hand, serum lipid levels and the incidence of hypertension and diabetes mellitus were within the normal ranges in the coronary spasm patients and were thus poorly associated with coronary spasm. These results showed that the risk factors for coronary spasm differ significantly from those for atherosclerosis-based coronary stenosis in the Japanese. Among the risk factors for coronary atherosclerosis (organic stenosis) smoking alone was a significant preventable risk factor for coronary artery spasm.
Nobuyoshi M, Abe M, Nosaka H, Kimura T, Yokoi H, Hamasaki N, Shindo T, Kimura K, Nakamura T, Nakagawa Y.
Statistical analysis of clinical risk factors for coronary artery spasm: identification of the most important determinant.
Am Heart J. 1992 Jul;124(1):32-8. doi: 10.1016/0002-8703(92)90917-k.
Abstract/Text
Coronary artery spasm plays an important role in acute ischemic events, and it has a close relationship with coronary atherosclerosis. Thus we attempted to determine the most significant risk factor for coronary artery spasm. Among 3000 consecutive patients who underwent coronary cineangiography with ergonovine maleate testing, 330 with typical angina pectoris (group 1) and 294 with old myocardial infarction (group 2) were studied. We divided each group into three or four subgroups according to the presence of fixed organic stenosis (FOS+) or a positive reaction to ergonovine maleate (coronary artery spasm [CAS]+). We examined the relationship between coronary artery spasm and eight coronary risk factors: age, sex, hypertension, diabetes mellitus, smoking, and serum cholesterol, uric acid, and high-density lipoprotein cholesterol levels. The proportion of smokers in the subgroups with CAS(+) was significantly higher than in the subgroups with CAS(-)(p less than 0.01). There was no correlation between smoking and fixed organic stenosis. According to the results of multiple regression analysis, there was a positive correlation between smoking and CAS(+) and between serum high-density lipoprotein cholesterol levels and CAS(+)(p less than 0.01). Thus we concluded that smoking is the most significant risk factor in discriminating between patients with and without coronary artery spasm.
Nabel EG, Ganz P, Gordon JB, Alexander RW, Selwyn AP.
Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test.
Circulation. 1988 Jan;77(1):43-52. doi: 10.1161/01.cir.77.1.43.
Abstract/Text
Increased vascular constriction has been observed at the site of atherosclerotic lesions, suggesting an association between atherosclerosis and altered vascular tone. While atherosclerosis may increase sensitivity to exogenous vasoconstrictors, little is known about the response of normal and atherosclerotic coronary arteries to an exogenous stimulus that excites the sympathetic nervous system. Therefore, we studied the response to cold pressor test (CPT) using quantitative angiography and Doppler flow velocity measurements in eight patients with angiographically normal coronary arteries (group I), nine patients with mild coronary atherosclerosis (less than 50% diameter narrowing) (group II), and 13 patients with advanced coronary stenoses (greater than 50% diameter narrowing) (group III). In 31 segments of angiographically smooth arteries in group I, the CPT produced vasodilation from a control mean diameter of 2.68 +/- 0.09 (mean +/- SE) to 2.99 +/- 0.09 mm at peak CPT (p less than 0.001), a 12 +/- 1% increase in diameter. In group II, 27 irregular segments constricted to peak CPT from a mean control diameter of 1.82 +/- 0.12 to 1.66 +/- 0.12 mm (p less than .001), a 9 +/- 1% decrease, while 10 smooth segments dilated from a mean control diameter of 1.98 +/- 0.11 mm to 2.34 +/- 0.15 mm (p less than .01), a 19 +/- 2% increase in diameter. Likewise, in group III, the 17 stenotic segments constricted from 1.16 +/- 0.09 to 0.89 +/- 0.09 mm (p less than .001), a 24 +/- 6% decrease; the irregular segments also constricted from 2.44 +/- 0.11 to 2.22 +/- 0.12 mm (p = .002), a 10 +/- 2% decrease. In contrast, two smooth segments dilated from 2.98 to 3.23 mm (mean), an 8% increase in diameter. Coronary blood flow increased 65 +/- 4% (mean) during CPT in group I, it increased 15 +/- 6% in group II, and it decreased 39 +/- 8% in group III. The vasodilator response in four normal patients was partly inhibited by the administration of intracoronary propranolol (17 +/- 3% increase during control, 10 +/- 2% increase after propranolol, 41% less dilation; p = .002). We conclude that the response of normal coronary arteries to the CPT test is dilation, in part related to beta-adrenoreceptor stimulation and possibly flow-mediated endothelial dilation or alpha 2-adrenergic activity. The paradoxical vasoconstrictor response induced by atherosclerosis may represent altered catecholamine sensitivity and/or a defect in endothelial vasodilator function. The presence of atherosclerosis impairs vasodilator responses and thus may contribute to the pathogenesis of myocardial ischemia.
Yasue H, Mizuno Y, Harada E, Itoh T, Nakagawa H, Nakayama M, Ogawa H, Tayama S, Honda T, Hokimoto S, Ohshima S, Hokamura Y, Kugiyama K, Horie M, Yoshimura M, Harada M, Uemura S, Saito Y; SCAST (Statin and Coronary Artery Spasm Trial) Investigators.
Effects of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin, on coronary spasm after withdrawal of calcium-channel blockers.
J Am Coll Cardiol. 2008 May 6;51(18):1742-8. doi: 10.1016/j.jacc.2007.12.049.
Abstract/Text
OBJECTIVES: The purpose of this study was to determine whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) suppresses coronary spasm.
BACKGROUND: Coronary spasm is associated with endothelial dysfunction. Statins have been shown to improve endothelial function.
METHODS: This was a prospective, randomized, open-label, end point study. Sixty-four patients who had no significant organic coronary stenosis and in whom coronary spasm was induced by intracoronary injection of acetylcholine (ACh) were randomly assigned to fluvastatin 30 mg/day plus the conventional calcium-channel blocker (CCB) therapy (31 patients, statin group) or the conventional CCB therapy (33 patients, nonstatin group). After 6 months of treatment, the intracoronary injection of ACh was repeated and the coronary spasm was assessed.
RESULTS: Coronary spasm was suppressed in 16 of the 31 patients (51.5%, p < 0.0001) of the statin group and in 7 of the 33 patients (21.2%, p = 0.0110) of the nonstatin group after 6 months of treatment. Thus, the number of patients with ACh-induced coronary spasm was significantly reduced in the statin group as compared with the nonstatin group (51.6% vs. 21.2%, p = 0.0231) after 6 months of treatment.
CONCLUSIONS: The addition of fluvastatin 30 mg/day to the conventional CCB therapy for 6 months significantly reduced the number of patients with ACh-induced coronary spasm as compared with the conventional CCB therapy. Thus, a statin (fluvastatin) may possibly be a novel therapeutic drug for coronary spasm.
Sakamoto T, Shintomi Y, Yoshimura M, Ogawa H.
Successful treatment of refractory angina pectoris due to multivessel coronary spasm with valsartan.
Intern Med. 2007;46(17):1425-9. doi: 10.2169/internalmedicine.46.0132. Epub 2007 Sep 3.
Abstract/Text
This case report describes a 78-year-old man with recurrent angina attacks due to coronary spasm. He was treated with maximum daily doses of antianginal and antioxidative medications, including isosorbide mononitrate (40 mg), diltiazem (200 mg), and tocopherol nicotinate (300 mg). Despite the use of these medications, rest angina occurred 2 or 3 times during sleep. Although his symptoms disappeared promptly with the use of sublingual glycerine trinitrate (GTN), an angiotensin II receptor blocker, valsartan (80 mg), was added on a daily basis with the intent of improving endothelial function and controlling his angina. After beginning 80 mg/day of valsartan, the number of the anginal attacks decreased by about 66%. The anginal attacks totally disappeared after the dose of valsartan was increased to 160 mg/day. To confirm the effect of valsartan on his angina, valsartan was stopped temporarily with his consent. His anginal attacks increased to the same frequency that was observed before valsartan; therefore, valsartan therapy was resumed. The data indicate that the addition of valsartan to maximum antianginal medications may be effective in helping to control angina attacks at rest due to coronary spasm.
Arakawa K, Himeno H, Gondo T, Kirigaya J, Otomo F, Matsushita K, Nakahashi H, Shimizu S, Nitta M, Yano H, Endo M, Kimura K, Umemura S.
Refractory vasospasms of the coronary arteries due to multiple factors: an autopsy case.
Intern Med. 2014;53(9):963-7. doi: 10.2169/internalmedicine.53.1900. Epub 2014 May 1.
Abstract/Text
A 41-year-old man was admitted with decompensated heart failure. Mechanical ventilation was maintained with a large dose of propofol. On day 4, significant ST elevation with complete atrioventricular block was noted, which subsequently induced cardiopulmonary arrest. Treatment with percutaneous cardiopulmonary support and therapeutic hypothermia was initiated. Emergent cardiac angiography showed simultaneous multivessel coronary spasms. Although nitroglycerin and nicorandil were ineffective, the intracoronary administration of fasudil, a Rho-kinase inhibitor, successfully resolved the vasospasms. However, during rewarming, the coronary vasospasms recurred, and the patient died of cardiogenic shock. In addition to hypertrophy, the autopsied heart demonstrated the accumulation of inflammatory cells in the pericardium and adventitia of the coronary arteries.
Inokuchi K, Ito A, Fukumoto Y, Matoba T, Shiose A, Nishida T, Masuda M, Morita S, Shimokawa H.
Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery.
J Cardiovasc Pharmacol. 2004 Sep;44(3):275-7. doi: 10.1097/01.fjc.0000134775.76636.3f.
Abstract/Text
We have recently demonstrated that fasudil, a Rho-kinase inhibitor, is effective in suppressing coronary artery spasm in patients with vasospastic angina. Thus, blockade of Rho-kinase may provide a novel therapeutic strategy to treat ischemic coronary syndrome caused by the spasm. Severe coronary artery spasm still remains a life-threatening serious complication of coronary artery bypass grafting (CABG). In this study, we examined the inhibitory effect of fasudil in patients with intractable severe coronary spasm after CABG. Three patients who underwent CABG showed severe myocardial ischemia resistant to intensive therapy with intravenous conventional vasodilators, including isosorbide dinitrate (ISDN), diltiazem, and nicorandil. Coronary angiography revealed severe coronary spasm in native coronary arteries and/or bypass arterial grafts in all patients. Since intracoronary and/or intragraft administration of ISDN was ineffective to resolve the spasm, we then administered fasudil (1.5 mg/min for 15 minutes) into the spastic arteries. Fasudil successfully resolved the spasm and improved myocardial ischemia in all patients without any systemic adverse effects. In conclusion, the treatment with fasudil may be useful to treat intractable and otherwise fatal coronary spasm resistant to intensive conventional vasodilator therapy after CABG.
Komiyama K, Tejima T, Tanabe Y, Nishimura T, Kitamura K, Watanabe T, Shimada H, Iwasawa J, Matsushita N, Ishikawa T, Hojo R, Hayashi T, Nakai M, Yoshimura H, Tatsumoto A, Fukamizu S, Sakurada H.
The impact of Rho-kinase inhibitor, "Fasudil", intracoronary bolus administration to improve refractory coronary vasospasm.
Cardiovasc Interv Ther. 2011 Sep;26(3):281-5. doi: 10.1007/s12928-011-0071-2. Epub 2011 Jun 18.
Abstract/Text
A 57 year-old man presenting with acute inferior myocardial infarction underwent percutaneous coronary intervention. Following the placement of TAXUS Liberte 2.5 × 24 mm (Boston Sientific, USA), for 99% stenosis with delay, severe vasospasm occurred at distal portion of the stent. However, persistent vasospasm was observed despite ISDN (isosorbide dinitrate), nitroprusside, and nicorandil, were used to control the repetitive vasospasm during the course of 90 min. Then the decision was made to use intra-coronary bolus of Rho-kinase inhibitor, fasudil 100 μg/kg. Then the vasospasm resolved and no recurrence was observed during the procedure and hospital stay for 25 days. We experienced a valuable case, whose repetitive vasospasm was resolved with intracoronary administration of Rho kinase inhibitor.
Ooshiro D, Yamaguchi S, Kakazu M, Arasaki O.
Effectiveness of continuous low-dose fasudil on refractory coronary vasospasm subsequent to cardiopulmonary arrest.
Clin Case Rep. 2017 Aug;5(8):1207-1209. doi: 10.1002/ccr3.830. Epub 2017 Jun 8.
Abstract/Text
Refractory coronary vasospasm subsequent to reperfusion, such as cardiopulmonary resuscitation or revascularization, for myocardial infarction may respond to fasudil in the superacute phase. Continuous low-dose fasudil administration should be an option for refractory coronary vasospastic angina (VSA).
Shimizu H, Lee JD, Ogawa KB, Sugiyama T, Yamamoto M, Hara A, Nakamura T.
Refractory variant angina relieved by denopamine--a case report.
Jpn Circ J. 1991 Jul;55(7):692-4. doi: 10.1253/jcj.55.692.
Abstract/Text
A 48-year-old man with severe variant angina refractory to conventional treatment with calcium antagonists and nitrates, or prazosin, or trihexyphenidyl hydrochloride, became symptom free rapidly when treated with denopamine, a adrenergic beta-1 agonist. Denopamine may prove to be an additional therapeutic agent in the management of severe variant angina. Therefore the response to denopamine and the lack of response to prazosin in this patient suggests that not only the adrenergic alpha receptor but also the adrenergic beta-1 receptor plays an important role in the production of coronary spasm, at least in some patients.
Shimizu H, Lee JD, Ogawa KB, Shimizu K, Yamamoto M, Hara A, Nakamura T.
Efficacy of denopamine, a beta 1 adrenoceptor agonist, in preventing coronary artery spasm.
Jpn Circ J. 1993 Mar;57(3):175-82. doi: 10.1253/jcj.57.175.
Abstract/Text
The selective beta 1 adrenoceptor agonist denopamine was studied for its effectiveness in abolishing active vasospastic angina in 10 patients without obstructive coronary artery stenosis. All patients had anginal attacks at least once a day during the 3-day placebo period. Denopamine, 40 mg/day, completely abolished the attacks in 7 patients (efficacy 70%). Denopamine reduced the mean daily number of anginal attacks and nitroglycerin consumption in comparison with placebo (0.56 +/- 1.23 vs 2.20 +/- 1.27; p < 0.005 and 0.10 +/- 0.24 vs 1.60 +/- 1.93; p < 0.05, respectively). Aggravation of anginal attacks was not seen in any patient. During placebo period, anginal attacks were provoked in 6 of the 10 patients who received exercise stress test, and in 6 of the 7 patients who received the cold pressor test in combination with hyperventilation. Denopamine prevented anginal attacks induced by exercise stress tests in 4 of the 6 patients (67%) and that induced by the cold pressor test in 4 of the 6 patients (67%). There were no severe adverse effects during denopamine therapy. These results suggest that 1) denopamine is a safe and effective medication for vasospastic angina; 2) beta 1 adrenoceptors may play an important role in the prevention of coronary artery spasm.
Nakajima D, Negoro N, Nakaboh A, Nakakoji T, Hoshiga M, Nariyama J, Ishihara T, Hanafusa T.
Effectiveness of low dose denopamine, a beta1-adrenoceptor agonist, in a patient with vasospastic angina refractory to intensive medical treatment.
Int J Cardiol. 2006 Apr 4;108(2):281-3. doi: 10.1016/j.ijcard.2005.03.012.
Abstract/Text
山崎武俊，峯尚志，土方康世．西洋薬による症状コントロール困難な冠攣縮性狭心症に対して四逆散と桂枝茯苓丸の併用が有効であった2症例．日東医誌 2014; 65: 287-292.
内藤真礼生，渡辺慎太郎．桂枝茯苓丸（駆於血薬）が著効した異型狭心症の1例．治療学 2006; 40: 444-447.
首藤達哉，蔭山充，西田愼二．冠攣縮性狭心症に柴朴湯が著効した3症例．漢方の臨床 2010; 57: 565-574.
首藤達哉，蔭山充，青木基夫，他．冠攣縮性狭心症の胸部痛に冠拡張剤と”柴朴湯” の併用が著効した1症例．痛みと漢方 2011; 21:76-79.
Miwa K, Kambara H, Kawai C.
Effect of aspirin in large doses on attacks of variant angina.
Am Heart J. 1983 Feb;105(2):351-5. doi: 10.1016/0002-8703(83)90548-3.
Abstract/Text
Ishii M, Kaikita K, Sato K, Yamanaga K, Miyazaki T, Akasaka T, Tabata N, Arima Y, Sueta D, Sakamoto K, Yamamoto E, Tsujita K, Yamamuro M, Kojima S, Soejima H, Hokimoto S, Matsui K, Ogawa H.
Impact of aspirin on the prognosis in patients with coronary spasm without significant atherosclerotic stenosis.
Int J Cardiol. 2016 Oct 1;220:328-32. doi: 10.1016/j.ijcard.2016.06.157. Epub 2016 Jun 29.
Abstract/Text
BACKGROUND: Coronary spasm is one of the mechanisms of myocardial infarction with nonobstructive coronary arteries (MINOCA). The aim of this study was to investigate the effects of aspirin on future cardiovascular events in patients with coronary vasospastic angina (VSA) with non-significant atherosclerotic stenosis.
METHODS: This was the retrospective analysis of the 640 VSA patients with non-significant atherosclerotic stenosis (≤50% stenosis) among 1,877 consecutive patients who underwent acetylcholine (ACh)-provocation testing between January 1991 and December 2010. The patients were divided into 2 groups treated with (n=137) or without (n=503) low-dose aspirin (81-100mg/day). We evaluated major adverse cardiac events (MACE), defined as cardiac death, nonfatal myocardial infarction, and unstable angina.
RESULTS: In the study population, 24 patients (3.8%) experienced MACE; there were 6 cases in VSA patients with aspirin and 6 in those without aspirin. Multivariate Cox hazards analysis for correlated factors of MACE indicated that use of statin (HR: 0.11; 95% CI: 0.02 to 0.84; P=0.033), ST-segment elevation during attack (HR: 5.28; 95% CI: 2.19-12.7; P<0.001), but not the use of aspirin as a significant predictor of MACE. After propensity score matching (n=112, each), Kaplan-Meier survival analysis indicated almost identical rate of 5-year survival free from MACE in those with aspirin, compared to those without aspirin in the entire and matched cohort (P=0.640 and P=0.541, respectively).
CONCLUSIONS: Low-dose aspirin might not reduce future cardiovascular events in VSA patients with non-significant stenosis.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Cho SS, Jo SH, Han SH, Lee KY, Her SH, Lee MH, Seo WW, Kim SE, Yang TH, Park KH, Suh JW, Lee BK, Rha SW, Gwon HC, Baek SH.
Clopidogrel plus Aspirin Use is Associated with Worse Long-Term Outcomes, but Aspirin Use Alone is Safe in Patients with Vasospastic Angina: Results from the VA-Korea Registry, A Prospective Multi-Center Cohort.
Sci Rep. 2019 Nov 28;9(1):17783. doi: 10.1038/s41598-019-54390-w. Epub 2019 Nov 28.
Abstract/Text
Anti-platelet agents are commonly used in vasospastic angina (VA) patients with comorbidity like coronary artery disease. However, long-term clinical outcomes in the use of aspirin, clopidogrel or the two agents together have rarely been investigated in VA patients. In a prospective study, we enrolled 2960 patients who received coronary angiography and ergonovine provocation test at 11 university hospitals in Korea. Among them, 1838 patients were diagnosed either with definite (n = 680) or intermediate (n = 1212) VA, using the criteria of chest pain, ECG changes and ergonovine provocation test results. They were analyzed according to their use of aspirin, clopidogrel or both, or no anti-platelet agent at all. The primary outcome was time to composite events of death from any cause, acute coronary syndrome (ACS) and symptomatic arrhythmia during a 3-year follow-up. A primary composite outcome was significantly more common in the aspirin plus clopidogrel group, at 10.8% (14/130), as compared with the non-antiplatelet group, at 4.4% (44/1011), (hazard ratio [HR] 2.41, 95% confidence interval [CI], 1.32-4.40, p = 0.004). With regard to the person-time event rate, similar results were shown, with the highest rate in the aspirin plus clopidogrel user at 4.72/1000 person months (95% CI, 2.79-7.96, log-rank test for primary outcome p = 0.016). The person-time event of the ACS rate was also highest in that group, at 2.81 (95% CI, 1.46-5.40, log-rank test for ACS p = 0.116). Kaplan-Meier survival analysis demonstrated poor prognosis in primary outcomes and ACS in aspirin plus clopidogrel users (log-rank test, p = 0.005 and p = 0.0392, respectively). Cox-proportional hazard regression analysis, adjusting for age, sex, history of coronary heart disease, hypertension, diabetes, presence or not of definite spasm, use of calcium channel blocker, demonstrated that the use of aspirin plus clopidogrel is an independent risk for the primary outcome (HR 2.01, CI: 1.07-3.81, p = 0.031). The aspirin-alone group had a similar primary and individual event rate compared to the no-antiplatelet agent group (HR 0.96, CI, 0.59-1.55, p = 0.872). Smokers using aspirin plus clopidogrel had poorer outcomes than non-smokers, with HR 6.36 (CI 2.31-17.54, p = 0.045 for interaction). In conclusion, among VA patients, aspirin plus clopidogrel use is associated with a poor clinical outcome at 3 years, especially in ACS. Aspirin alone appears to be safe for use in those patients.
Mori H, Takahashi J, Sato K, Miyata S, Takagi Y, Tsunoda R, Sumiyoshi T, Matsui M, Tanabe Y, Sueda S, Momomura S, Kaikita K, Yasuda S, Ogawa H, Shimokawa H, Suzuki H; Japanese Coronary Spasm Association.
The impact of antiplatelet therapy on patients with vasospastic angina: A multicenter registry study of the Japanese Coronary Spasm Association.
Int J Cardiol Heart Vasc. 2020 Aug;29:100561. doi: 10.1016/j.ijcha.2020.100561. Epub 2020 Jun 9.
Abstract/Text
BACKGROUND: Antiplatelet therapy (APT) is generally used in patients with coronary artery disease. However, for patients with vasospastic angina (VSA), the impact of APT is not fully understood.
METHODS: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without APT were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure and appropriate ICD (Implantable cardioverter defibrillator) shock. Propensity score matching and a multivariable cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors.
RESULTS: In the whole population, 669 patients received APT, while 760 patients did not receive APT. Patients with APT had a greater prevalence of comorbidities, such as hypertension, diabetes, dyslipidemia and smoking, than those without APT. The prevalences of previous myocardial infarction, spontaneous ST changes, significant organic stenosis and medications including calcium channel blocker, nitrate, statin and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker were greater in patients with APT than those without APT. After propensity matching (n = 335 for both groups), during the median follow-up period of 32 months, the incidence rate of MACE was comparable between the patients with and without APT (P = 0.24). MACEs occurred in 5.7% of patients with APT and in 3.6% of those without APT (P = 0.20). All-cause death occurred in 0.6% of patients with APT and 1.8% of those without APT (p = 0.16).
CONCLUSION: In this multicenter registry study, anti-platelet therapy exerted no beneficial effects for VSA patients.
© 2020 The Authors. Published by Elsevier B.V.
Kim MC, Ahn Y, Park KH, Sim DS, Yoon NS, Yoon HJ, Kim KH, Hong YJ, Park HW, Kim JH, Jeong MH, Cho JG, Park JC, Kang JC.
Clinical outcomes of low-dose aspirin administration in patients with variant angina pectoris.
Int J Cardiol. 2013 Sep 1;167(5):2333-4. doi: 10.1016/j.ijcard.2012.11.010. Epub 2012 Nov 22.
Abstract/Text
Lin Y, Chen Y, Yuan J, Qin H, Dong S, Chen Q.
Impact of aspirin use on clinical outcomes in patients with vasospastic angina: a systematic review and meta-analysis.
BMJ Open. 2021 Jul 29;11(7):e048719. doi: 10.1136/bmjopen-2021-048719. Epub 2021 Jul 29.
Abstract/Text
OBJECTIVES: The use of aspirin to prevent cardiovascular disease in vasospastic angina (VSA) patients without significant stenosis has yet to be investigated. This study aimed to investigate the efficacy of aspirin use among VSA patients.
DESIGN: Systematic review and meta-analysis.
DATA SOURCES: PubMed, Web of Science and Cochrane Central Register of Controlled Trials were searched for relevant information prior to October 2020.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Aspirin use versus no aspirin use (placebo or no treatment) among VSA patients without significant stenosis.
DATA EXTRACTION AND SYNTHESIS: Two investigators extracted the study data. ORs and 95% CIs were calculated and graphed as forest plots. The Newcastle-Ottawa Quality Assessment Scale tool and Begg's funnel plot were used to assess risk of bias.
RESULTS: Four propensity-matched cohorts, one retrospective analysis and one prospective multicentre cohort, in total comprising 3661 patients (aspirin use group, n=1695; no aspirin use group, n=1966) were included in this meta-analysis. Aspirin use and the incidence of major cardiovascular adverse events with follow-up of 1-5 years were not significantly correlated (combined OR=0.90, 95% CI: 0.55 to 1.68, p=0.829, I2=82.2%; subgroup analysis: OR=1.09, 95% CI: 0.81 to 1.47, I2=0%). No significant difference was found between aspirin use and the incidence of myocardial infarction (OR=0.62, 95% CI: 0.09 to 4.36, p=0.615, I2=73.8%) or cardiac death (OR=1.73, 95% CI: 0.61 to 4.94, p=0.444, I2=0%) during follow-up.
CONCLUSION: Aspirin use may not reduce the risk of future cardiovascular events in VSA patients without significant stenosis.
PROSPERO REGISTRATION NUMBER: CRD42020214891.
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Lee Y, Park HC, Shin J.
Clinical efficacy of aspirin with identification of intimal morphology by optical coherence tomography in preventing event recurrence in patients with vasospasm-induced acute coronary syndrome.
Int J Cardiovasc Imaging. 2018 Nov;34(11):1697-1706. doi: 10.1007/s10554-018-1399-9. Epub 2018 Jun 19.
Abstract/Text
Using optical coherence tomography (OCT), we found that there were morphological differences in the coronary intima between patients with vasospasm-induced acute coronary syndrome (VACS) and those with stable variant angina. We investigated whether aspirin use would protect against chest pain recurrence in patients with VACS. A retrospective cohort study was performed. Patients with ST-segment elevation who were confirmed to have VACS by a provocation test were included. OCT was performed at the index event and when chest pain recurred to assess intimal morphology. Chest pain recurrence was defined as the first revisit to the emergency room with angina. Propensity score matching was performed between the aspirin and non-aspirin groups. For 48 months, 154 patients were followed (77 patients in each group). The baseline characteristics and OCT findings were well balanced between the two groups after propensity score matching. Myocardial infarction (17 vs. 3%, p = 0.003) and chest pain recurrence (26 vs. 9%, p = 0.006) occurred more frequently in the non-aspirin group than in the aspirin group. Multiple Cox regression analysis showed that aspirin use was a significant predictor of lower risk of myocardial infarction [hazard ratio (HR) 0.13; 95% confidence interval (CI) 0.03-0.61] and chest pain recurrence (HR 0.33; 95% CI 0.12-0.71) during the follow-up period, after adjustments for relevant covariates including OCT findings. The use of aspirin may have a preventive effect on myocardial infarction and chest pain recurrence in patients with VACS. Randomized controlled trials are necessary to confirm the result.
Caralis DG, Deligonul U, Kern MJ, Cohen JD.
Smoking is a risk factor for coronary spasm in young women.
Circulation. 1992 Mar;85(3):905-9. doi: 10.1161/01.cir.85.3.905.
Abstract/Text
BACKGROUND: Risk factors for pure coronary spasm are not known. Clinical observations have pointed to cigarette smoking, a known risk factor for obstructive coronary artery disease.
METHODS AND RESULTS: We conducted a case-neighborhood control study of premenopausal women, a population segment with the lowest prevalence of obstructive coronary artery disease. The cases were 21 premenopausal women (age range, 36-41 years) with angiographically proven coronary spasm. All coronary arteriograms were analyzed by two independent experienced cardiologists on two occasions. There were no differences between analyses; all cases had normal baseline coronary angiogram except for two, who had less than 20% coronary luminal stenosis in segments other than the site of the focal vasospasm. All cases had normal hemodynamics at rest, normal left ventricular function, and were in sinus rhythm. Ascertainment of the cases was done by angiographic demonstration of focal coronary spasm spontaneously or by ergonovine provocation. Six cases developed spontaneous coronary spasm before catheter engagement, and in 15, coronary spasm was induced by ergonovine provocation. Each case was asked to name as many as possible female neighborhood acquaintances of similar age and racial background who were willing to answer the same standardized questionnaire. The same standardized questionnaire was completed for each case and each control (n = 63). The standardized questionnaire was designed to obtain information on health characteristics, habits, socioeconomic status, and education. Only cigarette smoking was significantly more prevalent among coronary spasm cases. Cigarette smokers were 13 cases (62%) and 11 controls (17.5%) (p less than 0.001). The odds ratio was 7.7, with a 95% confidence interval of 2.6-23.1.
CONCLUSIONS: These findings suggest that there is a very strong association between cigarette smoking and pure coronary spasm in young women.
Lombardi M, Morales MA, Michelassi C, Moscarelli E, Distante A, L'Abbate A.
Efficacy of isosorbide-5-mononitrate versus nifedipine in preventing spontaneous and ergonovine-induced myocardial ischaemia. A double-blind, placebo-controlled study.
Eur Heart J. 1993 Jun;14(6):845-51. doi: 10.1093/eurheartj/14.6.845.
Abstract/Text
This study was designed to assess the efficacy of oral nifedipine as compared to oral isosorbide-5-mononitrate in the prevention of spontaneous and induced vasospastic myocardial ischaemia. Twenty-one patients admitted to the Coronary Care Unit as a result of angina at rest underwent both Holter monitoring and an echo-ergonovine test during placebo and following either isosorbide-5-mononitrate or nifedipine according to a double-blind randomized trial. Both drugs caused a statistically significant reduction in spontaneous (87% and 95%, respectively) and induced ischaemic attacks (66% and 75%, respectively). No significant difference was found between the two drugs.
Lablanche JM, Bauters C, Leroy F, Bertrand ME.
Prevention of coronary spasm by nicorandil: comparison with nifedipine.
J Cardiovasc Pharmacol. 1992;20 Suppl 3:S82-5. doi: 10.1097/00005344-199206203-00014.
Abstract/Text
The efficacy of nicorandil was compared with that of nifedipine in 13 patients with vasospastic angina enrolled in a randomized, placebo-controlled, crossover study. All patients had a coronary spasm during coronary arteriography, either spontaneously or ergometrine-induced. During two consecutive periods of 2 days, patients received active drugs or placebo in a randomized order. Each patient received single oral doses of 30 mg nicorandil, 10 mg nifedipine, and, on 2 days, a placebo. One hour after drug intake, patients underwent an ergometrine test with increasing doses of Methergin (ergometrine) (0.05, 0.10, 0.20, and 0.40 mg every 5 min). After placebo, the tests always were positive, and the ECG changes occurred at the same +/- 1 dose of ergometrine in 10 cases, showing good reproducibility. After nicorandil, the tests were negative in nine patients and positive for a higher or lower dose of ergometrine in three and one patient, respectively (p = 0.0034 vs. placebo). After nifedipine, the tests were negative in five patients and positive for a higher or the same dose of ergometrine in four and four patients, respectively (p = 0.0039 vs. placebo). Nifedipine (10 mg) and nicorandil (30 mg) were equally effective in eight patients; in the remaining five patients, nicorandil had better results (p = 0.06). Nicorandil (30 mg) prevents ergometrine-induced coronary spasm. This compound may be beneficial in patients with vasospastic angina.
Meisel SR, Mazur A, Chetboun I, Epshtein M, Canetti M, Gallimidi J, Katz A, Strasberg B, Peled B.
Usefulness of implantable cardioverter-defibrillators in refractory variant angina pectoris complicated by ventricular fibrillation in patients with angiographically normal coronary arteries.
Am J Cardiol. 2002 May 1;89(9):1114-6. doi: 10.1016/s0002-9149(02)02283-x.
Abstract/Text
Chevalier P, Dacosta A, Defaye P, Chalvidan T, Bonnefoy E, Kirkorian G, Isaaz K, Denis B, Touboul P.
Arrhythmic cardiac arrest due to isolated coronary artery spasm: long-term outcome of seven resuscitated patients.
J Am Coll Cardiol. 1998 Jan;31(1):57-61. doi: 10.1016/s0735-1097(97)00442-7.
Abstract/Text
OBJECTIVES: Our aim was to look at the clinical features and long-term follow-up of seven patients without coronary artery disease, who had a history of life-threatening ventricular arrhythmias due to coronary spasm.
BACKGROUND: Arrhythmic cardiac arrest due to isolated coronary spasm is rare, and there is limited information on the patients affected by this entity alone.
METHODS: The seven patients were recruited retrospectively from a cohort of survivors of cardiac arrest. None had a history of angina pectoris, structural heart disease or significantly narrowed coronary segments. All had a positive ergonovine provocation test result.
RESULTS: The patients' mean age was 44 years; three were male and four female. All were habitual cigarette smokers. No arrhythmias were induced on programmed ventricular stimulation; corrected QT interval (QTc) and corrected JT interval (JTc) dispersion were within normal ranges. After the ergonovine provocation test, treatment with calcium channel blocking agents (diltiazem, verapamil, nifedipine or amlodipine) was initiated at a dose determined by titration until a negative test result was obtained. At a mean follow-up interval of 58 months for the total group, six patients remained free of symptoms, whereas the one patient who did not stop smoking had a new cardiac arrest despite treatment for coronary spasm.
CONCLUSIONS: A favorable long-term outcome may be expected in survivors of cardiac arrest due to coronary spasm, in the absence of significant coronary artery disease. Calcium channel blockers are the most appropriate therapy in these patients. These observations provide further evidence for the role of silent ischemia in cardiovascular death.
Matsue Y, Suzuki M, Nishizaki M, Hojo R, Hashimoto Y, Sakurada H.
Clinical implications of an implantable cardioverter-defibrillator in patients with vasospastic angina and lethal ventricular arrhythmia.
J Am Coll Cardiol. 2012 Sep 4;60(10):908-13. doi: 10.1016/j.jacc.2012.03.070. Epub 2012 Jul 25.
Abstract/Text
OBJECTIVES: The present study was performed to investigate the clinical implications of an implantable cardioverter-defibrillator (ICD) in patients with vasospastic angina (VSA) resuscitated from lethal ventricular arrhythmia.
BACKGROUND: The prognosis of VSA is known to be good with medication; however, ventricular arrhythmia and cardiopulmonary arrest are rare but life-threatening complications of this disease. The ICD is a proven modality for patients with ventricular arrhythmia, but the clinical implications in this population remain to be elucidated.
METHODS: We conducted a retrospective, observational, multicenter study involving patients with an ICD due to documented ventricular arrhythmia and VSA diagnosed by acetylcholine provocation test. All patients were followed up for appropriate ICD therapy, sudden cardiac arrest, or death from all causes.
RESULTS: Twenty-three patients were included in the present study and completely followed up. All patients are still alive. During a follow-up of 2.9 years (median 2.1 years), 4 ventricular fibrillations and 1 episode of pulseless electrical activity occurred in 5 patients (21.7%). There were no statistically significant differences in patient characteristics between the recurrence and nonrecurrence groups, including medication, smoking status, and whether the patient was or was not free of symptoms after ICD implantation.
CONCLUSIONS: Patients with VSA and lethal ventricular arrhythmia are a population at high risk for recurrence of cardiopulmonary arrest, and there is no reliable indicator for predicting recurrence of ventricular arrhythmia. Insertion of an ICD with medication for VSA is appropriate for this high-risk population.
Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
日本循環器学会/日本不整脈心電学会合同ガイドライン.不整脈非薬物治療ガイドライン（2018 年改訂版）.
Takagi Y, Takahashi J, Yasuda S, Miyata S, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Sato T, Ogawa S, Kubo N, Momomura S, Ogawa H, Shimokawa H; Japanese Coronary Spasm Association.
Prognostic stratification of patients with vasospastic angina: a comprehensive clinical risk score developed by the Japanese Coronary Spasm Association.
J Am Coll Cardiol. 2013 Sep 24;62(13):1144-53. doi: 10.1016/j.jacc.2013.07.018. Epub 2013 Jul 31.
Abstract/Text
OBJECTIVES: The present study aimed to develop a comprehensive clinical risk score for vasospastic angina (VSA) patients.
BACKGROUND: Previous studies demonstrated various prognostic factors of future adverse events in VSA patients. However, to apply these prognostic factors in clinical practice, the assessment of their accumulation in individual patients is important.
METHODS: The patient database of the multicenter registry study by the Japanese Coronary Spasm Association (JCSA) (n = 1,429; median 66 years; median follow-up 32 months) was utilized for score derivation.
RESULTS: Multivariable Cox proportional hazard model selected 7 predictors of major adverse cardiac events (MACE). The integer score was assigned to each predictors proportional to their respective adjusted hazard ratio; history of out-of-hospital cardiac arrest (4 points), smoking, angina at rest alone, organic coronary stenosis, multivessel spasm (2 points each), ST-segment elevation during angina, and beta-blocker use (1 point each). According to the total score in individual patients, 3 risk strata were defined; low (score 0 to 2, n = 598), intermediate (score 3 to 5, n = 639) and high (score 6 or more, n = 192). The incidences of MACE in the low-, intermediate-, and high-risk patients were 2.5%, 7.0%, and 13.0%, respectively (p < 0.001). The Cox model for MACE between the 3 risk strata also showed prognostic utility of the scoring system in various clinical subgroups. The average prediction rate of the scoring system in the internal training and validation sets were 86.6% and 86.5%, respectively.
CONCLUSIONS: We developed a novel scoring system, the JCSA risk score, which may provide the comprehensive risk assessment and prognostic stratification for VSA patients.
Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Sueda S, Shinohara T, Takahashi N, Shite J, Shoji T, Akao M, Kijima Y, Masuyama T, Miyaji T, Yamamoto K, Iwasaki Y, Yoshida R, Nakamura S, Ogino Y, Kimura K, Sasai M, Suzuki H, Wakatsuki T, Asajima H, Teragawa H, Ishikawa T, Kitamura K, Oda T, Nakayama T, Kobayashi Y, Sunada D, Yamaki M, Nishizaki F, Tomita Y, Usuda K, Fujinaga H, Kuramitsu S, Andou K, Kiyooka T, Kadota K, Ishii Y, Ohtani H, Maekawa Y, Taguchi E, Nakao K, Kobayashi N, Seino Y, Nakagawa H, Saito Y, Komuro I, Sasaki Y, Ikeda S, Yamaguchi O, Kakutani A, Imanaka T, Ishihara M, Ishii M, Kaikita K, Tsujita K.
Questionnaire in patients with aborted sudden cardiac death due to coronary spasm in Japan.
Heart Vessels. 2020 Dec;35(12):1640-1649. doi: 10.1007/s00380-020-01644-7. Epub 2020 Jun 12.
Abstract/Text
OBJECTIVES: We investigated the medical or mechanical therapy, and the present knowledge of Japanese cardiologists about aborted sudden cardiac death (ASCD) due to coronary spasm.
METHODS: A questionnaire was developed regarding the number of cases of ASCD, implantable cardioverter-defibrillator (ICD), and medical therapy in ASCD patients due to coronary spasm. The questionnaire was sent to the Japanese general institutions at random in 204 cardiology hospitals.
RESULTS: The completed surveys were returned from 34 hospitals, giving a response rate of 16.7%. All SCD during the 5 years was observed in 5726 patients. SCD possibly due to coronary spasm was found in 808 patients (14.0%) and ASCD due to coronary spasm was observed in 169 patients (20.9%). In 169 patients with ASCD due to coronary spasm, one or two coronary vasodilators was administered in two-thirds of patients [113 patients (66.9%)], while more than 3 coronary vasodilators were found in 56 patients (33.1%). ICD was implanted in 117 patients with ASCD due to coronary spasm among these periods including 35 cases with subcutaneous ICD. Majority of cause of ASCD was ventricular fibrillation, whereas pulseless electrical activity was observed in 18 patients and complete atrioventricular block was recognized in 7 patients. Mean coronary vasodilator number in ASCD patients with ICD was significantly lower than that in those without ICD (2.1 ± 0.9 vs. 2.6 ± 1.0, p < 0.001). Although 16 institutions thought that the spasm provocation tests under the medications had some clinical usefulness of suppressing the next fatal arrhythmias, spasm provocation tests under the medication were performed in just 4 institutions.
CONCLUSIONS: In the real world, there was no fundamental strategy for patients with ASCD due to coronary spasm. Each institution has each strategy for these patients. Cardiologists should have the same strategy and the same knowledge about ASCD patients due to coronary spasm in the future.
Ahn JM, Lee KH, Yoo SY, Cho YR, Suh J, Shin ES, Lee JH, Shin DI, Kim SH, Baek SH, Seung KB, Nam CW, Jin ES, Lee SW, Oh JH, Jang JH, Park HW, Yoon NS, Cho JG, Lee CH, Park DW, Kang SJ, Lee SW, Kim J, Kim YH, Nam KB, Lee CW, Choi KJ, Song JK, Kim YH, Park SW, Park SJ.
Prognosis of Variant Angina Manifesting as Aborted Sudden Cardiac Death.
J Am Coll Cardiol. 2016 Jul 12;68(2):137-45. doi: 10.1016/j.jacc.2016.04.050.
Abstract/Text
BACKGROUND: The long-term prognosis of patients with variant angina presenting with aborted sudden cardiac death (ASCD) is unknown.
OBJECTIVES: The purpose of this study was to evaluate the long-term mortality and ventricular tachyarrhythmic events of variant angina with and without ASCD.
METHODS: Between March 1996 and September 2014, 188 patients with variant angina with ASCD and 1,844 patients with variant angina without ASCD were retrospectively enrolled from 13 heart centers in South Korea. The primary endpoint was cardiac death.
RESULTS: Predictors of ASCD manifestation included age (odd ratio [OR]: 0.980 by 1 year increase; 95% confidence interval [CI]: 0.96 to 1.00; p = 0.013), hypertension (OR: 0.51; 95% CI: 0.37 to 0.70; p < 0.001), hyperlipidemia (OR: 0.38; 95% CI: 0.25 to 0.58; p < 0.001), family history of sudden cardiac death (OR: 3.67; 95% CI: 1.27 to 10.6; p = 0.016), multivessel spasm (OR: 2.06; 95% CI: 1.33 to 3.19; p = 0.001), and left anterior descending artery spasm (OR: 1.40; 95% CI: 1.02 to 1.92; p = 0.04). Over a median follow-up of 7.5 years, the incidence of cardiac death was significantly higher in ASCD patients (24.1 per 1,000 patient-years vs. 2.7 per 1,000 patient-years; adjusted hazard ratio [HR]: 7.26; 95% CI: 4.21 to 12.5; p < 0.001). Death from any cause also occurred more frequently in ASCD patients (27.5 per 1,000 patient-years vs. 9.6 per 1,000 patient-years; adjusted HR: 3.00; 95% CI: 1.92 to 4.67; p < 0.001). The incidence rate of recurrent ventricular tachyarrhythmia in ASCD patients was 32.4 per 1,000 patient-years, and the composite of cardiac death and ventricular tachyarrhythmia was 44.9 per 1,000 patient-years. A total of 24 ASCD patients received implantable cardioverter-defibrillators (ICDs). There was a nonsignificant trend of a lower rate of cardiac death in patients with ICDs than those without ICDs (p = 0.15).
CONCLUSIONS: The prognosis of patients with variant angina with ASCD was worse than other patients with variant angina. In addition, our findings supported ICDs in these high-risk patients as a secondary prevention because current multiple vasodilator therapy appeared to be less optimal.
Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Rodríguez-Mañero M, Oloriz T, le Polain de Waroux JB, Burri H, Kreidieh B, de Asmundis C, Arias MA, Arbelo E, Díaz Fernández B, Fernández-Armenta J, Basterra N, Izquierdo MT, Díaz-Infante E, Ballesteros G, Carrillo López A, García-Bolao I, Benezet-Mazuecos J, Expósito-García V, Larraitz-Gaztañaga, Martínez-Sande JL, García-Seara J, González-Juanatey JR, Peinado R.
Long-term prognosis of patients with life-threatening ventricular arrhythmias induced by coronary artery spasm.
Europace. 2018 May 1;20(5):851-858. doi: 10.1093/europace/eux052.
Abstract/Text
AIMS: Coronary artery spasm (CAS) is associated with ventricular arrhythmias (VA). Much controversy remains regarding the best therapeutic interventions for this specific patient subset. We aimed to evaluate the clinical outcomes of patients with a history of life-threatening VA due to CAS with various medical interventions, as well as the need for ICD placement in the setting of optimal medical therapy.
METHODS AND RESULTS: A multicentre European retrospective survey of patients with VA in the setting of CAS was aggregated and relevant clinical and demographic data was analysed. Forty-nine appropriate patients were identified: 43 (87.8%) presented with VF and 6 (12.2%) with rapid VT. ICD implantation was performed in 44 (89.8%). During follow-up [59 (17-117) months], appropriate ICD shocks were documented in 12. In 8/12 (66.6%) no more ICD therapies were recorded after optimizing calcium channel blocker (CCB) therapy. SCD occurred in one patient without ICD. Treatment with beta-blockers was predictive of appropriate device discharge. Conversely, non-dihydropyridine CCB therapy was significantly protective against VAs.
CONCLUSION: Patients with life-threatening VAs secondary to CAS are at particularly high-risk for recurrence, especially when insufficient medical therapy is administered. Non-dihydropyridine CCBs are capable of suppressing episodes, whereas beta-blocker treatment is predictive of VAs. Ultimately, in spite of medical intervention, some patients exhibited arrhythmogenic events in the long-term, suggesting that ICD implantation may still be indicated for all.
Vlastra W, Piek M, van Lavieren MA, Hassell MEJC, Claessen BE, Wijntjens GW, van de Hoef TP, Sjauw KD, Beijk MA, Delewi R, Piek JJ.
Long-term outcomes of a Caucasian cohort presenting with acute coronary syndrome and/or out-of-hospital cardiac arrest caused by coronary spasm.
Neth Heart J. 2018 Jan;26(1):26-33. doi: 10.1007/s12471-017-1065-1.
Abstract/Text
BACKGROUND: Coronary artery spasm may be the underlying mechanism in up to 10% of cases of acute coronary syndrome (ACS) and sudden cardiac death. Asian individuals exhibit a 3-times greater incidence of spasm than Caucasians; this is likely due to different types of mechanisms. Consequently, solid data is limited about the long-term prognosis in Caucasian patients presenting with ACS and/or out-of-hospital cardiac arrest (OHCA) caused by coronary spasm.
METHODS: Between 2002 and 2015, thirty Caucasian patients with coronary artery spasm presenting with ACS (N = 29) and/or OHCA (N = 11) were enrolled in this prospective registry. Follow-up, consisting of regular outpatient visits, was conducted with a mean follow-up period of 7.5 ± 3.3 years. Outcomes included presence of stable angina pectoris, recurrence of ACS, occurrence of implantable cardioverter defibrillator (ICD) shocks and death.
RESULTS: The majority of patients (60%) remained asymptomatic during the entire follow-up period. At the end of the follow-up period only 3 patients still experienced stable angina (10%). Only 2 patients (7%) had a recurrent cardiac event, in which the ICD provided appropriate shock therapy. Half of the patients treated with stenting (N = 6), required re-interventions.
CONCLUSION: Coronary spasm with ACS and/or OHCA in a Caucasian patient cohort has a relatively benign prognosis in the majority of patients in long-term follow-up, if treated appropriately with medical therapy. Both the role of ICD in OHCA secondary to coronary spasm, and the efficacy of stenting to treat vasospastic angina, warrant further study in large-sized prospective clinical trials.
Ogino Y, Ishikawa T, Minamimoto Y, Kiyokuni M, Kimura Y, Akiyama E, Okada K, Konishi M, Hosoda J, Matsuzawa Y, Maejima N, Iwahashi N, Matsumoto K, Hibi K, Kosuge M, Ebina T, Tamura K, Kimura K.
Characteristics and Prognosis of Patients with Vasospastic Angina Diagnosed by a Provocation Test with Secondary Prevention Implantable Cardioverter Defibrillator.
Int Heart J. 2021 Mar 30;62(2):224-229. doi: 10.1536/ihj.20-360. Epub 2021 Mar 17.
Abstract/Text
This study aimed to evaluate the characteristics and prognosis of patients with vasospastic angina (VSA) diagnosed by a provocation test with a secondary prevention implantable cardioverter defibrillator (ICD), compared with patients with organic coronary stenosis. We retrospectively evaluated 309 consecutive patients who received an ICD implantation between January 2010 and March 2018 in our institutions. Of these patients, 206 were implanted with an ICD for secondary prevention. In these 206 patients, 40 with VSA and 72 with organic coronary stenosis were evaluated. Patients with VSA were characterized by younger age (56.1 ± 13.1 versus 69.2 ± 9.5 years, respectively), and a lower prevalence of diabetes (15.0% versus 40.3%, respectively) and heart failure (2.5% versus 26.4%, respectively) than patients with organic coronary stenosis (P < 0.001). Using the Kaplan-Meier analysis, with the VSA group as the reference, the incidence of appropriate ICD shock was similar between the two groups (hazard ratio, 0.85; 95% confidence interval, 0.341-2.109; P = 0.722). The incidence of ventricular fibrillation was significantly higher in the VSA group (hazard ratio, 0.22; 95% confidence interval, 0.057-0.814; P = 0.024), whereas the incidence of major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, and heart failure, was significantly higher in the organic coronary stenosis group (hazard ratio, 13.1; 95% confidence interval, 1.756-98.17; P = 0.012). In conclusion, patients with VSA with an ICD implanted for secondary prevention have a higher risk of ventricular fibrillation and lower risk of major adverse cardiac events than patients with organic coronary stenosis.
Tateishi K, Saito Y, Kitahara H, Takaoka H, Kondo Y, Nakayama T, Fujimoto Y, Kobayashi Y.
Vasospastic angina and overlapping cardiac disorders in patients resuscitated from cardiac arrest.
Heart Vessels. 2021 Mar;36(3):321-329. doi: 10.1007/s00380-020-01705-x. Epub 2020 Sep 29.
Abstract/Text
BACKGROUND: Vasospastic angina (VSA) reportedly accounts for one form of sudden cardiac arrest (SCA). Intracoronary acetylcholine (ACh) testing is useful for diagnosing VSA although invasive provocation testing after SCA is a clinical challenge. In addition, even if the ACh test is positive, any causal relationship between VSA and SCA is often unclear because patients with VSA may have other underlying cardiac disorders.
METHODS: A total of 20 patients without overt structural heart disease who had been fully resuscitated from SCA were included. All patients underwent the ACh provocation test and scrutiny such as cardiac computed tomography or magnetic resonance imaging. Patients were followed up for all-cause death or recurrent SCA including appropriate implantable cardioverter defibrillator therapy.
RESULTS: An ACh provocation test was performed 20 ± 17 days after cardiac arrest. Fifteen out of 20 (75.0%) patients had a positive ACh test and 2 (10.0%) had adverse events such as ventricular tachycardia and transient cardiogenic shock during the test. In patients with a positive ACh test, 6 of 15 (40.0%) patients had other overlapping cardiac disorders such as long QT syndrome, Brugada syndrome, cardiac sarcoidosis, myocarditis, or cardiomyopathy. Long-term prognosis was not different regardless of a positive ACh test or the presence of other cardiac disorders overlapping with VSA.
CONCLUSIONS: Three-quarters of the patients who had been resuscitated from SCA had a positive ACh test. Further examinations revealed other overlapping cardiac disorders in addition to VSA in 40% of patients with a positive ACh test.
van der Lingen ACJ, Woudstra J, Becker MAJ, Mol MAE, van Rossum AC, Rijnierse MT, Allaart CP.
Recurrent ventricular arrhythmias and mortality in cardiac arrest survivors with a reversible cause with and without an implantable cardioverter defibrillator: A systematic review.
Resuscitation. 2022 Apr;173:76-90. doi: 10.1016/j.resuscitation.2022.02.019. Epub 2022 Feb 25.
Abstract/Text
BACKGROUND: Sudden cardiac arrest survivors with a reversible cause are not eligible for implantable cardioverter defibrillator (ICD) implantation. This study aims to evaluate the risk of recurrent ventricular arrhythmia in sudden cardiac arrest survivors with a reversible cause and evaluate if ICD implantation increases survival.
METHODS: We conducted a systematic review to identify studies evaluating ICD implantation in sudden cardiac arrest survivors with a reversible cause. Outcomes were mortality and appropriate device therapy. Sudden cardiac arrest patients were divided into 4 subgroups: due to acute myocardial infarction; due to coronary artery spasm; due to takotsubo cardiomyopathy; and studies with various reversible causes of cardiac arrest.
RESULTS: 27 studies were included, evaluating 11,402 patients. A total of 2570 patients received an ICD. Studies evaluating coronary artery spasm and with various reversible causes showed a relatively high rate of appropriate device therapy (17% and 20%) and described an increased survival in ICD patients. Takotsubo cardiomyopathy was associated with a low mortality and none of the ICD patients received appropriate device therapy. Studies evaluating acute myocardial infarction survivors reported inconsistent results, with high numbers of appropriate device therapy (12-66%), but the mortality-rate of patients with and without an ICD varied.
CONCLUSION: This study shows that the recurrence risk of ventricular arrhythmia varies between different reversible causes of sudden cardiac arrest and should not be evaluated as one entity. Cardiac arrest survivors with a reversible cause can be at risk of recurrent ventricular arrhythmia and selected patients may benefit from ICD implantation.
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
Yoshida K, Inoue T, Hirakawa N, Node K.
Endoscopic thoracic sympathectomy as a novel strategy for vasospastic angina refractory to medical treatments.
J Cardiol. 2008 Aug;52(1):49-52. doi: 10.1016/j.jjcc.2008.04.002. Epub 2008 Jul 3.
Abstract/Text
Although vasospastic angina (VSA) is usually controlled by medications, refractory or lethal cases are occasionally encountered. We performed bilateral endoscopic thoracic sympathectomy (ETS) in 5 male patients with refractory VSA. Prior to ETS, stellate ganglion blockade was performed in 4 patients to reduce VSA attacks and to confirm the effect of sympathetic blockade. Under endoscopic guidance, the second to fourth thoracic sympathetic ganglia were ablated with a YAG-laser. No patient had complications after ETS, including major sweating abnormalities. In 4 of 5 patients, ETS relieved all VSA symptoms. ST-segment elevation often detected before ETS was absent on repeated ambulatory 24-h Holter monitoring after ETS. ETS is an effective strategy for the treatment of refractory VSA.
Cardona-Guarache R, Pozen J, Jahangiri A, Koneru J, Shepard R, Roberts C, Abbate A, Cassano A.
Thoracic Sympathectomy for Severe Refractory Multivessel Coronary Artery Spasm.
Am J Cardiol. 2016 Jan 1;117(1):159-61. doi: 10.1016/j.amjcard.2015.10.018. Epub 2015 Oct 23.
Abstract/Text
Coronary artery spasm is a rare but potentially fatal disease. Herein, we report a case of recurrent ST-segment myocardial infarctions and ventricular fibrillation complicating severe multivessel coronary artery spasm successfully treated with bilateral thoracic surgical sympathectomy.
Copyright © 2016 Elsevier Inc. All rights reserved.
Lin Y, Liu H, Yu D, Wu M, Liu Q, Liang X, Pang X, Chen K, Luo L, Dong S.
Sympathectomy versus conventional treatment for refractory coronary artery spasm.
Coron Artery Dis. 2019 Sep;30(6):418-424. doi: 10.1097/MCA.0000000000000732.
Abstract/Text
BACKGROUND: There is no clear consensus on the potential efficacy and indications for sympathectomy to prevent recurrence of vasospasm in patients with refractory coronary artery spasm (CAS).
OBJECTIVE: To compare the clinical outcomes of sympathectomy with those of conventional treatment in patients with refractory CAS.
PATIENTS AND METHODS: Patients with refractory CAS were randomly assigned to sympathectomy group (n = 37) or conventional treatment group (n = 42). The primary end point was a composite of major adverse cardiac event (MACE) episodes (including cardiac death, nonfatal myocardial infarction, unstable angina, heart failure, and life-threatening arrhythmia), and the secondary end point was death from any cause within 24 months after randomization.
RESULTS: During the follow-up period of 24 months, the incidence of MACE in the sympathectomy and conventional treatment groups was 16.22 and 61.90%, respectively (P = 0.0001). All-cause death as the secondary end point occurred in zero and six (14.29%) patients, respectively (P = 0.0272). The Kaplan-Meier curve for MACE and all-cause death showed a significant between-group difference (log-rank test, P = 0.0013 and 0.0176, respectively).
CONCLUSION: Compared with conventional treatment, sympathectomy significantly reduced the composite end point of MACE episodes and death from any cause in patients with refractory CAS by effectively preventing recurrence of vasospasm.
Schick EC Jr, Liang CS, Heupler FA Jr, Kahl FR, Kent KM, Kerin NZ, Noble RJ, Rubenfire M, Tabatznik B, Terry RW.
Randomized withdrawal from nifedipine: placebo-controlled study in patients with coronary artery spasm.
Am Heart J. 1982 Sep;104(3):690-7. doi: 10.1016/0002-8703(82)90257-5.
Abstract/Text
A multicenter randomized double-blind withdrawal study was conducted to compare the efficacy of nifedipine to that of placebo in vasospastic angina. Following a 2-week single-blind nifedipine baseline period, during which nifedipine was maintained at prestudy levels, 38 patients, 19 taking placebo and 19 continuing nifedipine therapy, either completed a 4-week randomized phase or were prematurely withdrawn because of therapeutic failure. During the randomized phase, an increase in median anginal frequency (2.8 attacks/wk, p less than 0.003) and nitroglycerin usage (0.5 tablets/wk, p less than 0.03) occurred only in the placebo group. The randomized phase was prematurely terminated because of anginal exacerbation in 7 of 19 placebo patients (37%) (only 1 patient receiving nifedipine [p = 0.02] experienced anginal exacerbation). Double-blind therapy was judged effective in 16 patients (84%) receiving nifedipine and in 3 patients (16%) receiving placebo (p less than 0.001). Nifedipine was well tolerated. This study establishes the efficacy of nifedipine in the treatment of variant and validates previous clinical experience.
