Cimetidine induces coronary artery spasm in patients with vasospastic angina

We have previously reported that cimetidine, a histamine H2-receptor blocker, augments the histamine-induced coronary vasoconstriction at the site of spastic segments in the atherosclerotic coronary arteries of swine. To elucidate whether cimetidine has a coronary vasoconstrictive effect in humans, 14 patients with vasospastic angina (group 1) and 14 controls with atypical chest pain (group 2) were examined angiographically. Nitroglycerin-effective spontaneous angina with electrocardiographic ST-T changes and ergonovine-induced coronary artery spasm were confirmed in group 1, but not in group 2. Cimetidine was administered intravenously in a dose of 200 mg. Cimetidine induced coronary artery spasm in 4 patients in group 1 but none in group 2(29% vs. 0%, p less than 0.01). The extent of coronary vasoconstriction induced by cimetidine was greater at the site of spastic coronary segments than that at the site of non-spastic segments in group 1 or all segments in group 2 [14% vs. 4%, (p less than 0.01) or 14% vs. 2%, (p less than 0.01)] as well as the extent of ergonovine-induced coronary vasoconstriction [46% vs. 14%, (p less than 0.01) or 46% vs. 14%, (p less than 0.01)] and nitroglycerin-induced coronary vasodilatation [58% vs. 25%, (p less than 0.01) or 58% vs. 17%, (p less than 0.01)]. As it was suggested that cimetidine has potential vasoconstrictive effects in patients with coronary artery spasm, it should be administered with caution in patients with the vasospastic angina pectoris.     

Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm

OBJECTIVES: We sought to determine whether a potent Rho-kinase inhibitor fasudil prevents the occurrence of myocardial ischemia in patients with microvascular angina attributable to coronary microvascular spasm. BACKGROUND: Effective treatment of patients with angina who have normal coronary arteriograms (microvascular angina) has not yet been established. Rho-kinase-mediated calcium sensitization of the myosin light chain in smooth muscle cells has been implicated as substantially contributing to vascular hyperconstriction. METHODS: We studied consecutive 18 patients with angina and normal epicardial coronaries in whom intracoronary acetylcholine (ACh) induced myocardial ischemia (ischemic electrocardiographic changes, myocardial lactate production, or both) without angiographically demonstrable epicardial coronary vasospasm. All patients underwent a second ACh challenge test after pretreatment with either saline (n = 5) or fasudil (4.5 mg intracoronarily, n = 13). RESULTS: Myocardial ischemia was reproducibly induced by ACh in the saline group. In contrast, 11 of the 13 patients pretreated with fasudil had no evidence of myocardial ischemia during the second infusion of ACh (p < 0.01). The lactate extraction ratio (median value [interquartile range]) during ACh infusion was improved by fasudil pretreatment, from -0.16 (-0.25 to 0.04) to 0.09 (0.05 to 0.18) (p = 0.0125). CONCLUSIONS: Fasudil ameliorated myocardial ischemia in patients who were most likely having coronary microvascular spasm. The inhibition of Rho-kinase may be a novel therapeutic strategy for this group of patients with microvascular angina.     

Rho激酶抑制剂法舒地尔在冠心病中的应用进展

Rho/Rho激酶广泛分布于哺乳类动物的组织细胞中,是具有信息传导和分子开关功能的信号多肽[1].近年来的研究表明,Rho激酶通过与AT-11、ET-1和血小板衍生生长因子（PDGF）等多种血管活性物质的相互调控,影响平滑肌细胞（SMC）的功能和结构,直接参与心血管疾病的病理过程,与动脉粥样硬化（arteriosclerosis,AS）、高血压、冠脉痉挛、心肌缺血等主要心血管疾病的发生发展关系密切.用Rho激酶抑制剂防治冠心病的研究已取得令人瞩目的临床效果,有望成为防治冠心病的新方法.本文主要介绍Rho激酶抑制剂法舒地尔在冠心病治疗中的应用.     

The preventive effect of magnesium on coronary spasm in patients with vasospastic angina

STUDY OBJECTIVES: Previous studies have reported that magnesium (Mg) deficiency is associated with coronary spasm. However, little is known about the preventive effect of Mg on coronary spasm. The present study investigated whether Mg prevents coronary spasm in patients with vasospastic angina (VSA). DESIGN: Effectiveness trial. SETTING: University medical center. PATIENTS: Twenty-two patients with VSA. INTERVENTION: Coronary spasm was induced with an intracoronary infusion of acetylcholine (Ach). After spontaneous relief of the coronary spasm, Mg sulfate (0.27 mmol/kg body weight) was infused IV over 20 min in 14 patients and isotonic glucose was infused in 8 patients as control subjects. Intracoronary infusion of Ach was then repeated, and the diameter of the coronary arteries was measured quantitatively. MEASUREMENTS AND RESULTS: Mg infusion caused coronary artery dilatation at baseline in both the spastic (5. 9 +/- 2.3%) and nonspastic segments (5.5 +/- 1.5%). Mg infusion reduced the severity of chest pain and ST-segment deviations during coronary spasm. After the Mg infusion, the percent change in the diameter of the spastic segments improved from - 62.8 +/- 2.6% to - 43.7 +/- 4.7% during coronary spasm. Overall, 10 of 14 patients (71%) responded favorably to Mg infusion. Isotonic glucose infusion did not elicit changes in chest pain severity, ST-segment deviations, or the diameter of the coronary arteries during spasm. CONCLUSIONS: Mg infusion produces nonsite-specific basal coronary dilatation and suppresses Ach-induced coronary spasm in patients with VSA.     

Cardiac events in vasospastic angina: site and morphology of coronary artery spasm is related to the long-term prognosis of vasospastic angina

To determine whether the site and morphology of coronary artery spasm provoked with acetylcholine can predict the long-term prognosis of vasospastic angina, coronary artery spasm (more than 90% narrowing) provoked with acetylcholine was studied in 66 consecutive patients (56 males, 10 females, mean age 56 +/- 9 years) with vasospastic angina. All patients were followed for 6.7 +/- 0.9 years and the incidence of cardiac events such as sudden death, myocardial infarction or worsened unstable angina was compared with the site and morphology of provoked spasm. The site of spasm was regarded as proximal when spasm occurred in the proximal site of 3 major coronary arteries which was designated as segment 1, 6 or 11, according to the classification of the American Heart Association, and distal in other segments. The morphology of spasm was classified into 3 types, focal (12 cases, localized more than 90% narrowing with adjoining parts constricting less than 25%), diffuse (17 cases, diffuse more than 90% narrowing), and intermediate (37 cases, localized more than 90% narrowing with adjoining parts constricting 25-90%). The site of spasm was classified into 2 types, the proximal group (24 cases) and the distal group (42 cases). Cardiac events occurred in 7 patients during the follow-up period: sudden death in 2, myocardial infarction in 2, and worsened unstable angina in 3. As to the site of spasm, the incidence of cardiac events was 21% (5/24 patients) in the proximal group, significantly higher than 5% (2/42) in the distal group (p < 0.05). As to the site of spasm, the incidence of cardiac events was 41% (5/12) in the focal group, significantly higher than 3% (1/37) in the intermediate group and 6% (1/17) in the diffuse group (p < 0.001). The presence of proximal and focal coronary artery spasm was associated with a significantly higher incidence of cardiac events. The site and morphology of coronary artery spasm provoked with acetylcholine is related to the long-term prognosis of vasospastic angina.     

Tetrahydrobiopterin improves coronary endothelial function, but does not prevent coronary spasm in patients with vasospastic angina.

Reduced bioavailability of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthase, and the resulting decrease in NO in the coronary circulation may be involved in the pathogenesis of coronary spasm. The present study investigated the effects of BH4 on the vascular response to acetylcholine (ACh) in 28 patients with vasospastic angina (VA) using quantitative angiography. After recording the vascular responses to ACh (3 and 30 microg/min), either BH4 (1 mg/min) or saline was infused into the coronary artery for 2 min before and during a subsequent infusion of ACh. With the 3 microg/min dose of ACh, BH4 attenuated the ACh-induced decrease in coronary diameter in both the nonspastic segments (-1.1 +/- 2.2% ACh vs 6.0 +/- 2.8% ACh+BH4) and spastic segments (-6.3 +/- 2.7% ACh vs 2.9 +/- 2.7% ACh+BH4), but did not influence the ACh-induced coronary spasm at 30 microg/min (-57.3 +/-2.4% ACh vs -55.3 +/- 2.4% ACh+BH4). In the control patients, saline did not influence either the spastic or nonspastic vasoconstrictor responses to ACh. Acute administration of BH4 improves coronary endothelial function, but does not prevent coronary spasm in patients with VA.     

Induction of coronary arterial spasm by intracoronary administration of acetylcholine in patients with vasospastic angina

To examine whether intracoronary injections of acetylcholine induce coronary artery spasm in patients with vasospastic angina, incremental doses (20, 30 and 50 micrograms) were injected directly into the coronary arteries in 12 patients with variant angina (Group A: rest angina with electrocardiographic ST-segment elevation during attacks), 19 with vasospastic angina (Group B: rest angina and/or effort angina with variable threshold in the treadmill exercise stress test), 11 with organic coronary artery stenosis but without angina (Group C), and 14 without coronary artery disease (Group D). A temporary cardiac pacemaker was positioned in the right ventricle. Coronary artery spasm was defined as severe vasoconstriction (greater than or equal to 90% of reduction in the luminal diameter) with chest pain and/or ischemic changes in the electrocardiogram. Intracoronary injection of acetylcholine induced spasm of at least one coronary artery in all 12 patients (100%) of Group A, in 18 (95%) of Group B, in two (18%) of Group C, and in two (14%) of Group D. Thus, the sensitivity of this method for inducing coronary spasm was 100% in group A, 95% in Group B, and 97% in Group A plus Group B. The specificity for inducing spasm was 86% in Group D, and 84% in Group C and Group D. When acetylcholine was injected separately into the left and right coronary arteries, spasm of both the coronary arteries was observed in two (40%) of Group A, in five (33%) of Group B, and none (0%) of Group C and Group D. Acetylcholine (20 micrograms) induced coronary spasm in 10 (83%) of Group A and only in nine (47%) of Group B.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina

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."     

Increased plasma level of endothelin-1 and coronary spasm induction in patients with vasospastic angina pectoris.

To elucidate the pathogenic contribution of a potent vasoconstrictor, endothelin-1, to coronary artery spasm, we provoked spasm with intracoronary administration of acetylcholine or ergonovine and performed sensitive immunoassays of plasma levels of endothelin-1 and atrial natriuretic factor (ANF) in the peripheral vein and coronary sinus of patients with a tentative diagnosis of vasospastic angina (VSA, n = 19). The validity of coronary sinus blood sampling was verified by simultaneous measurement of the ANF level. The plasma endothelin-1 levels in venous and coronary sinus blood of the spasm-provoked patients (n = 12) were 1.71-fold and 2.16-fold higher, respectively, than those of nonprovoked cases (n = 5, p less than 0.01). During left coronary spasm, the endothelin-1 level in coronary sinus transiently decreased from 2.27 +/- 0.14 to 1.76 +/- 0.14 pg/ml (p less than 0.01) and returned to the control level (1.98 +/- 0.20 pg/ml) after the spasm resolved, whereas the change was equivocal during right coronary spasm. In contrast, the patients in whom spasm was not provoked showed no changes and maintained low endothelin-1 levels both before and after the maximal provocation (0.90 +/- 0.13 versus 0.90 +/- 0.13 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of coronary flow reserve in patients with vasospastic angina

OBJECTIVES: The presence of microvascluar impairment was evaluated in 154 patients with vasospastic angina identified by the acetylcholine provocation test. METHODS: Coronary flow reserve was evaluated with a Doppler flow guidewire in 128 vessels of 72 patients with chest pain, but no significant coronary stenosis(less than 50% stenosis) and no clinical factors that affect coronary flow reserve. Coronary flow reserve was obtained from the ratio of adenosine triphosphate-induced maximum/baseline averaged peak velocity. These vessels were classified into 2 categories according to whether acetylcholine-induced vasospasm was positive or negative. Vasospasm positive was defined as more than 90% stenosis provoked with chest pain and/or ischemic ST change. Positive vessels were subdivided according to focal or diffuse vasospasm. These vessels were also classified into 2 other categories according to whether vasospasm in the distal artery was positive or negative. RESULTS: Coronary flow reserve was significantly lower in vessels with vasospasm than in vessels without vasospasm in patients without vasospasm(2.9 +/- 0.8 vs 3.6 +/- 1.0, p = 0.0005). Coronary flow reserve was significantly lower in vessels without vasospasm in patients with vasospasm than in vessels without vasospasm in patients without vasospasm(3.0 +/- 0.8 vs 3.6 +/- 1.0, p = 0.03). There was no significant difference in coronary flow reserve between vessels with vasospasm and vessels without vasospasm in patients with vasospasm(2.9 +/- 0.8 vs 3.0 +/- 0.8, p = 0.8). There was no significant difference in coronary flow reserve between focal and diffuse vasospasm(3.2 +/- 0.8 vs 2.9 +/- 0.8, p = 0.3). Coronary flow reserve was significantly lower in vessels with vasospasm in the distal artery than in vessels without vasospasm in the distal artery (2.8 +/- 0.8 vs 3.4 +/- 1.0, p = 0.004). CONCLUSIONS: Patients with vasospastic angina have microvascular impairment in both vessels with vasospasm, and vessels without vasospasm. Microvascular impairment is prominent in vessels with vasospasm in the distal artery.     

Significance of coronary artery tone in patients with vasospastic angina

To investigate the relation between basal coronary artery diameter and development of coronary artery spasm, the diameters of the proximal, middle and distal segments of the three major coronary artery branches, together with that of the left main trunk, were measured on a control angiogram and after ergonovine and nitrate administration in 30 patients with vasospastic angina without significant organic stenosis, and in 35 patients without ischemic heart disease. The percent change in coronary diameter after ergonovine and nitrate administration compared with the control diameter was used as an index of coronary vasoreactivity. In patients with vasospastic angina, coronary artery responses to both ergonovine and nitrate were greater in the spastic segments than in the other segments (p less than 0.05), and those of the coronary arteries without spasm were greater than those of the coronary arteries in patients without ischemic heart disease (p less than 0.01). There were no significant differences between the coronary artery diameters in the two groups after nitrate administration, and the control diameters were less in patients with vasospastic angina than in patients without ischemic heart disease. These observations indicate that a coronary vasomotion disorder, which involves increased basal coronary artery tone and hypersensitivity to vasoconstrictive stimuli, not only at a localized segment but also in the entire coronary artery tree, is present in patients with vasospastic angina. Clinically, evaluation of basal coronary artery tone may be useful for predicting the occurrence and location of coronary artery spasm.     

Vasodilatory effect of subsequent administration of fasudil, a rho-kinase inhibitor, surpasses that of nitroglycerin at the concentric coronary stenosis in patients with stable angina pectoris.

BACKGROUND: Recent studies have suggested that the Rho/Rho-kinase mediated pathway (Rho-kinase pathway) regulates the vasomotion of arteries in pathological conditions. However, it remains unclear regarding whether this pathway regulates the coronary vasomotion of atherosclerotic lesions. METHODS AND RESULTS: The coronary diameter at the concentric stenotic site, which is considered to reflect the whole circumferential atherosclerosis, in patients with stable angina pectoris (SAP; n=11) and the control site in patients with SAP and chest pain syndrome (CPS; n=9), was measured at baseline and after the intracoronary administration of nitroglycerin (200 microg) and the subsequent intravenous infusion of fasudil (30 mg for 30 min), a Rho-kinase inhibitor, during coronary angiography. The change in the diameter with fasudil at the concentric stenotic site (22.0+/-10.0%) was significantly higher than that with nitroglycerin (4.7+/-6.0%, p<0.001) in patients with SAP. Meanwhile, the vasodilatory effect of nitroglycerin and fasudil at the control site was similar in both group of patients (25.5+/-17.3% and 21.9+/-14.9% in SAP and 34.4+/-20.8% and 33.2+/-23.6% in CPS, respectively). CONCLUSIONS: The vasodilatory effect of the subsequent administration of fasudil surpassed that of nitroglycerin at the concentric coronary stenosis in patients with SAP, thus suggesting that the Rho-kinase pathway regulates the coronary vasomotion of atherosclerotic lesions.     

Intravascular ultrasound findings of negative arterial remodeling at sites of focal coronary spasm in patients with vasospastic angina

BACKGROUND: There are few data about the intravascular ultrasound (IVUS) findings in patients with vasospastic angina, especially regarding patterns of vascular remodeling. METHODS AND RESULTS: Coronary spasm was documented by angiography and electrocardiographic evidence of ischemia in 36 patients after administration of ergonovine (cumulative doses up to 350 microg). After relief of spasm with 1000 microg of intracoronary nitroglycerin, quantitative angiography and IVUS imaging were performed and analyzed by standard methods. The 36 focal spasm sites were compared with the proximal and distal reference segments. The angiographic baseline minimum lumen diameter measured 1.78 +/- 0.66 mm, which decreased to 0.66 +/- 0.38 mm with ergonovine provocation (P <.0001), increased to 2.66 +/- 0.64 mm after intracoronary nitroglycerin (P <.0001 compared with baseline and after ergonovine), and did not change after IVUS imaging (2.66 +/- 0.63, P =.9). By IVUS, atherosclerotic lesions were observed at all coronary spasm sites; the mean plaque burden measured 56% at the spasm site and 35% at the reference. Spasm site plaque composition was hypoechoic in 31 and hyperechoic, noncalcific in 5; there was no calcium. The mean eccentricity index (maximum divided by minimum plaque thickness) was 6.7. Positive remodeling (spasm site arterial area greater than proximal reference) was present in 5; intermediate remodeling (proximal reference greater than spasm site greater than distal reference arterial area) was present in 7; and negative remodeling (spasm site arterial area less than distal reference) was present in 24. CONCLUSIONS: Sites of vasospasm in patients with variant angina showed characteristics of early atherosclerosis, except for an unusually high incidence of negative arterial remodeling.     

Evaluation of coronary microvascular function in patients with vasospastic angina

AIM: To investigate endothelium-dependent and independent coronary microvascular functions in patients with vasospastic angina (VSA). METHODS: Thirty-six patients with VSA (30 men and 6 women; mean age, 58 years) were enrolled in this study. VSA was defined as ≥ 90% narrowing of the epicardial coronary arteries on angiography performed during a spasm provocation test, presence of chest pain, and/or ST-segment deviation on an electrocardiogram (ECG). Patients (n = 36) with negative spasm provocation test results and those matched for age and sex were enrolled as a control group (nonVSA group). Low-dose acetylcholine (ACh; 3 μg/min) was infused into the left coronary ostium for 2 min during the spasm provocation test. Following the spasm provocation test, nitroglycerin (0.2 mg) was administered intracoronally. Coronary blood flow (was calculated from quantitativeangiography and Doppler flow velocity measurements, and the coronary flow reserve was calculated as the ratio of coronary flow velocity after injection of adenosine triphosphate (20 μg) to the baseline value. Changes in the coronary artery diameter in response to ACh and nitroglycerin infusion were expressed as percentage changes from baseline measurements. RESULTS: Body mass index was significantly lower in the VSA group than in the nonVSA group. The fre- quency of conventional coronary risk factors and the rate of statin use were similar between the 2 groups. The left ventricular ejection fraction as evaluated by echocardiography was similar between the 2 groups. The duration of angina was 9 ± 2 mo. The results of blood chemistry analysis were similar between the 2 groups. Low-dose ACh did not cause coronary spasms. The change in coronary artery diameter in response to ACh was lower in the VSA group (-1.4% ± 9.3%) than in the nonVSA group (3.1% ± 6.5%, P < 0.05), whereas nitroglycerin-induced coronary artery dilatation and coronary blood flow increase in response to ACh or coronary flow reserve did not differ significantly between the 2 groups. CONCLUSION: These findings suggest that microvascular coronary function may be preserved despite endothelial dysfunction of the epicardial coronary arteries in patients with VSA.     

Usefulness of intracoronary injection of acetylcholine as a provocative test for coronary artery spasm in patients with vasospastic angina

Summary In order to examine both the sensitivity and specificity of coronary artery spasm induced by intracoronary injection of acetylcholine in patients with vasospastic angina, incremental doses of acetylcholine (20, 30, and 50 µg) were injected directly into each coronary artery in 21 patients with variant angina (group A), in 28 patients with other types of vasospastic angina (group B), and in 20 patients without any significant coronary artery disease (group C). Coronary artery spasm was defined as severe vasoconstriction (90% of reduction in luminal diameter) with chest pain and/or ischemic changes in the electrocardiogram. Intracoronary injection of acetylcholine induced spasm of at least one coronary artery in 20 patients (95%) of group A, in 27 patients (96%) of group B, and in only 2 patients (10%) of group C. The low dose of acetylcholine (20 µg) induced coronary spasm more frequently in group A patients (81%) than in group B patients (43%) (P<0.05). ST-segment elevation associated with anginal attacks was significantly (P<0.05) more frequent in group A (71%) than in group B (39%). When acetylcholine was injected separately into the left and right coronary arteries, spasm of both coronary arteries was observed in 7 out of 14 of group A (50%), in 8 out of 22 of group B (36%), and in none of the 20 of group C. We concluded that intracoronary injection of acetylcholine is a sensitive and reliable method for the induction of coronary spasm in patients with vasospastic angina as well as in those with variant angina.