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)     

Disease activities and serum C-reactive protein levels in patients with vasospastic angina pectoris

OBJECTIVES. To evaluate the relationship between serum C-reactive protein (CRP) levels and disease activities of vasospastic angina pectoris. METHODS. We reviewed 284 consecutive patients who underwent the coronary artery vasospasm provocation test with intracoronary administration of acetylcholine. No patient had significant organic stenosis in the coronary artery on control angiography. No patient was given nitrates, calcium channel blockers, aspirin or statins before the provocation test. Serum CRP levels were measured on the day before the provocation test. RESULTS. Significant transient coronary artery stenoses associated with chest symptoms and ST-T changes in electrocardiogram was found in 132 patients (positive group), but the remaining 152 showed no spasm (negative group). Serum CRP levels were significantly higher in the positive group than in the negative group (0.29 +/- 0.12 vs 0.08 +/- 0.06mg/dl, p < 0.01). Furthermore, high frequency of angina pectoris ( > or = 3 times/week), low dose of acetylcholine required to induce vasospasm, provocation of total occlusion and provocation of multivessel spasm were associated with significantly higher serum CRP levels in the positive group. Multivariate logistic regression analysis showed low dose of acetylcholine required to induce vasospasm as the strongest predictor of elevated levels of serum CRP (p < 0.001, odds ratio 4.52, 95% confidence interval 2.00-10.44). CONCLUSIONS. Serum CRP levels were related to the inductivity of coronary artery spasm in patients clinically suspected of having vasospastic angina pectoris. Inflammation may be important in the disease activity through the endothelial dysfunction of coronary artery trees.     

Effect of cilostazol on vasomotor reactivity in patients with vasospastic angina pectoris

We examined the effects of cilostazol on impaired coronary arterial responses in patients with vasospastic angina (VSA). Thirty patients who were diagnosed with VSA based on an acetylcholine provocation test and 10 subjects with normal coronary arteries were enrolled. The patients were divided into the following 3 groups: no antiplatelet agent treatment group, aspirin treatment, or cilostazol treatment groups. Coronary flow reserve (CFR), coronary flow volume at maximum hyperemia, and epicardial coronary artery diameter after administration of N(G)-monomethyl-L-arginine (L-NMMA) were examined using a Doppler flow wire before and 6 months after the start of this study. CFR, coronary flow volume at maximum hyperemia, and diameter changes by L-NMMA were significantly increased in the cilostazol treatment group compared with the other 2 groups. In conclusion, cilostazol increased CFR and flow-dependent coronary dilation; these changes were attributable to nitric oxide. Cilostazol may improve coronary vascular endothelial dysfunction and coronary hemodynamics in patients with VSA.     

Decreased plasma extracellular superoxide dismutase level in patients with vasospastic angina

OBJECTIVE: Extracellular superoxide dismutase (EC-SOD) is the major extracellular scavenger of superoxides, and one of the main regulators of nitric oxide bioactivity in vessel walls. Here, we examined whether plasma EC-SOD level was associated with vasospastic angina (VSA), and if it was a risk factor for VSA. METHODS AND RESULTS: We assigned 105 patients with normal or mildly stenotic coronary arteries into either a VSA (n=58) or chest pain syndrome (CPS) (n=47) groups. Plasma EC-SOD and other biochemical variables were measured, and major coronary risk factors were assessed. Results showed that apart from smoking status there were no significant differences in patient characteristics and biochemical variables between the two groups. In the VSA group, prevalence of smoking was significantly higher (53% versus 26%, p=0.0055), and plasma EC-SOD level was significantly lower (68.9+/-18.5 ng/ml versus 83.8+/-25.9 ng/ml; p=0.0009). Not only smoking (OR 2.742, 95% CI 1.032-7.287, p=0.0431) but also plasma EC-SOD (OR 0.971, 95% CI 0.949-0.993, p=0.0102) was an independent risk factor for VSA. CONCLUSIONS: In patients with VSA, plasma EC-SOD level was substantially reduced. Furthermore, plasma EC-SOD level followed by cigarette smoking was the most predictive risk factor for coronary spasms.     

血浆vaspin浓度与不稳定型心绞痛的相关性研究

目的:腹腔脂肪型丝氨酸蛋白酶抑制剂(vaspin)是新发现的脂肪因子,对代谢性疾病具有预防作用.该研究旨在探讨血浆vaspin浓度与冠心病及不稳定型心绞痛的关系.方法:经血管造影诊断明确的冠心病患者88例(其中稳定型心绞痛47例,不稳定型心绞痛41例),同期入院的103例无心脏疾病的患者作为对照.测量患者血浆中vaspin的浓度,记录临床一般情况及血脂、血糖、高敏C反应蛋白等指标.并根据冠状动脉的病变支数来评定冠心病严重程度.结果:不稳定型心绞痛的血浆vaspin浓度(0.43±0.38)μg/L较稳定型心绞痛(0.91±0.95)μg/L显著降低(P<0.01).在冠心病患者中血管病变支数与血浆vaspin浓度负相关(r=-0.350,P<0.01).ROC曲线分析血浆vaspin对冠心病有鉴别价值(AUC=0.684,P<0.001),对不稳定型心绞痛也有鉴别价值(AUC=0.640,P=0.024).结论:不稳定型心绞痛患者具有较低的血浆vaspin浓度;低血浆vaspin浓度与冠心病严重程度呈相关.     

Clandestine ischemia in patients with vasospastic angina

BACKGROUND: Coronary vasospasms generally occur at rest, but can also be triggered by physical exercise. Anginal pain and ST-segment elevation may be seen during exercise-stress tests. ST-segment depression, due to nonocclusive vasospasms, has also been found to occur. When the result of a test is positive, scintigraphy usually reveals perfusion defects. True silent or clandestine ischemia (normal result of exercise test with perfusion defects) in these patients is very uncommon. OBJECTIVE: To stress the need for suspecting occurrence of coronary vasospasms in order to perform a proper diagnosis. METHODS: Eight patients with angina were selected for this study. They had negative results of exercise tests with perfusion defects detected by thallium-201 tomography, normal coronary arteries and vasospasms. Maximal exercise-stress tests with thallium-201 tomography were performed. Sizes of perfusion defects were quantified by examining polar maps. Coronary angiography and then an intracoronary ergonovine test were performed for each patient. RESULTS: Significant defects were seen in territory of the right coronary artery, the left anterior descending artery, or both. Lung:heart ratio was normal in every case. The coronary arteries were normal and vasospasms were elicited with ergonovine in all the patients. Correspondence between the location of perfusion defects and angiographic spasms was generally observed. After treatment with calcium antagonists and nitrates all of them improved and defects detected by thallium tomography were no longer found when tests were repeated. CONCLUSIONS: Some patients with vasospastic angina may have normal results of exercise-stress tests and reversible perfusion defects detectable by scintigraphy. This finding must lead one to perform coronary angiography without administration of nitroglycerine beforehand and an ergonovine test if the coronary arteries are normal.     

Autonomic hyperactivity in patients with vasospastic angina

To evaluate the role of the autonomic nervous system in vasospastic angina, plasma catecholamine and cyclic nucleotide levels were measured and the pilocarpine test was performed in 19 patients with vasospastic angina, 14 patients with nonvasospastic angina and 7 control subjects who were hospitalized patients without heart disease. Diurnal and nocturnal levels of plasma catecholamines were significantly higher in patients with angina pectoris, especially in patients with vasospastic angina, as compared with those of controls. In addition, an increase in plasma catecholamines preceded the onset of spontaneous and pilocarpine induced anginal attacks associated with significant increases in plasma catecholamines in patients with vasospastic angina. On the other hand, while nifedipine significantly suppressed both spontaneous and pilocarpine induced anginal attacks, the increase in plasma catecholamines remained. These results indicate that increased activity and responsiveness of the sympathetic nervous system may possibly contribute to the development of vasospastic angina on the basis of parasympathetic hyperactivity.     

Selective thromboxane A2 synthetase inhibition in vasospastic angina pectoris

To investigate whether thromboxane A2 is responsible for the initiation of vasospastic angina pectoris, thromboxane B2 levels were measured in the great cardiac vein and the arterial blood of 12 patients with clinically and angiographically proved vasospastic angina and therapeutic trials were performed with selective thromboxane A2 synthetase inhibitor OKY-046, an imidazole derivative. During ergonovine-provoked (11 cases) and spontaneous (1 case) anginal attacks, great cardiac vein thromboxane B2 increased from 121 +/- 27 to 430 +/- 382 pg/ml (p less than 0.05, n = 12), arterial thromboxane B2 increased from 93 +/- 18 to 122 +/- 33 pg/ml (NS, n = 12) and thromboxane B2 production increased from 3.18 +/- 1.88 to 25.16 +/- 22.32 ng/min (p less than 0.05, n = 6). Subsequently, OKY-046, 400 mg/day orally, was administered to 7 of the 12 patients, while a continuous electrocardiogram was recorded on a dual channel Holter monitor during a 3 day placebo period and the 3 day OKY-046 regimen. Although peripheral plasma thromboxane B2 levels decreased significantly from 98 +/- 15 to 12 +/- 8 and 28 +/- 10 pg/ml (1 and 6 hours after ingestion, respectively) (p less than 0.05 for both), 6-keto-prostaglandin F1 alpha production in serum increased significantly from 0.48 +/- 0.22 to 2.3 +/- 0.72 (1 hour) and 1.8 +/- 0.46 ng/ml (6 hours) (p less than 0.05 for both) during OKY-046 administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

The incidence of stent-edge spasm after stent implantation in patients with or without vasospastic angina pectoris

Although several investigations have reported that stent implantation is an option for the treatment of vasospastic angina (VSA) that is resistant to medical treatment, we are concerned about the occurrence of new stent-edge spasms after stenting. The purpose of this study was to determine the incidence of new stent-edge spasms after stenting. Twenty-seven patients with VSA and 23 patients without VSA were enrolled. About 6 months after stent implantaion, a spasm provocation test was performed by intracoronary infusion of acetylcholine or ergonovine in 26 patients with VSA and all patients without VSA, and the induced stent-edge spasms were classified as either moderate (stent-edge spasm > 75% and < 95% reduction in coronary artery diameter) or severe (stent-edge spasm > 95% reduction in coronary artery diameter). In one patient with VSA, stent-edge spasm and acute thrombosis occurred several hours after stent implantation. The remaining 26 patients with VSA had no complications during or after stent implantation. However, during the chronic phase, severe stent-edge spasm was provoked in 5 patients with VSA (19.2%) and in 2 patients without VSA (8.7%). Moderate stent-edge spasm was provoked in 5 patients with VSA (19.2%) and 5 patients without VSA (21.7%). The results suggest new onset stent-edge spasm in patients either with or without VSA should not be neglected.     

Plasma adrenomedullin levels in the coronary circulation in vasospastic angina pectoris

This study evaluated the role of adrenomedullin in patients with vasospastic angina pectoris. Adrenomedullin may be involved in regulating a basal tone of the coronary artery in these patients.     

Coexistence of familial hypertrophic cardiomyopathy and vasospastic angina pectoris in two brothers

Two brothers had familial hypertrophic cardiomyopathy and vasospastic angina pectoris concurrently. Their family history showed that one of their sisters had hypertrophic cardiomyopathy and another brother died suddenly at age 52. The clinical diagnosis of hypertrophic cardiomyopathy was confirmed by an echocardiogram and left ventriculography. They had typical chest pain at rest, and a significant vasospasm of coronary arteries with chest pain and obvious ST-T changes in the electrocardiograms was provoked by intracoronary injection of acetylcholine in both patients. The administration of a calcium antagonist and nitrate was effective for ameliorating chest pain with no cardiovascular events during the follow up period of more than 3 years. Although underlying pathophysiologic abnormalities of familial hypertrophic cardiomyopathy and vasospastic angina pectoris are considered to be transmitted genetically, the genetic backgrounds of these cases remain to be clarified.     

Examination of the microcirculation damage in smokers versus nonsmokers with vasospastic angina pectoris

Endothelial dysfunction is considered one of the mechanisms underlying vasospastic angina pectoris (VSA). It is also known that smokers have abnormalities in endothelial dysfunction. Although smoking is a major risk factor for coronary artery disease, microvascular abnormalities have not been well shown. We investigated clinical characteristics and coronary reactivity with adenosine triphosphate in smokers with VSA. Twenty-two consecutive patients whose coronary spasm was documented in the left anterior descending (LAD) coronary artery with acetylcholine were enrolled. Coronary blood flow responses were also evaluated by intracoronary Doppler flow velocity recordings in the LAD coronary artery. Average peak velocities (APVs) were measured at baseline and intracoronary administration of adenosine triphosphate (50 microg) in 11 smokers (age 60+/-9 years; 8 men) and 11 nonsmokers (age 61+/-10 years, 5 men). Coronary flow reserve (CFR) was calculated by the ratio of baseline to hyperemic APV. Multivessel spasm was demonstrated in 6 smokers and only 2 nonsmokers (p<0.05). APV at rest in smokers (13.4+/-3.0 cm/s) was similar to that in nonsmokers (13.5+/-2.9 cm/s). However, CFR in smokers (2.6+/-0.7) was significantly lower than in nonsmokers (3.4+/-0.8; p<0.05). In conclusion, multivessel spasm was demonstrated in smokers in clinical settings, and microcirculation damage is prominent in smokers with VSA.     

Location of focal vasospasm provoked by ergonovine maleate within coronary arteries in patients with vasospastic angina pectoris

This study examined whether coronary focal vasospasm occurs in a nonuniform distribution within the coronary tree and whether a longitudinal plaque distribution pattern is present in patients with vasospastic angina using 3-dimensional intravascular ultrasound analysis. Of 121 patients with clinically suspected angina without fixed stenosis in the coronary arteries, vasospasm was provoked in 82 patients with 92 lesions (42 focal, 50 diffuse) by intravenous ergonovine maleate injection. Most focal vasospasms occurred in the proximal third of the coronary arteries (proximal 28, mid 8, distal 6, p <0.01), corresponding to the historical high-risk zones for acute coronary occlusion. More plaque burden also existed in the proximal third of the coronary arteries in patients with focal vasospasm.     

The nature of ventricular arrhythmias during ergonovine-induced vasospastic angina pectoris

The peak incidence of ventricular fibrillation in acute myocardial infarction usually occurs during the first hours after the onset. Electrophysiological changes immediately after the onset have been studied in animal models, but are still incompletely understood in humans. For clarification of the characteristic features of ventricular arrhythmias during acute myocardial ischemia, ventricular arrhythmias were studied in 81 patients with vasospastic angina pectoris induced by ergonovine. Ventricular arrhythmias occurred in 45 of these patients, including ventricular tachycardia in 15, and ventricular fibrillation requiring repeated DC defibrillation in two patients. Most ventricular extrasystoles occurred before the ST segment reached maximum elevation, while reperfusion arrhythmias were less common. In many patients the coupling intervals varied, and the configuration was multiform. It is concluded that ventricular arrhythmias occurring during ergonovine-induced coronary spasm show different characteristics from those occurring during chronic ischemia. As the arrhythmias in this study seem, in some ways, to resemble arrhythmias occurring at the onset of myocardial infarction, the results might provide useful information on ventricular arrhythmias in myocardial ischemia in humans.     

Effect of dipyridamole on QT dispersion in vasospastic angina pectoris.

Life-threatening ventricular arrhythmias have frequently been documented in patients with vasospastic angina. Moreover, the incidence of ventricular arrhythmias has been closely associated with increased QT dispersion. However, the underlying mechanism responsible for this arrhythmogenesis has not been clarified. The effects of dipyridamole and subsequent aminophylline administration on QT dispersion were examined in 35 patients with vasospastic angina and 30 patients with atypical chest pain. None of the patients enrolled in this study revealed any significant stenosis in coronary angiography. QT dispersion during dipyridamole followed by aminophylline administration was compared between the 2 groups. The baseline QT dispersion was similar in both groups (vasospastic angina: 27 +/- 8 ms; atypical chest pain: 28 +/- 7 ms). No significant changes in QT dispersion were observed in patients with atypical chest pain by dipyridamole (23 +/- 9 ms) and subsequent aminophylline administration (23 +/- 5 ms). However, the QT dispersion in patients with vasospastic angina increased significantly by dipyridamole administration (53 +/- 14 ms, p <0.0001) and returned to baseline by subsequent aminophylline administration (26 +/- 10 ms). Our data suggest that the disparity of ventricular repolarization in vasospastic angina may be mediated by increased endogenous adenosine.     

Clinical significance of plasma concentration of macrophage colony-stimulating factor in patients with vasospastic angina

OBJECTIVES: The concentration of macrophage colony-stimulating factor (M-CSF), an inflammatory cytokine, increases with the progression of coronary lesions, but no clinical investigations have evaluated the relationship to coronary vascular tone. The present study investigated the relationship between M-CSF and vasoreactivity of the coronary arteries in patients with vasospastic angina. METHODS: Vasospastic angina (VSA) was characterized by transient chest pain and ischemic ST segment changes at rest, or by a positive result in spasm provocation testing with acetylcholine. The subjects were 24 patients with stable VSA(inactive VSA group) treated on an outpatient basis, 31 VSA patients hospitalized with unstable angina (active VSA group), and 13 healthy subjects(control group). The sensitivity of determination of plasma M-CSF in blood was 40 pg/ml. The levels of this factor in each group were compared. Based on the findings of the acetylcholine vasospasm-induction test, patients were divided into those with single-vessel vasospasm and those with multivessel vasospasm, and, according to the dose of acetylcholine required to induce spasm, into high- and low-dose groups. Plasma M-CSF levels in each group were compared. RESULTS: Mean plasma M-CSF was 598 +/- 180 pg/ml in the inactive VSA group, 775 +/- 194 pg/ml in the active VSA group, and 632 +/- 103 pg/ml in the control group. The mean plasma M-CSF level in the active VSA group was significantly higher than that in the inactive VSA group(p < 0.01). Mean plasma M-CSF level in the single-vessel and multivessel vasospasm groups was highest for active VSA patients with multivessel vasospasm (872 +/- 173 pg/ml). The relationship with the acetylcholine induction dose clarified that plasma M-CSF levels were highest in patients with active VSA in the acetylcholine low-dose group (825 +/- 177 pg/ml, p < 0.001). CONCLUSIONS: Plasma M-CSF concentration reflects the vasoreactivity of coronary spasm in the VSA group, and may be an indicator of the severity of coronary endothelial dysfunction.     

Magnesium content of erythrocytes in patients with vasospastic angina

The possibility that a magnesium deficiency might be the underlying cause of vasospastic angina (VA) and the efficacy of Mg administration in its treatment were studied. Subjects included 15 patients with VA and 18 healthy subjects as the control group. The erythrocyte Mg content was measured by atomic absorption, and serum Mg was measured by conventional chemical assay. The efficacy of Mg administration was studied in seven patients with VA. The results were as follows: a) The mean erythrocyte Mg content was less in the group with frequent episodes of angina (1.59 +/- 0.11 mg/dl) than in the group without angina (2.11 +/- 0.38 mg/dl, p less than 0.01) and in the control group (2.22 +/- 0.29 mg/dl, p less than 0.01). There was no significant difference between the control group and patients of each group with respect to serum Mg. b) Coronary arterial spasm was induced by ergonovine maleate in seven patients and was completely inhibited by the administration of Mg sulfate (40-80 mEq, hourly) in six of these patients; in the remaining patient neither obvious ST change nor chest pain occurred. Thus, it was concluded that the measurement of erythrocyte Mg content is useful to determine how easily vasospasm might occur in VA and that the administration of Mg might be developed as a new therapy for spasm associated with a low erythrocyte Mg content.