Vasospastic angina in Kawasaki disease

We report vasospastic angina in a young female with a history of Kawasaki disease (KD). She had had KD at the age of 20 months. Selective coronary angiograms at the age of 4 years revealed no coronary aneurysms or stenosis. She remained symptom-free for 29 years, but coronary angiograms at the age of 31 years revealed a localized 50% stenosis of the left anterior descending artery. Aging in addition to endothelial dysfunction of the coronary arterial wall resulting from acute KD vasculitis may underlie the late development of angina. This is the first case which is reported as vasospastic angina after KD. The occurrence of acute coronary syndromes in patients with a history of KD should be investigated carefully from now on. Attention should be paid to coronary endothelial dysfunction after KD in adults.     

Comparison of frequency of coronary spasm in Korean patients with versus without myocardial bridging

The longstanding compression-relaxation effects of myocardial bridging may produce endothelial dysfunction by direct stress on the endothelium. We tested the hypothesis that myocardial bridging induces endothelial dysfunction and subsequently increases the risk of coronary spasm and investigated the symptomatic response to medication in patients with documented myocardial bridging and coronary spasm. In 81 patients with myocardial bridging (44 men; mean age 57.2 years) and 195 control patients without bridging and atherosclerotic lesions confirmed by angiography (97 men; mean age 58.4 years), spasm provocation testing was done by incremental acetylcholine infusion into the left coronary artery. Spasm was documented in 62 of 81 patients with bridging and in 31 of 195 controls (p <0.001). A focal spasm was limited to the bridging segments compared with controls (p <0.001). In conclusion, the results of this study showed that myocardial bridging increased the risk of coronary spasm by endothelial dysfunction in the bridging segment.     

High sensitivity C-reactive protein and endothelial function in Chilean patients with history of Kawasaki disease

Kawasaki disease (KD) produces endothelial inflammation, which may lead to dilatation and aneurysms of coronary and peripheral arteries. Previous studies have suggested that these patients can present endothelial dysfunction that can predispose to coronary vascular events late after KD. The purpose of this study was to determine the cardiovascular risk profile and endothelial function of Chilean children with history of KD. In a prospective case-control study, 11 patients with history of KD (age 10.6 +/- 2.0 years, interval from initial episode 8.1 +/- 3.6 years) and 11 healthy, age-, gender-, and BMI z score-matched controls were evaluated with blood pressure (BP), a fasting lipid profile, high sensitivity C-reactive protein (hsCRP), and flow-mediated dilatation of the brachial artery (FMD). One KD patient (9.1%) had persistent coronary aneurysms. There was a significant difference of mean and log-transformed concentrations of hsCRP between case and control groups (2.3 +/- 3.0 vs 0.5 +/- 0.3 mg/l, P = 0.045). None of the patients with elevated hsCRP had persistent coronary arterial lesions. No difference was found in systolic BP z score between the case and control groups. Diastolic BP z score was significantly higher in cases than controls (P = 0.039). There were no significant differences of FMD between cases and controls. Mean fasting total cholesterol, high-density and low-density lipoprotein, and triglycerides in cases were normal, with no significant difference vs controls. This study shows that Chilean children with history of KD have increased levels of hsCRP, possibly reflecting persistent low-grade inflammation. The prognostic value of hsCRP in KD patients deserves further investigation.     

Endothelial function and coronary spastic angina

Coronary spasm plays an important role in the pathogenesis of not only variant angina but also coronary heart disease in general including acute coronary syndromes, especially in the Japanese population. The vascular endothelium has been reported to be a multifunctional organ whose integrity is essential for normal vascular physiology. Vascular endothelial dysfunction can be a critical factor in the pathogenesis of ischemic heart disease. Acetylcholine and methacholine cause vasodilation by endothelium-derived relaxing factor when the endothelium is functioning normally, whereas they cause vasoconstriction when the endothelium is removed or damaged. Coronary spasm can be induced by a variety of stimuli with different mechanisms of action, including acetylcholine and methacholine. Patients with coronary spasm may have a disturbance in endothelial function as well as local hyperreactivity of the coronary arteries.     

The Glu298Asp polymorphism in the endothelial nitric oxide synthase gene is strongly associated with coronary spasm

BACKGROUND: Coronary spasm seems to be associated with coronary nitric oxide deficiency. OBJECTIVES: We investigated whether the Glu298Asp polymorphism in the endothelial nitric oxide synthase (eNOS) gene is a definite risk factor for coronary spasm and whether diffuse spasm involving normal-looking coronary artery correlates significantly with the Glu298Asp polymorphism, in contrast with focal spasm superimposed on an atherosclerotic plaque. METHODS: A polymerase chain reaction followed by restriction fragment length polymorphism analysis was performed in 118 control participants and in 102 patients with variant angina and a similar degree of atherosclerotic burden. Patients with coronary spasm were divided into diffuse spasm and focal spasm subgroups according to morphological criteria. RESULTS: There was a significantly higher incidence of the Glu298Asp polymorphism in the coronary spasm group than in the control group (21.5% compared with 8.5%, P=0.006). Multiple logistic regression analysis using risk factors and the Glu298Asp polymorphism showed that the most important predictive factor for coronary spasm was the Glu298Asp polymorphism (odds ratio 2.83, 95% confidence interval 1.25-6.41, P=0.009). The diffuse spasm subgroup had a significantly higher frequency of the Glu298Asp polymorphism than the control group (25.9% compared with 8.5%, P=0.002). However, the focal spasm subgroup did not differ from the control group in the frequency of Glu298Asp polymorphism. CONCLUSION: The Glu298Asp polymorphism in the eNOS gene is a definite risk factor for coronary spasm, especially for diffuse coronary spasm. This result supports the notion that diffuse coronary spasm is significantly associated with endothelial dysfunction, in contrast to focal spasm.     

Systemic endothelial function is preserved in men with both active and inactive variant angina pectoris

To test the hypothesis that coronary spasm could be a coronary manifestation of systemic endothelial dysfunction and that the activity of coronary spasm could influence systemic endothelial function, we examined brachial flow-mediated, endothelium-dependent vasodilation and nitroglycerin-induced endothelium-independent vasodilation with high-resolution ultrasound in 11 men with variant angina pectoris (6 active and 5 inactive) without established coronary atherosclerosis. Endothelium-dependent vasodilation in peripheral circulation was preserved in men with active and inactive variant angina pectoris, suggesting that systemic endothelial dysfunction is not involved in either the pathogenesis or the activity of coronary spasm.     

Evaluation by high-resolution ultrasonography of endothelial function in brachial artery after Kawasaki disease and the effects of intravenous administration of vitamin C.

Previous studies in patients with a history of Kawasaki disease (KD) have focused on the endothelial function of the coronary arteries and that of the systemic arteries is not fully understood. Furthermore, the effect of vitamin C on systemic vascular endothelial function after KD has not yet been elucidated. In the present study, 39 patients (age, 7.1 +/- 2.7 years) at 1-10 years after acute KD were compared with 17 matched healthy subjects (7.0 +/- 3.1 years). High-resolution ultrasonography was used to analyze brachial artery responses to reactive hyperemia (with increased flow causing endothelium-dependent dilation) and sublingual nitroglycerin (causing endothelium-independent dilation) after KD, and to investigate whether the acute administration of vitamin C can restore systemic endothelial dysfunction. The percent change in diameter of the brachial artery induced by reactive hyperemia in the patients with a history of KD (6.2 +/- 3.9%) was significantly less than that in the control group (14.1 +/- 6.8%, p < 0.0001). No significant difference could be found in the percent change in diameter induced by sublingual nitroglycerin between the controls (33.2 +/- 13.7%) and the patients (30.6 +/- 9.2%, p = 0.49). There was no significant difference in percent change in diameter of the brachial artery induced by reactive hyperemia between the patients who received gamma globulin (6.0 +/- 4.0) and those who did not (7.9 +/- 3.3, p = 0.33). Intravenous infusion of vitamin C significantly increased the percent change in diameter of the brachial artery induced by reactive hyperemia in 19 patients with history of KD (6.6 +/- 3.5% to 13.0 +/- 5.5%, p < 0.0001). After placebo administration in 20 patients with history of KD there was no significant increase in the percent change in the diameter of the brachial artery induced by reactive hyperemia (6.5 +/- 4.5% to 7.3 +/- 4.9%, p = 0.20). The decreased percent change in the diameter of the brachial artery induced by reactive hyperemia in patients with a history of KD compared with the healthy children indicates that systemic endothelial dysfunction exists after KD. Although it is not influenced by early treatment with high-dose gamma globulin in the acute stage of KD, systemic vascular endothelial function can be restored by acute intravenous administration of vitamin C.     

Severe spontaneous three-vessel coronary artery spasm

Coronary artery spasm is usually defined as a focal constriction of a coronary artery segment, reversible, and causing myocardial ischaemia by coronary blood flow restriction. Sometimes this condition is not focal and can compromise all the coronary tree. This is a very rarely described event. Generally, coronary vasospasm may occur spontaneously or induced, either physically by catheter, physiological manoeuvres (hyperventilation), or by pharmacological agents. It may also occur with or without underlying atheromatous coronary disease. The mechanism of coronary spasm remains unclear but endothelial dysfunction seems to be the main triggering factor in all causes.     

Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment

Coronary (artery) spasm plays an important role in the pathogenesis of ischemic heart disease, including stable angina, unstable angina, myocardial infarction, and sudden death. The prevalence of coronary spasm differs among populations, is higher in Japan and Korea than in the Western countries probably due to genetic as well as environmental factors. Coronary spasm occurs most often from midnight to early morning and is usually not induced by exercise in the daytime. The attacks of coronary spasm are associated with either ST segment elevation or depression, or negative U wave on ECG. Patients with multi-vessel coronary spasm may suffer from lethal arrhythmia, including advanced AV block, ventricular tachycardia or fibrillation, or even sudden death, and they are often resistant to conventional medical therapy including Ca-channel blockers (CCBs). Endothelial nitric oxide (NO) activity is reduced and markers of oxidative stress are elevated in patients with coronary spasm. Thrombogenesis is enhanced and plasma levels of hsCRP and P-selection are elevated in patients with coronary spasm. Thus, patients with coronary spasm have endothelial dysfunction and are suffering from a low-grade chronic inflammation. Polymorphisms of endothelial NO synthase, smoking, and low-grade inflammation are the most important risk factors for coronary spasm. Coronary spasm is a hyper-contraction of coronary smooth muscle triggered by an increase of intracellular Ca2+ in the presence of an increased Ca2+ sensitivity. It has been shown that RhoA/ROCK pathway is involved in Ca2+ sensitivity and that the reduced endothelial NO activity results in increased Ca2+ sensitivity through enhanced RhoA/ROCK pathway. Accordingly, it is possible that in addition to CCBs, RhoA/ROCK pathway blockers may prove to be useful for the treatment of coronary spasm.     

Assessment of coronary function in children with a history of Kawasaki disease using (15)O-water positron emission tomography

BACKGROUND: Coronary abnormalities after Kawasaki disease (KD) may be associated with endothelial dysfunction due to intimal hypertrophy. The purpose of this study was to evaluate myocardial flow reserve (MFR) and endothelial function in regressed aneurysmal regions after KD. Methods and Results- Subjects were 12 patients aged 16.0+/-2.6 years who suffered from KD at 1.7+/-1.5 years and 12 normal subjects aged 26.5+/-3.4 years. MFR and endothelial function were estimated, respectively, by changes in myocardial blood flow (MBF) during ATP infusion and by that during cold pressor test using (15)O-water positron emission tomography. Data from 24 regressed aneurysmal regions were compared with those from the corresponding regions (n=36) in the control group. Although the MBF at rest in the regressed aneurysmal regions was similar to that in controls, the MBF at a hyperemic state induced by ATP infusion in the regressed aneurysmal regions was significantly lower than that in the control regions. Therefore, the MFR in regressed aneurysmal regions was significantly lower than that in controls (3.53+/-0.95 versus 4.60+/-1.14; P<0.05). MBF at rest and during the cold pressor test did not change in the control regions, but it was significantly reduced in regressed aneurysmal regions. The ratio of MBF during the cold pressor test to MBF at rest was significantly lower in regressed aneurysmal regions than in control regions (0.67+/-0.15 versus 1.00+/-0.15; P<0.05). CONCLUSIONS: MFR and endothelial function are often impaired in regressed aneurysmal regions after KD, and tomography enables the noninvasive evaluation of coronary function.     

乙酰胆碱诱发冠状动脉痉挛时的心电图改变及其与血管内皮功能关系

目的探讨血管内皮细胞功能紊乱与乙酰胆碱试验诱发冠状动脉痉挛时心电图ST段变化与缓慢型心律失常的关系。方法选择以静息性胸痛为主要临床表现、接受乙酰胆碱激发试验的患者为研究对象,根据是否发生冠状动脉痉挛分为阳性组和阴性组,冠状动脉痉挛发作时心电图变化分为ST段抬高和非ST段抬高组以及缓慢型心律失常和无缓慢型心律失常组,测定其血浆一氧化氮和内皮素1浓度,比较各组一氧化氮和内皮素1水平以及痉挛血管的分布。结果ST段抬高组一氧化氮水平显著低于阴性组,而内皮素1显著高于阴性组(P<0.01),非ST段抬高组一氧化氮水平亦显著低于阴性组,但高于ST段抬高组(P<0.05),而内皮素1显著高于阴性组但低于ST段抬高组(P<0.05);缓慢型心律失常组和无缓慢型心律失常组的血浆一氧化氮和内皮素1水平以及痉挛血管的分布差异无统计学意义(P>0.05)。结论乙酰胆碱试验诱发的冠状动脉痉挛以及ST段变化与血管内皮细胞功能紊乱有关,乙酰胆碱试验中的缓慢型心律失常与血管内皮细胞功能或痉挛血管的分布无关。     

Dobutamine-induced transmural myocardial ischemia in a patient with mild coronary lesions

A 70-year-old man was admitted for evaluation of retrosternal pain at rest. During infusion of dobutamine (25 μg/kg/min) the patient developed angina, ST-segment elevation in the inferior leads, and echocardiographic hypokinesia in the inferior-basal myocardial wall. Coronary angiography revealed insignificant (20-30%) stenosis of the right coronary artery and a normal remaining tree. This case suggests that dobutamine may induce transmural myocardial ischemia in patients with mild coronary lesions, probably by producing occlusive coronary spasm on a substrate of arterial endothelial dysfunction.     

Variant angina associated with coronary artery endothelial dysfunction and myocardial bridge: a case report and review of the literature

The association of variant angina (VA) and myocardial bridges is a rare finding. We describe a case of VA with recurrent coronary spasm triggered by different stimuli at the site of a myocardial bridge. The interplay of endothelial dysfunction, coronary vasoconstriction and myocardial bridging was detected by intracoronary acetylcholine test and IVUS. We speculate that mechanical stimulation at the bridge site caused endothelial dysfunction and enhanced local susceptibility to vasoconstrictor stimuli. Variant angina should always be suspected in cases of ST-elevation acute coronary syndrome without any significant angiographic coronary stenosis.     

Mechanisms of coronary artery spasm

Coronary artery spasm, the pathogenic mechanism most frequently observed in the syndrome of Prinzmetal's variant angina, appears to be caused by a local, nonspecific smooth muscle hyperreactivity. The relationship between coronary atherosclerosis, endothelial dysfunction, and coronary artery spasm is still speculative. Coronary artery spasm should be distinguished from other forms of coronary vasoconstriction, which may also play a role in angina pectoris. Occlusive coronary spasm causes complete interruption of coronary blood flow and may contribute to thrombus formation. Segmental coronary hyperreactivity may also be a component of acute coronary syndromes.     

Provocation of microvessel spasm by low-dose acetylcholine in patients with suspected coronary artery disease--two case reports

Endothelial dysfunction plays an important role in the pathogenesis of cardiac syndrome X, and intracoronary low-dose acetylcholine infusion is a widely used diagnostic modality for studying the coronary artery endothelial function. The authors herein report 2 cases of cardiac syndrome X with coronary artery endothelial dysfunction and microvessel spasm. The findings of non-invasive testing were positive for ischemia. Coronary angiograms appeared entirely normal in both cases. However, the intracoronary infusion of low-dose (1.5-15 microg/minute) acetylcholine demonstrated an impairment of the coronary blood flow response and consequently provoked an ST-segment elevation in an electrocardiogram. The coronary angiograms showed no spasm in the epicardial arteries. These patients are thus suggested to have cardiac syndrome X with microvessel spasms associated with coronary artery endothelial dysfunction.     

Carotid intima-media thickness in children with Kawasaki disease

Kawasaki disease (KD) is an acute medium vessel vasculitis seen in children. The most significant long-term complication is related to coronary artery abnormalities. Use of intravenous immunoglobulins, however, has led to significant reduction in incidence of coronary aneurysms. What is more alarming is the fact that higher risk of cardiovascular disease is seen in even those children who do not have coronary artery aneurysms during subacute phase. Various factors like abnormal lipid profiles, abnormal vessel wall reactivity and endothelial dysfunction have been implicated for this. Carotid intima-media thickness (cIMT) has been used as a surrogate marker for atherosclerosis. This study was planned to evaluate cIMT in children with KD. Twenty-seven children with diagnosis of KD at least 1 year prior to enrolment were evaluated for cIMT at enrolment and then after 3 months. Fasting lipid profile was done for all patients. Mean cIMT was significantly higher in children with KD compared to controls. In lipid profiles, undesirable HDL-C and triglyceride levels were seen in 2 and 3 children, respectively. Undesirable and borderline LDL-C levels were seen in 1 and 2 patients, respectively. Undesirable and borderline total cholesterol levels were seen in 1 and 3 patients, respectively. Higher cIMTs were seen in our cohort of KD patients. Proatherogenic abnormalities in lipid profile were seen in a few patients. Both abnormalities may predict a higher risk of atherosclerosis in future. The results of this study need to be replicated on a larger study sample and over longer follow-up periods.     

Usefulness of the response of flow velocity in the left anterior descending coronary artery to the cold pressor test for evaluating endothelium-dependent vascular relaxation in the coronary microvasculature by transesophageal echocardiography in subjects with angiographically normal coronary arteries

Measurement of flow velocity in the left anterior descending coronary artery by transesophageal echocardiography in subjects without risk factors for coronary artery disease (group 1) and in subjects with normal coronary arteries but conditions associated with endothelial dysfunction (group 2) revealed that there was a significantly impaired coronary flow velocity response to the cold pressor test in group 2 subjects. Thus, transesophageal echocardiography provides a minimally invasive tool for the functional assessment of endothelium and can be valuable in evaluating endothelial dysfunction and recovery in a variety of disease states.     

Antioxidant is a useful supportive agent for the treatment of coronary vasospasm with endothelial dysfunction in pig

OBJECTIVES: Recently, many antioxidants have been tested in cardiovascular disease. The effect of antioxidants on alleviation of coronary vasospasm, however, remains unclear. We investigated whether chronic administration of ascorbic acid and glutathione prevents coronary vasospasm in pigs. MATERIALS AND METHODS: Balloon-induced endothelial injury in the left anterior descending coronary artery was performed every 2 weeks until 6 weeks (0, 2, 4, 6 weeks). Ten micrograms per kilogram serotonin-induced vasoconstriction was assessed before each endothelial injury and at eighth week by coronary angiography. RESULTS: In endothelial injury without antioxidant group (ED group, n=12), serotonin-induced left anterior descending coronary artery vasoconstriction was augmented from 7+/-4% (0 week) to 88+/-8% (8th week, P<0.01) with electrocardiogram-ST elevation, and an increase of cyclooxygenase-2 expression and a decrease of endothelial nitric oxide synthase expression was observed at the spasm portion removed from the endothelial denuded site. In the endothelial injury group with oral administration of ascorbic acid 3 g/day and glutathione 1 g/day after the first endothelial injury (ASC+GSH group, n=12), serotonin-induced vasoconstriction was suppressed (8th week, 60+/-6%, P<0.01 vs. ED group) and endothelial nitric oxide synthase expression was fairly well maintained. Intimal thickening was observed at the left anterior descending artery spasm portion in the endothelial injury without antioxidant group but not at the corresponding portion in the ASC+GSH group. CONCLUSION: Antioxidant therapy was partially effective to prevent coronary vasospasm, whereas intimal thickening after endothelial injury was nearly restored. From these results, chronic antioxidant therapy may well be a useful supportive therapy for the treatment of coronary vasospasm, although it has limited availability despite amelioration of endothelial dysfunction.     

Lipoprotein(a) is a risk factor for occurrence of acute myocardial infarction in patients with coronary vasospasm

OBJECTIVES: The purpose of this study is to determine whether lipoprotein(a) (Lp[a]) is an independent risk factor for coronary spasm and occurrence of acute myocardial infarction (AMI) in patients with coronary spasm. BACKGROUND: Although elevated serum Lp(a) levels are known to be associated with coronary atherosclerosis and AMI, the association between the elevated level of this lipoprotein and coronary spasm remains to be elucidated. METHODS: Serum Lp(a) levels were measured using a latex immunoassay in 77 patients with coronary spasm but without a significant (>75%) fixed coronary stenosis, including 16 with prior myocardial infarction (MI), in 177 patients with a fixed stenosis but without rest angina, including 114 with prior MI and in 81 control subjects without coronary artery disease. RESULTS: The serum Lp(a) level in patients with coronary spasm (median; 17 mg/dl) was higher (p < 0.01) than in control subjects (12 mg/dl) but lower (p < 0.01) than in patients with a fixed stenosis (23 mg/dl). The incidence of subjects with higher (>25 mg/dl) serum Lp(a) levels was higher in patients with a fixed stenosis (46%, p < 0.01) but not in patients with coronary spasm (27%), compared with control subjects (21%). Among the patients with coronary spasm, the incidence of higher Lp(a) levels was higher in patients with than in those without a history of prior MI (56% vs. 21%, p < 0.05). The patients with higher Lp(a) levels had a higher incidence of prior MI than those without (41% vs. 13%, p < 0.05). The multivariate analysis confirmed that higher serum Lp(a) level is an independent determinant for prior MI in these patients (odds ratio, 4.19; 95%, confidence interval, 1.03 to 17.00). CONCLUSIONS: Elevated serum level of Lp(a) was found to be associated with a history of prior MI in patients with coronary spasm, suggesting that Lp(a) may play an important role in the genesis of thrombotic coronary occlusion and the occurrence of AMI subsequent to coronary spasm.     

Vitamin C attenuates abnormal vasomotor reactivity in spasm coronary arteries in patients with coronary spastic angina

Objectives. This study sought to examine effect of vitamin C, an antioxidant, on the abnormal vasomotor reactivity in spasm coronary arteries.Background. Oxygen free radicals generated in the arterial walls have been shown to cause endothelial vasomotor dysfunction.Methods. Responses of the epicardial arterial diameters of the left coronary arteries to the intracoronary infusion of acetylcholine (ACh) (10 and 50 μg/min) were measured by quantitative coronary angiography before and during combined intracoronary infusion of vitamin C (10 mg/min) or saline as a placebo in 32 patients with coronary spastic angina and in 34 control subjects.Results. Vitamin C infusion suppressed the constrictor response of the epicardial diameter to ACh in spasm coronary arteries but had no significant effect in the control coronary arteries (percent change in distal diameter in response to 10 μg/min of ACh [constriction (−), dilation (+), mean ± SEM] before vitamin C: −8.2 ± 2.9% in spasm arteries, +8.4 ± 2.9%1 in control arteries; during vitamin C: +0.2 ± 3.8%1 in spasm arteries, +7.2 ± 1.3%1 in control arteries [1p < 0.01 vs. spasm arteries before vitamin C]). The coronary sinus–arterial difference in plasma thiobarbituric acid reactive substances during ACh infusion, an indicator of lipid peroxidation in coronary circulation, was higher in patients with coronary spastic angina than in control subjects (p < 0.01) but was suppressed in patients with coronary spastic angina to comparable levels in control subjects by combined infusion of vitamin C. Saline infusion had no effect.Conclusions. The results indicate that vitamin C attenuates vasomotor dysfunction in epicardial coronary arteries in patients with coronary spastic angina. Oxygen free radicals may at least in part play a role in the abnormal coronary vasomotor reactivity in response to ACh in spasm coronary arteries.