Structural and Functional Coronary Artery Abnormalities in Patients With Vasospastic Angina Pectoris.

Coronary spasm is involved in many clinical scenarios, such as stable angina, acute coronary syndrome, sudden cardiac death, non-ischemic cardiomyopathy, arrhythmia and syncope. In recent years, imaging tools such as computerized tomographic angiography, intravascular ultrasound or optical coherence tomography have been applied to study the coronary pathology in patients with vasospastic angina. Patients with vasospastic angina represent a heterogeneous cohort of patients with regard to the extent of concomitant coronary atherosclerosis. They share the common pathophysiological phenomenon of vascular smooth muscle hyperreactivity leading to spasm caused by various factors that may also overlap. Focal coronary spasm is related to epicardial atherosclerosis and in the presence of obstructive coronary artery disease it may be useful to treat the lesion to prevent further spasm. The aim of this article is to review structural and functional coronary artery abnormalities in patients with vasospastic angina.

Coronary artery spasm: review and update.

Coronary artery spasm (CAS), an intense vasoconstriction of coronary arteries that causes total or subtotal vessel occlusion, plays an important role in myocardial ischemic syndromes including stable and unstable angina, acute myocardial infarction, and sudden cardiac death. Coronary angiography and provocative testing usually is required to establish a definitive diagnosis. While the mechanisms underlying the development of CAS are still poorly understood, CAS appears to be a multifactorial disease but is not associated with the traditional risk factors for coronary artery disease. The diagnosis of CAS has important therapeutic implications, as calcium antagonists, not ß-blockers, are the cornerstone of medical treatment. The prognosis is generally considered benign; however, recurrent episodes of angina are frequently observed. We provide a review of the literature and summarize the current state of knowledge regarding the pathogenesis of CAS.

Morphological findings in typical variant angina presenting as acute coronary syndrome using optical coherence tomography.

BACKGROUND: Coronary vasospasm causes variant angina, as well as acute myocardial infarction, ventricular tachycardia, and sudden cardiac death. We evaluated morphological changes due to vasospastic lesions, which may cause acute coronary syndrome (ACS), using a novel technique called optical coherence tomography (OCT). METHODS: Twenty patients (40-83 years old, 19 males) with vasospasm-induced ACS who visited the emergency room because of continuous chest pain and displayed transient ST segment elevation in their electrocardiogram were enrolled in the study. None of these patients had significant coronary artery disease and all had positive results in the provocation test. OCT examinations were performed for evaluation of vasospastic lesions. RESULTS: Intraluminal thrombi and intimal erosion were found in 6 (33.3%) and 2 patients (10%), respectively. High-sensitivity C-reactive protein levels were significantly higher in patients with microthrombi (2.66 ± 3.33 mg/L) compared with those in patients without microthrombi (0.49 ± 0.30 mg/L; P = 0.022). Serum cardiac troponin-I levels were not significantly different between patients with or without microthrombi (2.37 ± 5.31 ng/mL vs. 1.45 ± 4.68 ng/mL; P = 0.704). Other parameters, including creatinine kinase-myocardial band isoenzyme, total cholesterol, pain duration, residual stenosis, lesion length, and coronary risk factors, were not significantly different between the 2 groups. CONCLUSION: In patients with vasospasm-induced ACS, microthrombi with or without intimal erosion are major abnormal morphologic findings of OCT examinations. However, further large-scale studies are required for validation.

Eosinophilic coronary periarteritis (vasospastic angina and sudden death), a new type of coronary arteritis: report of seven autopsy cases and a review of the literature.

A previously reported autopsy case of eosinophilic coronary periarteritis (ECPA, or isolated eosinophilic coronary periarteritis, IECPA), and an additional six autopsy cases of ECPA are reported. In addition, another four autopsy cases of ECPA reported in the literature are discussed. Fifteen cases of ECPA with spontaneous coronary dissection (hematoma), which appeared in the literature from 1987 to 2011, are also reviewed. The characteristic clinico-pathological findings of ECPA are: (a) variant angina (Prinzmetal's vasospastic angina) appeared mainly from evening to early in the morning; (b) allergy or allergic history could be identified in only three of a total of 11 cases; (c) sudden unexpected death (sudden cardiac death) usually occurred early in the morning; (d) eosinophilic inflammation limited to the adventitia and periadventitial soft issue appeared in the epicardial large coronary arteries, chiefly in the left coronary anterior descending artery; (e) fibrinoid necrosis or granuloma could not be found in or around the inflammatory area; (f) no type of vasculitis could be found in any other tissues or organs (i.e., localized and non-systemic periarteritis); (g) ECPA was frequently accompanied by spontaneous coronary arterial dissection (SCAD) in the affected wall; and (h) ECPA without SCAD appeared mainly in men (male/female ratio was 8:3), while EPCA with SCAD appeared in almost all female cases (male/female ratio was 1:14). Although the etiology and pathogenesis are still unknown, we believe that ECPA (with or without SCAD) might be a distinct new type of coronary arteritis.

Prinzmetal's angina in a patient with angiosarcoma of the right cardiac chambers.

Variant (Prinzmetal's) angina pectoris is a clinical syndrome characterized by the presence of angina at rest, coinciding with a transient ST-segment elevation. This syndrome is often caused by vasospasm, either on a normal coronary artery or at the site of a coronary atherosclerotic stenosis. We describe a classic case of variant angina associated with an angiosarcoma of the right heart chambers.

Variant angina and coronary artery spasm: the clinical spectrum, pathophysiology, and management.

Variant angina is a form of angina pectoris that shows transient ST-segment elevation on electrocardiogram during an attack of chest pain. Ischemic episodes of variant angina show circadian variation and often occur at rest from midnight to early morning. Ischemic episodes also occur during mild exercise in the early morning. However, they are not usually induced by strenuous exercise in the afternoon. Other important clinical features of variant angina include the high frequency of asymptomatic ischemic episodes and the syncope that sometimes occur during the ischemic episodes. Syncope is due to severe arrhythmias, including ventricular tachycardia, ventricular fibrillation, and high-degree atrioventricular block. Coronary artery spasm is the mechanism of ischemic episodes in variant angina. The incidence of coronary artery spasm shows a racial difference and is higher in Japanese than in Caucasians. Coronary arteriograms are normal or near-normal in most Japanese patients with variant angina. Deficient basal release of nitric oxide (NO) due to endothelial dysfunction, and enhanced vascular smooth muscle contractility with the involvement of the Rho/Rho-kinase pathway are reported to play important roles in the pathogenesis of coronary artery spasm. Other precipitating factors of coronary artery spasm include imbalance in autonomic nervous activity, increased oxidative stress, chronic low-grade inflammation, magnesium deficiency, and genetic susceptibility. The genetic risk factors associated with coronary artery spasm include gene polymorphisms of endothelial NO synthase (NOS), paraoxonase, and other genes. Calcium channel blockers are extremely effective in preventing coronary spasm. The long-acting nitrate, nicorandil, and Rho-kinase inhibitor are also useful for inhibiting coronary artery spasm. Because variant angina can lead to acute myocardial infarction, fatal arrhythmias, and sudden death, early treatment is important. The prognosis of patients with variant angina is favorable, if early complications can be overcome. However, because coronary artery spasm cannot be suppressed in some patients, even with multiple medications, medications to suppress intractable coronary artery spasm must be developed.

Gender difference of clinical characteristics in Chinese patients with spontaneous variant angina.

BACKGROUND: Spontaneous attack of variant angina (VA) is a unique component of coronary artery disease (CAD), and associated with severe cardiac events. However, no data are available regarding sex differences in Chinese patients with spontaneous attacks of VA. Accordingly, the present retrospective study was initiated to evaluate the Clinical characteristics of Chinese female patients with spontaneous attacks of VA. METHODS: From January 2003 to January 2008, a total of 209 patients were diagnosed to have had a spontaneous attack of VA at Fu Wai Hospital. Of them, 27 were female, and their clinical findings were collected and compared with male patients for aspects of risk factors, clinical features and angiographical findings. RESULTS: Spontaneous attacks of VA was relatively uncommon in female (12.9%) compared with male patients. The female patients were less likely to have a history of smoking (14.8% vs. 79.7%, P < 0.001), more likely to have a family history of CAD (33.3% vs. 11.0%, P < 0.01), and to have had a greater incidence of ventricular fibrillation during attack (11.1% vs. 2.2%, P < 0.05). There were no significant differences in other characteristics between the two groups. CONCLUSION: Chinese female patients who experienced a spontaneous attack of VA had the characteristics of less smoking history, more family history of CAD and higher occurrence of ventricular fibrillation than male patients.

Plaque components at coronary sites with focal spasm in patients with variant angina: virtual histology-intravascular ultrasound analysis.

BACKGROUND: We compared the plaque components at coronary sites with focal spasm after ergonovine provocation test in 30 variant angina (VA) patients with those at culprit coronary sites in 32 unstable angina (UA) patients using virtual histology-intravascular ultrasound (VH-IVUS). METHODS: VH-IVUS classified and color-coded tissue into four major components: fibrotic; fibro-fatty; dense calcium (DC); and necrotic core (NC). Thin-cap fibroatheroma (TCFA) was defined as a NC≥10% of plaque area in at least 3 consecutive frames without overlying fibrous tissue in the presence of ≥40% plaque burden. RESULTS: The lesion site plaque burden was significantly smaller (44.5±10.8% vs. 70.5±13.1%, p<0.001), the plaque volume was significantly smaller (135±118 mm³ vs. 223±160 mm³, p=0.020), the remodeling index was significantly lower (0.90±0.14 vs. 0.97±0.23, p=0.023), and more plaque was hypoechoic with less calcium (87% vs. 56% and 0% vs. 19%, respectively, p=0.033) in VA patients compared with UA patients. The % NC and DC areas were significantly smaller at the minimum lumen site within spasm/culprit lesion (12.9±12.9% vs. 22.3±11.7%, p=0.004, and 6.5±8.0% vs. 12.8±10.8%, p=0.011, respectively), and the % NC and DC volumes were significantly smaller in VA patients compared with UA patients (12.2±10.3% vs. 17.7±8.1%, p=0.025, and 6.4±6.0% vs. 11.8±8.5%, p=0.007, respectively). The TCFA within lesion segments was less frequently observed in VA patients compared with UA patients (13% vs. 53%, p=0.001). CONCLUSIONS: VA patients have less plaque, more negative remodeling behavior, more hypoechoic plaque with less calcification, and less NC- and DC-containing lesions and less TCFA lesions compared with UA patients.

Endothelial dysfunction, increased carotid artery intima-media thickness and pulse wave velocity, and increased level of inflammatory markers are associated with variant angina.

BACKGROUND: Endothelial dysfunction and vascular inflammation may be associated with variant angina (VA). Flow-mediated vasodilation (FMD), carotid artery intima-media thickness (IMT), and pulse wave velocity (PWV) are widely used as non-invasive modalities for evaluating atherosclerosis. METHODS AND RESULTS: A total of 254 patients with chest pain were divided into three groups according to coronary angiogram (CAG) finding. There were 76 patients (VA group: 53.5+/-10.2 years, 41 males) with normal CAG with positive ergonovine-provocation test (EPT), 58 patients (control group: 55.3+/-8.7 years, 30 males) with normal CAG with negative EPT, and 120 patients with angiographically diagnosed coronary artery disease (CAD group: 56.3+/-9.7 years, 79 males). The level of FMD was lower in the VA group than in the control group (7.7+/-3.5% vs. 9.4+/-3.8%, p=0.014). Carotid IMT was higher in the VA group than in the control group (0.58+/-0.1 mm vs. 0.54+/-0.1 mm, p=0.029). The brachial-ankle PWV (baPWV) was higher in the VA group than in the control group (1445.3+/-211.8 cm/s vs. 1396.7+/-394.5 cm/s, p=0.020). The levels of monocyte cell counts was higher in patients of the VA group than in the other two groups (7545.7+/-2611.1/mm(3) vs. 6548.2+/-2156.4/mm(3) vs. 6740.9+/-1730.4/mm(3), p=0.015, respectively; monocyte cell counts: 657.2+/-242.6/mm(3) vs. 442.5+/-219.3/mm(3) vs. 490.0+/-172.0/mm(3), p=0.025). CONCLUSION: VA is associated with endothelial dysfunction and increased carotid IMT, baPWV, and inflammatory markers.

Vasoespasmo coronario inducido por un cuadro vasovagal como forma de presentación de angina variante / Vasovagal-induced coronary vasospasm as a presentation form of variant angina

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Absence of Kir6.1/KCNJ8 mutations in Italian patients with abnormal coronary vasomotion.

The disturbances in coronary vasomotor tone have been extensively analyzed, but the exact molecular mechanisms underlying abnormal coronary vasomotion remain to be elucidated. It has been suggested that impaired coronary vasoreactivity can be the expression of a defect in vascular smooth muscle cells. A mouse model of human variant (vasospastic) angina has been recently obtained by disruption of Kir6.1/Kcnj8, a gene coding for a small pore-forming inward rectifier potassium channel. A phenotype resembling variant angina was also reported in mice lacking Sur2, the partner protein of Kir6.1. To better define the role of the smooth muscular ATP-sensitive potassium channels in the pathogenesis of abnormal coronary vasomotion, a complete mutational analysis of Kir6.1/KCNJ8 gene was performed in a series of 18 Italian patients with impaired coronary vasomotility. Polymerase chain reaction and direct sequencing of PCR products were done. No mutations were detected in the sample analyzed, thus suggesting that Kir6.1/KCNJ8 aberrations are not a common cause of abnormal coronary vasomotion in Italians. To the best of our knowledge, this study represents the first mutational analysis of Kir6.1/KCNJ8 gene in humans. Since major racial differences in the prevalence of abnormal coronary vasomotion have been described, further mutation screenings of Kir6.1/KCNJ8 gene are required to assess its role in the pathogenesis of impaired coronary vasomotility among various ethnic groups.

Endothelial dysfunction is an independent factor responsible for vasospastic angina.

In order to evaluate peripheral endothelial function in patients with vasospastic angina (VSA), we measured flow-mediated dilation (FMD) of the brachial artery in patients with VSA and compared it with FMD in patients without VSA. Endothelial dysfunction is considered one of the mechanisms underlying VSA. However, its exact role remains to be clarified. The study included 30 patients with positive spasm-provocational test results without evidence of significant coronary stenosis (VSA group) and 30 patients with negative spasm-provocational test results without evidence of significant coronary stenosis (control group). In each patient, brachial artery diameter responses to hyperemic flow and glyceryl trinitrate spray were measured using high-resolution ultrasound. The carotid intima-media thickness was also measured as a marker of systemic atherosclerosis. FMD was lower in the VSA group (4.8+/-0.5%) compared with the control group (9.4+/-0.7%, P<0.0001). In the VSA group, FMD was not affected by coronary risk factors or the presence of atherosclerotic changes on coronary angiography. Glyceryl trinitrate-induced dilation did not differ between the two groups. The intima-media thickness was comparable between the VSA (0.85+/-0.04 mm) and control groups (0.81+/-0.05 mm). These findings indicated that peripheral endothelial function is impaired only in the VSA group, whereas the atherosclerotic changes were similar in the two groups. We conclude that endothelial dysfunction may be an independent factor responsible for the development of VSA.

Vasospastic total occlusion at the left main tract in a single coronary artery.

A 64-year-old man was admitted to hospital under the suspicion of unstable angina pectoris. Coronary angiography showed that he has a single coronary artery originating from the right coronary artery (RCA) without significant fixed stenosis. Acetylcholine was superselectively infused into the left main coronary artery (LMCA), and confirmed the coronary vasospastic occlusion associated with chest pain and elevation of the ST-segment in the precordial leads. This is the first report of the induction of a totally occlusive spasm of the LMCA of a patient with a RCA type single coronary artery, and this case suggests that spasm of the aberrant coronary artery is a potential mechanism for sudden death in patients with a single coronary artery.

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.

[Effect of left ventricular diastolic dysfunction on pathogenesis of angina decubitus].

OBJECTIVE: To investigate the effect of left ventricular diastolic dysfunction on the pathogenesis of angina decubitus. METHODS: The study population consisted of three groups: (1) group 1, 31 patients with angina decubitus who had ejection fraction > 50%; (2) group 2, 20 patients with coronary artery disease but without angina decubitus; group 2 and 1 were matched for age, EF and extent of coronary artery disease; (3) group 3, 20 patients without cardiovascular diseases. RESULTS: Left ventriculography (LVG) showed that LV first 1/3 filling fraction (1/3 FF) and LV late 1/3 FF were 0.30 +/- 0.12, 0.41 +/- 0.12, 0.46 +/- 0.07 and 0.36 +/- 0.09, 0.31 +/- 0.08, 0.29 +/- 0.06 in groups 1 to 3 respectively. LV first 1/3 FF was significantly lower in group 1 than in group 2 and 3 (both P < 0.001), but LV late 1/3 FF was much higher in group 1 than in groups 2 and 3 (P < 0.05 and P < 0.01, respectively). Left ventricular end-diastolic pressure (LVEDP) was markedly increased before and after LVG in groups 1 and 2 as compared with group 3 (P < 0.001 and P < 0.05, respectively). The difference of LVEDP caused by left atrial contraction (LACD) was much higher before and after LVG in group 1 than in group 3 (P < 0.01 and P < 0.001, respectively). However, there were significant differences in LVEDP and LACD tested between before and after LVG in group 1 (both P < 0.01). No statistical differences were found in LVEDP and LACD tested between before and after LVG in both group 2 and group 3. CONCLUSION: Patients with angina decubitus have LV diastolic dysfunction, which may be closely related to the pathogenesis of angina decubitus.

Histological evaluation of coronary plaque in patients with variant angina: relationship between vasospasm and neointimal hyperplasia in primary coronary lesions.

OBJECTIVES: This study was designed to determine whether coronary vasospasm in patients with variant angina pectoris (VAP) may produce focal organic lesions at the site of vasospasm that would contribute to disease progression. BACKGROUND: Recent clinical angiographic and experimental studies have demonstrated the potential role of vasospasm in the worsening of organic coronary stenosis. METHODS: We studied histologically the coronary plaques obtained at atherectomy in 202 patients with moderate to severe coronary stenosis. This population included 22 patients with VAP, 100 patients with chronic stable angina and 80 patients with restenosis following angioplasty or atherectomy. Diagnosis of VAP was based on both the clinical feature of angina at rest associated with ST elevation and a positive response to acetylcholine provocation test. RESULTS: The most common histological appearance in 92% of patients with stable angina was hypocellular fibroatheromatous plaques, whereas neointimal hyperplasia was the characteristic feature of the plaque observed in 90% of patients with restenosis. The coronary specimens at the site of spasm in 15 of the 22 patients (68%) with VAP demonstrated intimal injuries such as neointimal hyperplasia (15), thrombus formation (2), and intimal hemorrhage (3). Neointimal hyperplasia was significantly more common in the patients with VAP as compared with those with stable angina (68% vs. 8%; p < 0.0001). A rapid progression of organic stenosis within three years was angiographically found in 5 of the 22 patients with variant angina. In all five cases, neointimal hyperplasia was the main contributor to the worsening of the organic lesion at the site of spasm. These histological findings in patients with VAP extremely resembled those in restenosis. Except for vasospasm, no factors significantly predicted the presence of neointimal formations in primary coronary lesions. CONCLUSIONS: Coronary vasospasm may provoke vascular injury that leads to the formation of neointima in VAP patients similar to that seen with restenosis. Coronary spasm may thus play a key role in the rapid coronary stenosis progression in certain patients with VAP.