Prinzmetal's variant form of angina with arteriographic evidence of coronary arterial spasm

Spasm of the proximal right coronary artery was arteriographically demonstrated during an episode of chest pain in a patient with Prinzmetal's variant form of angina. A right aortocoronary saphenous vein bypass procedure was performed but, despite a patent graft, the angina recurred and the patient died. The only significant finding at autopsy was an eccentric atherosclerotic plaque that narrowed the right coronary artery by 75 percent at the site of the spasm. These findings support Prinzmetal's hypothesis that this variant form of angina is produced by spasm of a coronary artery with a seriously compromised lumen.     

Coronary fistulas can develop collateral vessels: angiographic follow-up of an embolized giant right coronary artery-superior vena cava fistula in a patient with variant angina

A 54-year-old man was transferred to our emergency department because of acute inferior myocardial infarction. However, ST-segment elevation resolved after intravenous nitrate administration on admission and coronary angiography revealed a nonobstructive atherosclerotic plaque at the mid-portion of the circumflex artery and a giant tortuous fistula from the right sinus of Valsalva to the superior vena cava. The patient was diagnosed with variant angina and coronary arteriovenous fistula after vasodilator treatment and maximal treadmill stress test. After effective medical treatment of variant angina and successful percutaneous coil embolization of the fistula, the patient had not experienced any angina episodes for 1 year. However, control coronary angiography revealed partial persistence of fistula flow because of new collateral vessels, bridging distal and proximal parts of the occluded segment. We present the first coexistence of coronary to superior vena cava fistula and variant angina in the literature. This report also shows the ability of coronary fistulas to develop collateral vessels, like coronary arteries.     

Coronary spasm, prostaglandin and HLA factors

To elucidate the contribution of prostanoids in coronary spasm, plasma levels of thromboxane B2 (TXB2) and 6-keto PGF1 alpha at the coronary sinus and ascending aorta in 21 patients with variant angina were measured, as compared with findings in 20 with effort angina and 13 subjects with normal coronaries. In the coronary sinus blood, plasma TXB2 in patients with effort angina exhibited statistically significant high levels, as compared with data in the controls. On the contrary, the data obtained from patients with variant angina were not statistically significant. However, eight patients whose coronary angiogram revealed more than 50% of coronary stenoses had statistically significant high levels of TXB2 and other patients with normal coronaries or less than 50% of narrowing showed almost the same levels of TXB2 as the controls. In contrast to TXB2, the plasma levels of 6-keto PGF1 alpha in patients with variant angina were very low in both groups with variant angina. These data suggest that high levels of TXB2 observed in patients with atherosclerotic coronaries may be an accelerating factor while low levels of prostacyclin may be an essential factor leading to spasm. HLA analysis of 23 patients with variant angina was performed to search for genetic factors, under the hypothesis that such may contribute to the low levels in prostacyclin. This preliminary study revealed statistically significant high frequencies of Bw52 and B-40 in the patients, as compared with frequencies among 152 normal Japanese. Genetic studies are ongoing in our clinic.     

Elevation of C-reactive protein in "active" coronary artery disease

Unstable angina occurs most commonly in the setting of atherosclerotic coronary artery disease (CAD), but there is little information concerning the mechanisms responsible for the transition from clinically stable to unstable coronary atherosclerotic plaque. Recently, increased focal infiltration of inflammatory cells into the adventitia of coronary arteries of patients dying suddenly from CAD and activation of circulating neutrophils in patients with unstable angina have been observed. To characterize the presence of inflammation in "active" atherosclerotic lesions, the acute phase reactant C-reactive protein (CRP) was measured in 37 patients admitted to the coronary care unit with unstable angina, 30 patients admitted to the coronary care unit with nonischemic illnesses and 32 patients with stable CAD. CRP levels were significantly elevated (normal less than 0.6 mg/dl) in 90% of the unstable angina group compared to 20% of the coronary care unit group and 13% of the stable angina group. The average CRP values were significantly different (p = 0.001) for the unstable angina group (2.2 +/- 2.9 mg/dl) compared to the coronary care (0.9 +/- 0.7 mg/dl) and stable angina (0.7 +/- 0.2 mg/dl) groups. There was a trend for unstable angina patients with ischemic ST-T-wave abnormalities to have higher CRP values (2.6 +/- 3.4) than those without electrocardiographic changes (1.3 +/- 0.9, p = 0.1). The data demonstrate increased levels of an acute phase reactant in unstable angina. These findings suggest that an inflammatory component in "active" angina may contribute to the susceptibility of these patients to vasospasm and thrombosis.     

Pathophysiology and clinical significance of atherosclerotic plaque rupture.

Atherosclerotic plaque rupture and resulting intracoronary thrombosis are thought to account for most acute coronary syndromes. These syndromes include unstable angina, non-Q-wave myocardial infarction (MI) and Q-wave MI. In addition, many cases of sudden cardiac death may be attributable to atherosclerotic plaque disruption and its immediate complications. Our understanding of the atherosclerotic process and the pathophysiology of plaque disruption has advanced remarkably. Despite these advances, event rates after acute coronary syndromes remain unacceptably high. This review will focus on the pathophysiology underlying atherosclerotic plaque development, the sequellae of coronary plaque rupture, and current therapies designed to treat the acute coronary syndromes. It is hoped that as our understanding of the atherosclerotic plaque improves, treatment strategies for the acute coronary syndromes will advance.     

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.     

Morphologic features of unstable atherothrombotic plaques underlying acute coronary syndromes

Unstable angina appears to be a good clinical marker for rapidly progressing coronary artery disease. Pathologically, an unstable atherothrombotic coronary lesion, represented by a raised atherosclerotic plaque with ruptured surface causing variable degree of hemorrhage into the plaque and luminal thrombosis (rapid plaque progression), usually is present in patients at autopsy after a period of unstable angina. The thrombus at the rupture site may be mural and limited (just sealing the rupture) or occlusive, depending on the degree of preexisting atherosclerotic stenosis. An occlusive thrombus is seldom seen over ruptured plaques causing less than 75% stenosis (histologic cross-sectional area reduction), but it is found with increasing frequency when severity of stenosis increases beyond 75%. Most occlusive thrombi have a layered structure with thrombus material of differing age indicating an episodic growth by repeated mural deposits, and microemboli/microinfarcts are frequently found in the myocardium downstream to coronary thrombi, indicating intermittent thrombus fragmentation with peripheral embolization. Such a "dynamic thrombosis" (with or without a concomitant focal vasospastic phenomenon) at the site of an unstable (ruptured) atherosclerotic lesion obviously may lead to the other thrombus-related acute coronary events: myocardial infarction or sudden death. Accordingly, progression of unstable angina to myocardial infarction or sudden death should, in principle, be preventable by the correct timing of current available therapies aimed to prevent or eliminate (1) the chronic atherosclerotic obstruction, (2) the acute plaque disruption, (3) luminal thrombosis, and (4) vasospasm.     

Calcium antagonists for Prinzmetal's variant angina, unstable angina and silent myocardial ischemia: therapeutic tool and probe for identification of pathophysiologic mechanisms

The calcium antagonists provide a unique tool to reduce myocardial oxygen demand and prevent increases in coronary vasomotor tone. For patients with Prinzmetal's variant angina, diltiazem, nifedipine and verapamil are extremely effective in preventing episodes of coronary vasospasm and symptoms of ischemia. Unstable angina pectoris is a more complex pathophysiologic syndrome with episodes of ischemia due to increases in coronary vasomotor tone, intermittent platelet aggregation or alterations in the underlying atherosclerotic plaque. Each of the calcium antagonists is effective as monotherapy in decreasing the frequency of angina at rest. Nifedipine is the only calcium antagonist that has been studied in a combination regimen with beta blockers and nitrates for patients with unstable angina, and control of angina is better with the combination regimen than with either form of therapy alone. Although symptoms of myocardial ischemia in unstable angina are reduced by calcium antagonists, these agents do not seem to decrease the incidence of adverse outcomes. Antiplatelet therapy appears to improve morbidity and mortality in patients with unstable angina, suggesting that thrombus formation may play a central role in that disorder. Episodes of silent or asymptomatic myocardial ischemia, identified by ST-segment monitoring, occur in a variety of disorders of coronary disease. Among patients with Prinzmetal's variant angina and unstable angina, episodes of silent ischemia appear to be as frequent as episodes of angina and the calcium antagonists are effective in decreasing episodes of ischemia regardless of the presence or absence of symptoms. Persisting episodes of silent ischemia among patients with unstable angina despite maximal medical therapy identify patients at high risk for an early unfavorable outcome. Among patients with stable exertional angina, episodes of silent ischemia may be up to 5 times as frequent as episodes of angina, and may be due to increases in coronary vasomotor tone, transient platelet aggregation or increases in myocardial oxygen demand. Preliminary experience suggests that calcium antagonists and beta blockers are effective in decreasing episodes of silent ischemia in patients with stable exertional angina and that a combination regimen may be more effective than either form of therapy alone.     

Relation of CD39 to plaque instability and thrombus formation in directional atherectomy specimens from patients with stable and unstable angina pectoris

To determine whether the expression of CD39 in coronary atherosclerotic lesions is related to plaque instability and thrombus formation, we assessed directional coronary atherectomy (DCA) specimens from patients with stable and unstable angina pectoris. CD39 immunoreactivity was decreased in culprit lesions in patients with unstable angina pectoris compared with those with stable angina pectoris, and was reduced in DCA specimens with thrombus formation. These results suggest that CD39 expressed in atheromatous plaque plays an important role in preventing acute coronary syndromes.     

不稳定性心绞痛患者冠状动脉内粥样斑块的稳定性与血栓形成关系的探讨

目的　应用冠状动脉血管内视镜技术对不稳定性心绞痛(unstableanginapectoris, UA)患者的罪犯血管内粥样斑块的稳定性与血栓形成之间的关系进行探讨,为研究急性冠状动脉综合征(acutecoronarysyndromes, ACS)的发生提供临床病理基础。方法　选择UA患者68例,男性48例,女性20例,年龄40~73(62.4±8 .6)岁,除外心肌梗死后心绞痛和变异性心绞痛患者。上述患者在进行冠状动脉介入性检查和治疗的同时,对其“罪犯”血管进行血管内视镜检查。结果　(1) 68例患者(68支“罪犯”血管)中均观察到粥样斑块(100% ),其中有血栓者63例(92 .7% ),有内膜损伤者46例(67. 7% )。(2)68例冠状动脉粥样斑块者中,黄色斑块者48例( 70 .5% ),淡黄色斑块者18例(26. 5% ),白色斑块者2例(2. 9% )。(3)63例血栓均为附壁性非闭塞性血栓,其中红色或混合性血栓11例(17. 5% ),白色或粉红色血栓52例(82. 5% )。(4)46例内膜损伤者中均可见到血栓形成,其中红色或混合性血栓11例(23.9% ),白色或粉红色血栓35例(76. 1% )。结论　在UP患者中观察到黄色不稳定性斑块破裂及其伴随的血栓形成,是引起UA的病理基础。因此,在黄色斑块破裂之前采取何种治疗措施使其稳定化,是预防ACS的关键。     

Comparison of levels of serum matrix metalloproteinase-9 in patients with acute myocardial infarction versus unstable angina pectoris versus stable angina pectoris

Matrix metalloproteinases (MMPs) are important for resorption of extracellular matrixes and may degrade the fibrous cap of an atherosclerotic plaque, thus contributing to coronary plaque rupture. Histologic studies have shown MMP expression in lesions of acute coronary syndrome. In this study, we evaluated the relation between plaque morphology as obtained by intravascular ultrasound before percutaneous coronary intervention and serum MMP levels in patients who had coronary artery disease. We enrolled consecutive 47 patients who had acute myocardial infarction (AMI), 23 who had unstable angina pectoris (UAP), and 19 who had stable effort angina pectoris and underwent intravascular ultrasound before percutaneous coronary intervention followed by successful primary percutaneous coronary intervention. Peripheral blood was obtained from all patients before angiography and serum levels of MMP-1,-2, and -9 were analyzed. Serum levels of MMP-9 in the AMI and UAP groups were significantly higher than that in the stable effort angina pectoris group (p = 0.007 and 0.04, respectively). From the intravascular ultrasound findings before percutaneous coronary intervention, plaque rupture was detected in 26 patients (55%) in the AMI group and in 11 patients (48%) in the UAP group. In these 2 groups, patients with plaque rupture had significantly higher levels of MMP-9 than patients who did not have plaque rupture (p = 0.03 and 0.01, respectively). Multiple logistic regression analysis showed that MMP-9 was the only independent predictor of plaque rupture (p = 0.004). In conclusion, high levels of MMP-9 in patients who have AMI and UAP are related to the presence of plaque rupture in the culprit lesion.     

Plaque disruption and thrombosis: potential role of inflammation and infection

Acute coronary syndromes (unstable angina, acute myocardial infarction, and ischemic sudden death) result from coronary thrombosis superimposed on an atherosclerotic plaque. Thrombosis is generally a consequence of disruption of the atherosclerotic plaque in the form of a fissure/rupture in the fibrous cap overlying a lipid-rich pool or superficial endothelial erosion covering a smooth muscle and proteoglycan-rich matrix with or without a lipid-core. Approximately 2/3 of acute coronary syndromes evolve from atherosclerotic plaques that are minimally or mildly obstructive of the lumen before the acute event. Inflammation with accumulation of activated mononuclear cells may play a potential role in plaque disruption through the elaboration of proteases, such as matrix degrading neutral metalloproteinases and other proteases, inhibition of function and/or survival, or promotion of apoptosis of matrix synthesizing smooth muscle cells. Inflammation may also contribute to thrombosis after plaque disruption by providing a source for tissue factor in the plaque. Inflammation in the plaque may result from accumulation of modified lipids, oxidant and hemodynamic stress, and infectious agents, such as Chlamydia pneumoniae or pro-inflammatory triggers from distant sites of infection and inflammation (eg, chronic gingivitis and chronic bronchitis). Improved insights into the pathophysiology of plaque disruption and thrombosis are likely to provide new and improved methods of stabilizing atherosclerotic disease process.     

Inflammation and acute coronary syndromes

The presence of inflammatory infiltrates in unstable coronary plaques suggests that inflammatory processes may contribute to the pathogenesis of these syndromes. In patients with unstable angina, coronary atherosclerotic plaques are characterized by the presence of macrophages, and to a lesser extent, T-lymphocytes, at the immediate site of either plaque rupture or superficial erosion; moreover, the rupture-related inflammatory cells are activated, indicating ongoing inflammation at the site of plaque disruption. These observations are confirmed by clinical studies demonstrating activated circulating neutrophils, lymphocytes and monocytes, and increased concentrations of pro-inflammatory cytokines, such as interleukin (IL) 1 and 6, and of acute phase reactants in patients with unstable angina and myocardial infarction. In particular elevated levels of C-reactive protein are associated with an increased risk of in-hospital and 1 to 2 years new coronary events in patients with unstable angina, but are also associated with an increased long-term risk of death and myocardial infarction in apparently normal subjects. Thus, accumulating evidence suggests that inflammation may cause local endothelial activation and, possibly, plaque fissure, leading to unstable angina and infarction. Although no information is yet available on the causes of inflammation and on its localization, these novel lines of research may open the way to a different approach to the patient with acute coronary syndromes.     

Matrix metalloproteinases and coronary artery diseases

Matrix metalloproteinases (MMPs) play an important role in cardiovascular remodeling by degrading the extracellular matrix. Enhanced MMP expression has been detected in the atherosclerotic plaque, and activation of MMPs appears to be involved in the vulnerability of the plaque. Circulating MMP levels are elevated in patients with acute myocardial infarction and unstable angina. Increased MMP expression is also observed after coronary angioplasty, which is related to late loss index after the procedure. These observations suggest that MMP expression may be not only related to instability of the plaque, but also to the formation of restenotic lesions. The development of therapeutic drugs targeted specifically against MMPs may be useful in the prevention of atherosclerotic lesion development, plaque rupture, and restenosis.     

Sudden death and variant angina.

Variant angina is defined by chest pain occurring at rest associated with transitory ST segment elevation on ECG, and is caused by a spasm of a coronary artery. Frequently, variant angina is associated with atherosclerotic coronary obstruction and patients with normal coronary arteries are rare. Patients with variant angina and normal coronary arteries have good prognosis, and the development of ventricular arrhythmias or sudden death is rare. The authors present two cases of sudden cardiac death in patients with variant angina and normal coronary arteries.     

The heart in fatal unstable angina pectoris

Compared to patients with sudden coronary death and acute myocardial infarction, relatively little morphologic data has been reported in patients with unstable angina pectoris. This article reviews necropsy data collected from one laboratory on unstable angina pectoris. From these data, several observations are appropriate: (1) Patients with unstable angina as a group have more coronary narrowing by atherosclerotic plaque than do patients with sudden coronary death or acute or healed myocardial infarction. (2) Patients with unstable angina have a much higher frequency of severe narrowing of the left main coronary artery than do patients in other coronary subsets. (3) The coronary atherosclerotic plaques in unstable angina consist primarily of fibrous tissue, and they are more similar to those found in patients with sudden coronary death than in patients with acute myocardial infarction. (4) The frequency of acute coronary lesions (thrombi, plaque rupture, and plaque hemorrhage) is similar to that observed in patients with sudden coronary death and significantly less than that observed in acute myocardial infarction. (5) The frequency of multiluminal channels throughout the major coronary arteries is significantly higher in unstable angina compared to sudden coronary death or acute myocardial infarction. (6) The major epicardial arteries and the heart are smaller in patients with unstable angina than in patients with sudden coronary death or acute myocardial infarction. (7) The left ventricular cavity is usually of normal size in patients with unstable angina and therefore left ventricular function is usually normal.     

Coronary artery imaging with intravascular high-frequency ultrasound

Safe and effective clinical application of new interventional therapies may require more precise imaging of atherosclerotic coronary arteries. To determine the reliability of catheter-based intravascular ultrasound as an imaging modality, a miniaturized prototype ultrasound system (1-mm transducer; center frequency, 25 MHz) was used to acquire two-dimensional, cross-sectional images in 21 human coronary arteries from 13 patients studied at necropsy who had moderate-to-severe atherosclerosis. Fifty-four atherosclerotic sites imagined by ultrasound were compared with formalin-fixed and fresh histological sections of the coronary arteries with a digital video planimetry system. Ultrasound and histological measurements correlated significantly (all p less than 0.0001) for coronary artery cross-sectional area (r = 0.94), residual lumen cross-sectional area (r = 0.85), percent cross-sectional area (r = 0.84), and linear wall thickness (plaque and media) measured at 0 degrees, 90 degrees, 180 degrees, and 270 degrees (r = 0.92). Moreover, ultrasound accurately predicted histological plaque composition in 96% of cases. Anatomic features of the coronary arteries that were easily discernible were the lumen-plaque and media-adventitia interfaces, very bright echoes casting acoustic shadows in calcified plaques, bright and homogeneous echoes in fibrous plaques, and relatively echo-lucent images in lipid-filled lesions. These data indicate that intravascular ultrasound provides accurate image characterization of the artery lumen and wall geometry as well as the presence, distribution, and histological type of atherosclerotic plaque. Thus, ultrasound imaging appears to have great potential application for enhanced diagnosis of coronary atherosclerosis and may serve to guide new catheter-based techniques in the treatment of coronary artery disease.     

Expression of inducible nitric oxide synthase in human coronary atherosclerotic plaque.

OBJECTIVE: Macrophages in atherosclerotic plaque may express the inducible isoform of NO synthase (iNOS), which produces large amounts of NO. On one hand, the production of NO can be protective by its vasodilatory, antiaggregant and antiproliferative effects. On the other hand, the formation of peroxynitrite from NO may favour vasospasm and thrombogenesis. In this study, we investigated whether iNOS is present in human coronary atherosclerotic plaque, and we correlated these data with the clinical instability of the patients. METHODS: Fragments were retrieved by coronary atherectomy from 24 patients with unstable angina and 12 patients with stable angina. The presence of macrophages, and the production of TNF alpha, iNOS and nitrotyrosine were detected by immunocytochemistry. RESULTS: Macrophage clusters were found in 67% of stable patients and 87% of patients with unstable angina (NS). TNF alpha was expressed in about 50% of cases in both groups. iNOS was not expressed in fragments from stable patients but was found in macrophages from 58% of unstable patients (P < 0.001). The expression of iNOS was associated with the presence of nitrotyrosine residues, a marker of peroxynitrite formation. Expression of iNOS was correlated both with complaints of angina at rest (P < 0.05) and with the presence of thrombus at morphological examination (P < 0.001). CONCLUSION: The expression of iNOS may be induced in human coronary atherosclerotic plaque and is associated with different factors of instability.     

Louis F. Bishop lecture. Role of coronary artery spasm in symptomatic and silent myocardial ischemia

The revival of the concept of coronary spasm has stimulated research into coronary artery disease. Observations in patients with variant angina have substantially contributed to the appreciation of painless myocardial ischemia. However, the presence or absence of pain during ischemic episodes is not related to the cause of ischemia, because painless ischemia can be observed in variant angina (caused by spasm), in effort-induced angina (caused by increased myocardial demand) and in myocardial infarction (caused by thrombosis). Continuous monitoring initially of patients with variant angina and subsequently of patients with unstable and stable angina proved that often painful and painless ischemic episodes are caused by a transient impairment of regional coronary blood flow rather than by an excessive increase of myocardial demand. The transient impairment of coronary flow appears to be caused by dynamic stenosis of epicardial coronary arteries. This most often occurs at the site of atherosclerotic plaques encroaching on the lumen to a variable extent. Dynamic stenosis can be caused by 1) "physiologic" increase of coronary tone, as in stable angina, 2) spasm, as in variant angina, and 3) thrombosis, usually in combination with "physiologic" changes in tone or with spasm, or both, as in unstable angina. The mechanisms of spasm, as typically observed in variant angina, are different from those of "physiologic" increase of tone; they appear to be related to a local alteration that makes a segment of coronary artery hyperreactive to a variety of constrictor stimuli causing only minor degrees of constriction in other coronary arteries. The nature of this abnormality, which may remain stable for months and years, is yet unknown.