A. Biagini

“Variant” angina: One aspect of a continuous spectrum of vasospastic myocardial ischemia: Pathogenetic Mechanisms, Estimated Incidence and Clinical and Coronary Arteriographic Findings in 138 Patients☆

Abstract From January 1970 to December 1977, transient reversible episodes of S-T segment elevation were documented in 138 patients (80 with angina only at rest, 58 with angina both on exertion and at rest). Electrocardiographic monitoring in 33 patients with hemodynamic monitoring revealed that (1) during 6,009 transient episodes of myocardial ischemia, pain was always a late phenomenon and, in some patients, often did not occur; (2) during such transient episodes, ST-T wave behavior was often variable in the same patient with alternation of elevation, depression or only T wave changes with or without pain; (3) independent of the direction of the S-T segment and T wave changes, the episodes were never preceded by an increase of the hemodynamic determinants of myocardial demand but were associated with obvious impairment of left ventricular function. Thallium scintigraphy in 32 patients revealed a regional massive and localized reduction of myocardial perfusion during S-T segment elevation and pseudonormalization of T waves. During S-T segment depression the reduction of thallium uptake was diffuse with fuzzy limits. Coronary angiography revealed no significant stenosis in 8 patients and single, double and triple vessel disease in 38, 34 and 26 patients, respectively. Angiography in all 37 patients studied during angina revealed a severe coronary vasospasm involving vessels with extremely variable extent of atherosclerosis. Severe arrhythmias were recorded in 27 patients, and a myocardial infarction occurred in 28. A total of five patients died within 1 month of hospital admission. Thus, variable intensity and extension of coronary vasospasm and the presence of collateral vessels may result in different degrees of ischemia and various electrocardiographic patterns with or without anginal pain. Vasospastic angina can occur in the presence of extremely variable degrees of coronary atherosclerosis and in any phase of ischemie heart disease. It may evolve into acute myocardial infarction and sudden death: Variant angina appears to be only its most striking electrocardiographic manifestation. When vasospastic angina is appropriately searched for, its incidence rate appears to be high.

Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the study of "preinfarction" angina.

To investigate the pathogenesis of myocardial infarction we undertook a systematic study of patients with angina at rest, a syndrome known to evolve frequently into infarction. Among 187 consecutive patients, 37 had infarction, all in the area that showed electrocardiographic changes during angina. In all 76 patients who underwent hemodynamic monitoring, 201thallium myocardial scintigraphy or angiography during angina, a vasospastic origin of the attacks was documented. In six patients with infarction shortly after these studies and in two in whom the infarction developed during hemodynamic monitoring or during angiography the onset of infarction was indistinguishable from the onset of anginal attacks. One patient in whom spasm was observed at the onset of infarction died six hours later; at post-mortem examination, a fresh laminar thrombus was found at the site of the spasm. After infarction, complete thrombotic occlusion of the branch shown to undergo vasospasm was documented in two patients by angiography.

Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease

BACKGROUND Endothelial nitric oxide synthase (eNOS) could be a candidate gene for coronary artery disease (CAD). This study investigated the relationship of the eNOS Glu(298)-->Asp and T(786)-->C polymorphisms with the presence and severity of CAD in the Italian population. METHODS We enrolled 415 unrelated individuals who underwent coronary angiography. The severity of CAD was expressed by means of the Duke score. The eNOS Glu(298)-->Asp and T(786)-->C variants were analyzed by PCR. RESULTS There was significant linkage disequilibrium between the two eNOS polymorphisms (P <0.0001). Both variants were significantly associated with the occurrence and severity of CAD (P = 0.01 and 0.004 for Glu(298)-->Asp and T(786)-->C, respectively). The risk of CAD was increased among individuals homozygous for the C allele of the T(786)-->C polymorphism compared with individuals homozygous for the T allele (odds ratio = 2.5; P <0.01) and was independent of the other common risk factors (P = 0.04). Moreover, individuals with both the Asp/Asp genotype of the Glu(298)-->Asp polymorphism and at least one C allele of the T(786)-->C variant in the promoter region of the eNOS gene had an increased risk of CAD (odds ratio = 4.0; P <0.001) and a significantly higher mean Duke score (26.2 +/- 2.9 vs 45.2 +/- 3.7; P = 0.002) compared with individuals with the TT genotype and the Glu allele. CONCLUSIONS The present study provides evidence that the Glu(298)-->Asp and T(786)-->C polymorphisms of the eNOS gene are associated with the presence and severity of angiographically defined CAD in the Italian population and that those individuals carrying both eNOS variants simultaneously might have a higher risk of developing CAD.

Vasospastic ischemic mechanism of frequent asymptomatic transient ST-T changes during continuous electrocardiographic monitoring in selected unstable angina patients☆

Asymptomatic episodes of ST segment and/or T wave changes are often reported during Holter monitoring in patients with angina pectoris. However, the interpretation of such changes is debated relative to silent myocardial ischemia. We studied 11 patients admitted to the CCU because of frequent episodes of unstable anginal attacks who had undergone repeated periods of Holter monitoring, characterized by predominantly occurring asymptomatic episodes of ST segment and/or T wave changes associated with less frequent typical anginal attacks. In a total of 89 days of Holter monitoring, the patients evidenced 520 episodes of transient ECG changes including 180 of ST elevation, 73 of ST depression, and 267 of T wave alterations. Only 12% of episodes were symptomatic. Coronary injection during asymptomatic ST-T changes was performed in eight patients. In six it was possible to document spontaneous coronary spasm. In seven patients ergonovine administration induced anginal pain, ST-T changes, and coronary spasm. In all patients the anginal attacks completely disappeared with medical treatment and the asymptomatic episodes were abolished in six and reduced in four. Our findings support the hypothesis that in certain selected unstable anginal patients, transient asymptomatic ECG changes are caused by acute myocardial ischemia.

Significance of spasm in the pathogenesis of ischemic heart disease

Abstract The role of coronary arterial vasospasm in the pathogenesis of ischemic heart disease is reviewed on the basis of investigations carried out in our laboratory. Patients were selected because they had angina either at rest or both at rest and during exercise. With continuous hemodynamic and electrocardiographic monitoring of these patients, as well as thallium-201 scintigraphy and coronary arteriography during ischemic episodes, we were able to demonstrate a vasospastic origin for the attacks. During anginal episodes, electrocardiographic changes were variable, with S-T segment elevation, S-T segment depression, a rise in T wave potential and pseudonormalization of inverted T waves corresponding to various distributions of myocardial ischemia in different patients and even in the same patient at different times. Increases in hemodynamic variables that control myocardial oxygen consumption never preceded the onset of ischemic episodes, which challenges the theory that the limitation of a possible increase in flow caused by critical organic stenosis is the only cause of myocardial ischemia. In some patients in whom myocardial infarction developed, the lesion was always found in the same area in which the vasospastic phenomena had been seen angiographically. Vasospasm led to serious arrhythmias in some patients. We therefore believe that independent of atherosclerosis or superimposed on it, vasospasm plays an important role in producing myocardial ischemia—angina, myocardial infarction and possibly sudden death. Elucidation of its mechanisms will lead to more appropriate therapy.

Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298→Asp polymorphism) to the presence, extent, and severity of coronary artery disease

Background: Genetic variants of endothelial nitric oxide synthase (eNOS) could influence individual susceptibility to coronary artery disease. Objective: To assess whether Glu298→Asp polymorphism of the eNOS gene is associated with the occurrence and severity of angiographically defined coronary artery disease in the Italian population. Methods: Polymerase chain reaction/restriction fragment length polymorphism analysis was done to detect the Glu298→Asp variant of the eNOS gene in 201 patients with coronary artery disease and 114 controls. The severity of coronary artery disease was expressed by the number of affected vessels and by the Duke scoring system. Results: The frequencies of the eNOS Glu/Glu, Glu/Asp, and Asp/Asp genotypes in the coronary artery disease group were significantly different from those of controls (45.3%, 38.8%, and 15.9% v 42.1%, 51.8%, and 6.1%, respectively; χ2 = 8.589, p = 0.0136). In comparison with subjects who had a Glu298 allele in the eNOS gene, the risk of coronary artery disease was increased among Asp/Asp carriers (odds ratio 2.9, 95% confidence interval 1.2 to 6.8, p = 0.01) and was independent of the other common risk factors (p = 0.04). There was a significant association between the eNOS Glu298→Asp variant and both the number of stenosed vessels (mean (SEM), 2.3 (0.1) for Asp/Asp v 1.9 (0.1) and 1.8 (0.1) for Glu/Glu and Glu/Asp, respectively; p = 0.01) and the Duke score (56.1 (3.1) for Asp/Asp v 46.7 (2.0) and 46.1 (1.9) for Glu/Glu and Glu/Asp, respectively; p = 0.02). Conclusions: Glu298→Asp polymorphism of the eNOS gene appears to be associated with the presence, extent, and severity of angiographically assessed coronary artery disease.

Management of vasospastic angina at rest with continuous infusion of isosorbide dinitrate. A double crossover study in a coronary care unit.

Abstract Twelve patients were studied who had frequent transient ischemic episodes at rest with a variable degree of coronary atherosclerosis and vasospastic origin of angina as evidenced by good exercise tolerance and results of thallium-201 scintigraphy during angina at rest, ergonovine maleate provocative test and coronary angiography. With the aim of keeping a constant blood drug level, the trial consisted of a continuous intravenous infusion of isosorbide dinitrate (1.25 to 5.0 mg/hour) during two periods (T 1 and T 2 ) of 24 hours (four patients) or 12 hours (eight patients) alternating with two equal periods (P 1 and P 2 ) of infusion of saline solution with a double crossover design (T 1 , P 1 , T 2 and P 2 ). Continuous electrocardiographic monitoring revealed that the total number of transient ischemic attacks at rest characterized by S-T segment elevation (four patients), S-T depression (two patients) and either S-T depression or elevation (six patients), with or without pain, was 100, 104 and 91, respectively, during the introductory control period and during P 1 and P 2 , but was reduced to 13 and 20, respectively, during periods T 1 and T 2 ( P = 0.002). Transient ischemic attacks at rest were completely prevented during both T 1 and T 2 in four patients and during T 1 or T 2 in three patients, and were not abolished but significantly reduced in T 1 and T 2 in the other five patients. The reduction in ischemic attacks was similar for episodes characterized by S-T segment elevation or depression and with or without pain. Side effects were negligible. Therefore, infusion of isosorbide dinitrate appears to be a very effective treatment for patients with vasospastic angina at rest.

Ventricular arrhythmias in dilated cardiomyopathy as an independent prognostic hallmark

Prevalence and characteristics of ventricular arrhythmias (VA) on Holter monitoring were evaluated in 218 patients with invasively documented idiopathic dilated cardiomyopathy to clarify their relation to pump dysfunction, and their prognostic role. VA were observed in 205 patients (94%) and were high grade (ventricular pairs or tachycardia) in 130 (60%). No simple or multiform ventricular premature complexes were present in 88 patients (group 1; 41%), ventricular pairs in 63 (group 2; 32%), and ventricular tachycardia in 67 (group 3; 27%). Only echocardiographic right ventricular dimensions (p less than 0.05) and prevalence of VA during effort (8% in group 1, 15% in group 2, and 14% in group 3; p = 0.0005) differed significantly between groups. VA severity, and number of ventricular premature beats and tachycardia episodes were not correlated to right/left ventricular dimensions and pump function indexes. During a mean follow-up of 29 +/- 16 months, 27 patients died from cardiac events, and 16 received transplants. Three-year survival probability was lower in groups 2 (0.82) and 3 (0.81) than in group 1 (0.94). By Cox multivariate analysis, VA severity (p less than 0.01) was a major independent predictor of prognosis after markers of ventricular dysfunction such as left ventricular ejection fraction (p less than 0.001) and stroke work index (p less than 0.001).

Evidence for enhanced 8-isoprostane plasma levels, as index of oxidative stress in vivo, in patients with coronary artery disease.

Background It is well known that free radicals contribute to endothelial dysfunction and are involved in ageing and in the pathogenesis and development of many cardiovascular diseases, such as atherosclerosis. Measurement of F(2)‐isoprostanes has emerged as probably the most reliable approach to assess oxidative stress status in vivo. In particular, 8‐isoprostane (8‐epiPGF2ct) has been indicated as a marker of antioxidant deficiency and oxidative stress of potential relevance to assess human vascular diseases. Design To provide evidence for enhanced oxidative stress in coronary artery disease (CAD). Methods Plasma levels of 8‐epiPGF2a (EIA, Cayman Chemicals, Ann Arbor, Michigan, USA) were measured in 51 patients (19 females, 32 males, age: 58.7 ± 1.6 years, mean±SEM). Subjects included 13 healthy control subjects (group I), and 38 patients underwent coronary angiography; 11 patients without coronary artery atherosclerotic lesions (group II), and 27 with angiographically proven CAD (group III). Results Plasma levels of 8‐epiPGF2&agr; were 123.2 ± 9.5, 314.6 ± 40 and 389.6 ± 36.2 pg/ml in groups I, II and III respectively (P <0.05 and P < 0.001 groups II and III versus group I, respectively). In group III, 8‐epiPGF2&agr; levels increased with the number of affected vessels (324.4 ± 47.2 and 408.3 ±44.1 pg/ml for one‐ and multi‐vessel disease, P =0.07 and P < 0.001 versus control subjects, respectively). A significant difference in 8‐epiPGF2&agr; levels was observed between patients with and without hypertension (394.2 ± 42.7 and 232.7 ± 25.1 pg/ml, P < 0.01, respectively). In addition, patients with dyslipidaemia presented higher 8‐epiPGF2a levels with respect to non‐dyslipidaemic patients (359.1 ± 35.6 and 240.3 ± 34.3 pg/ml, P <0.05, respectively). A positive relationship was found between age and 8‐epiPGF2&agr; levels (r= 0.42, P < 0.01) in the whole population. Conclusion These findings indicate that elevated levels of plasma 8‐epiPGF2&agr; levels are associated with the extent and the severity of coronary artery disease and with the occurrence of different atherogenic risk factors, supporting the hypothesis that the evaluation of oxidative stress may represent an additional prognostic predictor in such events and a potential target of future therapeutic interventions. Coron Artery Dis 14:213‐218

Elevated levels of oxidative DNA damage in patients with coronary artery disease

BackgroundSomatic DNA damage has been suggested to contribute to the pathogenesis of atherosclerosis. However, little is known about the role of oxidative DNA damage in patients with coronary artery disease (CAD). MethodsIn this study, we used the comet assay to measure oxidative DNA damage (DNA strand breaks and enzyme-sensitive sites) in peripheral blood lymphocytes from 13 patients with angiographically documented CAD and 11 age- and sex-matched control participants. ResultsMean values of DNA strand breaks, oxidized pyrimidines and altered purines were significantly higher in CAD patients than in the control group (11.9 ± 1.4, 18.0 ± 2.7 and 18.1 ± 3.1 compared with 3.3 ± 0.2, 2.7 ± 0.5 and 4.5 ± 1.1; P < 0.0001, P < 0.0001 and P = 0.0009, respectively). Moreover, oxidized purines (for example, 8-oxo-guanine) increased with the number of affected vessels and positively correlated with the extent of CAD measured by means of the number of the coronary lesions (r = 0.76, P = 0.003) and the Duke scoring system (r = 0.66, P = 0.01). Diabetic patients showed higher levels of oxidized pyrimidines (31.3 ± 5.5 compared with 14.1 ± 2.7; P = 0.013), while patients with dyslipidemia had elevated altered purines compared with normal patients (20.4 ± 2.6 compared with 4.9 ± 3.1; P = 0.03). ConclusionsThese data indicate an overall elevation of oxidative DNA damage in CAD patients correlated with the severity of the disease and some atherogenic risk factors, suggesting a possible role of oxidative genetic damage in the pathogenesis of atherosclerosis.