Silva Severi

“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.

Transient transmural reduction of myocardial blood flow demonstrated by thallium-201 scintigraphy, as a cause of variant angina.

SUMMARY In previous studies we demonstrated that variant angina could not be attributed to increased myocardial demands. In order to investigate whether a reduction of regional myocardial blood supply could be responsible for these ischemic episodes, we studied regional myocardial perfusion in six patients admitted to our coronary care unit. Myocardial scintigrams, obtained 5-7 min following i.v. injection of I mCi of thallium-201, performed during an episode of ST-segment elevation, showed transmural deficits of tracer uptake in the heart wall corresponding to the leads showing ST-segment elevation. These regional deficits had disappeared by 2 hours because of late uptake in previously ischemic myocardium. One week later, following injections performed in the absence of acute ischemia, no deficit was apparent. Tracer uptake in ischemic areas was 60% to 85% of that observed a week later. After adjusting for thallium-201 kinetics and counting geometry problems, these scintigrams actually represent large underestimations of actual flow reduction. Thus variant angina appears to be caused by massive transmural reduction of myocardial blood supply.

Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomised clinical trial. The PICCOLETO Study

Background Percutaneous coronary intervention (PCI) of small vessels is limited by an increased risk of restenosis and adverse outcome, even when drug-eluting stents (DES) are employed. In recent years, the paclitaxel-coated balloon (PCB) has been shown to reduce neointimal proliferation and the need for target lesion revascularization (TLR) in an in-stent restenosis setting. The impact of a PCB during PCI of small coronary vessels was evaluated and compared to one of the most widely used DES. Methods In the PICCOLETO randomised clinical trial, patients with stable or unstable angina undergoing PCI of small coronary vessels (≤2.75 mm) were randomised to Dior PCB (28 patients) or Taxus DES (29 patients). The primary study end point was per cent diameter stenosis at 6-month angiographic follow-up (non-inferiority), secondary end points were angiographic binary restenosis and occurrence of major adverse cardiac events (MACE: death, Q-wave myocardial infarction, TLR) at 9 month follow-up. Results The two groups were not dissimilar regarding clinical and angiographic characteristics. Study was interrupted after enrolment of two-thirds of patients due to a clear superiority of one study group. The primary end point was not met, because the PCB group showed higher per cent diameter stenosis (43.6% vs 24.3%, p=0.029); angiographic restenosis was higher as well (32.1 vs 10.3%, p=0.043), whereas MACE were 35.7% in the PCB group and 13.8% in the DES group (p=0.054). Conclusions Dior PCB failed to show equivalence to Taxus DES regarding angiographic end points during PCI of small coronary arteries. Clinical Trial Registration Number (EudraCT code) 2009-012268-15.

Prognostic value of dipyridamole echocardiography early after uncomplicated myocardial infarction: A large-scale, multicenter trial

PURPOSE To determine the prognostic capability of the dipyridamole echocardiography test (DET) early after an acute myocardial infarction. PATIENTS AND METHODS On the basis of 11 different echocardiographic laboratories, all with established experience in stress echocardiography and fulfilling quality-control requirements for stress echocardiographic readings, 925 patients were evaluated after a mean of 10 days from an acute myocardial infarction and followed up for a mean of 14 months. RESULTS During the follow-up, there were 34 deaths and 37 nonfatal myocardial infarctions; 104 patients developed class III or IV angina and 149 had coronary revascularization procedures (bypass or angioplasty). Considering all spontaneous events (angina, reinfarction, and death), the most important univariate predictor was the presence of an inducible wall motion abnormality after dipyridamole administration (chi 2 = 45.8). With a Cox analysis, echocardiographic positivity, age, and male gender were found to have an independent and additive value. Considering survival (and, therefore, death as the only event), age was the most meaningful parameter, followed by the wall motion score index during dipyridamole administration (chi 2 = 12.1). Among other parameters, the resting wall motion score index was a significant predictor of death. In a multivariate analysis, the prognostic contributions of age (relative risk estimate = 1.08) and wall motion score index during dipyridamole administration (relative risk estimate = 4.1) were independent and additive. In particular, considering death only, the event rate was 2% in patients with negative DET results, 4% in patients with positive high-dose DET results, and 7% in patients with positive low-dose DET results. CONCLUSIONS DET is feasible and safe early after uncomplicated myocardial infarction and allows effective risk stratification on the basis of the presence, severity, extent, and timing of the induced dyssynergy.

Prognostic importance of dipyridamole-echocardiography test in coronary artery disease.

We studied the value of dipyridamole-echocardiography test in comparison with clinical, resting electrocardiogram and echocardiogram variables in predicting cardiac events occurring in 539 consecutive patients referred for dipyridamole-echocardiography test from 1984 to 1987. There were 118 cardiac events: 11 cardiac deaths, 12 nonfatal myocardial infarctions, and 95 coronary revascularization (bypass or angioplasty) procedures. A Cox survival analysis identified echocardiographic positivity after dipyridamole administration as the best predictor of cardiac events (relative risk ratio, 2.7). The next most powerful predictor was angina after dipyridamole administration (relative risk ratio, 1.9). Cardiac events occurred in 14 (6%) of 253 patients with normal high-dose dipyridamole echocardiographic test results, in 21 (26%) of 82 patients with high-dose dipyridamole echocardiographic positivity (0.84 mg/kg during 10 minutes), and in 83 (41%) of 204 patients with low-dose dipyridamole echocardiographic positivity (0.56 mg/kg during 4 minutes) (p less than 0.0001). In a subset of 341 patients, exercise electrocardiography stress test and coronary angiography were also available. A Cox survival analysis again identified echocardiographic positivity after dipyridamole as the best predictor of cardiac events (relative risk ratio, 1.9) followed by a pathologic coronary arteriography (relative risk ratio, 1.2). We conclude that the presence and timing of a transient dyssynergy during dipyridamole stress are useful predictors of subsequent cardiac events.

Diagnostic and prognostic value of dipyridamole echocardiography in patients with suspected coronary artery disease. Comparison with exercise electrocardiography.

BACKGROUND Before any new diagnostic test is accepted in clinical practice, such a test should be compared with established diagnostic tools in an appropriately large series of patients encompassing the complete spectrum of challenges to which the test is exposed. The aim of the present study was to assess the relative diagnostic and prognostic accuracies of high-dose dipyridamole echocardiography (two-dimensional echocardiographic monitoring during dipyridamole infusion up to 0.84 mg/kg over 10 hours) versus maximal symptom-limited bicycle exercise ECG test in patients with angina. METHODS AND RESULTS We studied 429 consecutive in-hospital patients who met the following inclusion criteria: history of chest pain, off antianginal therapy for at least 2 days (1 week for beta-blockers), no previous myocardial infarction and/or obvious regional left ventricular dyssynergy of contraction (akinesis or dyskinesis) at baseline, and acceptable acoustic window under resting conditions. All patients underwent dipyridamole echocardiography and exercise ECG--on different days and in random order--within 1 week of coronary angiography (which was performed independent of test results) and were followed up for 37.8 +/- 14 months (range, 1 to 73 months). Criteria of positivity were for dipyridamole echocardiography, a transient regional dyssynergy absent in the baseline examination; for exercise ECG, an ST-segment shift of > or = 0.1 mV from baseline; and for coronary angiography, a luminal reduction of > or = 75% in at least one major coronary vessel (50% for left main). There were 183 patients without and 246 with coronary artery disease; 132 had one-, 70 had two-, and 44 had three- and/or left main vessel disease. The specificity was higher for dipyridamole echocardiography than for exercise ECG (90% versus 51%, P < .001). The overall sensitivity of dipyridamole echocardiography was similar to that of exercise ECG (75% versus 74%, P = NS), with no significant differences in the subset with one- (67% versus 69%, P = NS), two- (79% versus 77%, P = NS), or three- (93% versus 86%, P = NS) vessel disease. During the follow-up, there were 20 deaths, 13 nonfatal myocardial infarctions, and 126 revascularization procedures. In the univariate analysis, dipyridamole resulted in higher chi 2 values than did exercise stress testing. A Cox forward stepwise survival analysis identified the dipyridamole time as the most powerful prognostic predictor of death (chi 2 = 19.4, P < .0001) of all invasive and noninvasive parameters. The dipyridamole time also provided independent and additional prognostic information when it was adjusted for age, diabetes, resting ECG, and exercise stress test according to a modified, interactive stepwise procedure. This is true when death only, death and myocardial infarction, and death, myocardial infarction, and revascularization procedures were considered end points. CONCLUSIONS In patients with no previous myocardial infarction and good resting left ventricular function, compared with exercise ECG, dipyridamole echocardiography has a similar sensitivity and a higher specificity for the noninvasive detection of angiographically assessed coronary artery disease. Dipyridamole echocardiography also provides information in addition to that provided by exercise ECG for predicting death, infarction, and all events when the presence as well as the timing, severity, and extension of dipyridamole-induced wall motion abnormalities are considered.

Long-term prognosis of “variant” angina with medical treatment

Abstract One hundred thirty-eight patients with “variant angina” were followed up for periods of 2 to 8 years. All patients had a history of angina at rest, and 42 percent also had exertional angina. Normal coronary arteries were found in 9 of the 107 patients who underwent coronary arteriography; the remainder had stenosis greater than 50 percent in diameter of at least one major vessel. Coronary vasospasm was demonstrated in all 37 patients studied with coronary arteriography during angina at rest. Twenty-eight patients had acute myocardial infarction and five patients died within 1 month of admission to hospital. Of the 133 surviving patients, 120 were treated medically and 13 underwent coronary arterial surgery. In the medically treated group, only seven patients died and only four had acute myocardial infarction during the remainder of the follow-up period. Symptoms became less frequent and less severe; approximately 50 percent of the patients remained completely asymptomatic for at least 12 months by the end of the 4th year. Death, acute myocardial infarction and persistence of symptoms were more frequent in those patients with more severe coronary atherosclerotic disease although, even in this group, the overall incidence of death and acute myocardial infarction was small. It is concluded that the prognosis of patients with “variant” angina receiving appropriate medical therapy is reasonably good after the acute phase, even in the presence of severe coronary atherosclerosis.

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.

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.