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- C.Richard Conti, MD, MACCa
In this edition of the Journal, we release the first in a series of reviews of influential articles that have been previously published in ACC journals, including the American Journal of Cardiology(from 1958 to 1982), and JACC(from 1983 to the present). The publication of these articles is only one aspect of the ACC’s 50th anniversary commemoration, which highlights 50 years of leadership in cardiovascular care and education. The articles are intended to encourage reflection on the remarkable progress made in cardiovascular medicine over time, as well as to acknowledge the amazing prescience of some early investigators in anticipating and, in many cases, later guiding developments in their field.
The working group responsible for selecting these articles and asking reviewers to write editorials solicited suggestions from the ACC’s clinical committees and individual members.
The group achieved consensus fairly easily, including whom the group should ask to prepare the accompanying editorials. We initially drew up a list of 14 general areas to cover in this series, but later found that there are several major areas of modern cardiology, prominently molecular cardiology and echocardiography, in which the truly landmark articles have, alas, not yet been published in JACC. Therefore, the working group decided not to categorize by subject, but instead, to concentrate on the most important articles.
The working group, a task force of the Subcommittee for the Commemoration of the ACC 50th Anniversary, owes a great deal to Ms. May A. Roustom and the efficient and tireless staff at Heart House for facilitating this project. We also wish to thank all who suggested articles and, most important, the authors who prepared reviews for their willingness to contribute their time and wisdom.
Influential Articles in JACC Working Group
Sharon A. Hunt, M.D., F.A.C.C.
Rick A. Nishimura, M.D., F.A.C.C.
H.J.C. Swan, M.D., Ph.D., M.A.C.C.
Michael J. Wolk, M.D., F.A.C.C.
This brief review summarizes two important articles that were published in the American Journal of Cardiology in the 1970s. Both of these articles set the tone for what was to follow in the complicated and rapidly changing field of ischemic heart disease.
The natural history of angina pectoris
By Reeves, Oberman, Jones and Sheffield (1)
An understanding of the natural history of angina pectoris is crucial to decision making in the management of patients with this disease. Early investigations suggested a highly variable annual mortality rate, ranging from 2.5 to 9 percent. These studies clearly pointed to the association of certain electrocardiographic changes, hypertension, cardiac enlargement and congestive heart failure with increased mortality. Several recent studies based on findings at coronary arteriography indicate a high degree of correlation between the extent of coronary atherosclerotic occlusive disease and the likelihood of early death. A combination of data from several laboratories indicates that if only one of the three major coronary arterial branches (left anterior descending, left circumflex or right) is significantly stenosed, the annual mortality rate will be approximately 2 percent of the cohort. If two of the three major arteries are stenosed, the rate will be approximately 7 percent, and if all three arteries are stenosed, it will be approximately 11 percent. Some data suggest that these mortality figures based on the extent of atherosclerotic occlusive disease are importantly modulated by the extent of ventricular myocardial impairment as reflected by cardiac enlargement or symptoms of congestive heart failure.
Originally published in The American Journal of Cardiology, March 1974
The changing mortality rate
Reeves and colleagues made several important observations. The first observation was that the survival rate in angina pectoris patients steadily improved from the early- to mid- twentieth century. Their review of the literature revealed that years from onset of angina pectoris to death was prolonged in 1956 compared with 1918. The first study by Herrick and Nuzum in 1918 reported an average of three years from onset to death, whereas the 1956 study by Richards et al. revealed 9.7 years from onset to death.
Prognosis in women
It was also noted that women had a better prognosis than men and that patients with hypertension, cardiomegaly, congestive heart failure and certain electrographic abnormalities had a much greater likelihood for early death than patients without such findings. Angiographic studies of patients with chest pain consistently show that a higher proportion of women have normal coronary angiograms. Reeves et al. pointed out that this finding implies that women may have a higher percentage of “false positive” clinical diagnoses of angina pectoris, a possibility that may explain this apparent gender difference. They commented that this question merited further study. This question has indeed merited further study, and there are current investigations underway sponsored by the National Heart, Lung, and Blood Institute (NHLBI) called “The Women’s Health Initiative, the ‘WISE’” (Women’s Ischemic Syndrome Evaluation) Study and several others relating to coronary artery disease and chest pain in women.
Simple prognostic indicators
In their review of the literature, Reeves et al. pointed out that several factors influenced the survival of patients with angina pectoris. They noted that the use of simple and noninvasive measurements such as the ECG could discriminate angina patients at high risk of death from those with a very low risk of death. For example, five year survival rate in patients with a normal electrocardiagram was 73.1%; for those with an abnormal electrocardiagram, the five year survival rate was 29.1%.
Coronary angiography and prognosis
These authors highlighted the 1970 study of Friesinger et al., in which 224 patients with chest pain who underwent coronary angiography were studied for an average period of 50 months. (This study is particularly close to my heart, because I worked in the catheterization laboratory at Hopkins at the time and I helped classify the coronary angiograms.) Each of three major arterial branches—right, left anterior descending and left circumflex arteries—were assigned a score of “0” if no disease was recognized, “1” if trivial disease was present, “2” if the extent of the stenosis was between 50% and 90%, “3” if multiple narrowings between 50% and 90% were present in a single artery, “4” if the stenosis were greater than 90% but no occlusion and “5” if the artery was occluded. In this investigation, if the angiographic score was greater than “10”, mortality rate at 50 months was 53% contrasted with 5% in those who with a score greater than “3” but less than “10”. Only one of thirty two patients with single vessel disease died within the 50 month follow up and that patient died in a single person automobile accident.
Data from several different investigators showed clearly recognizable trends; that is, the mortality rate of patients with angina is strongly associated with the number of arteries involved. Several investigators showed that diseases of the proximal left anterior descending coronary artery associated with a relatively serious prognosis with the annual mortality rate being 4% to 7.4%. It also seems clear from several studies that patients with disease limited to the circumflex or the right coronary artery have an excellent prognosis over a period of two to seven years. Patients with all three major vessels involved have a high mortality rate of approximately 10% to 15% per year. In any patient, cardiac enlargement, congestive heart failure, or both, grossly diminishes the likelihood of survival. Reeves and colleagues further indicated that a “more sophisticated analysis of the coronary arteriograms would almost certainly increase the precision of delineation of subgroups.” Thus, they predicted the usefulness of quantitative coronary angiography as well as the description of coronary vessel morphology as well as Thrombolysis in Myocardial Infarction (TIMI) flow.
Coronary angiography and other risk factors
Oberman and colleagues also substantiated the data of Friesinger and coworkers and expanded that work by assessing electrocardiographic evidence of myocardial infarction, history of heart failure and heart volume. In patients with myocardial infarction on ECG, the 22 month mortality rate was 31%, in contrast with a 7% mortality rate in 182 without this ECG abnormality. The history of heart failure was clearly related to prognosis. The 22 month mortality rate for 45 patients with symptoms of pulmonary venous hypertension was 40% compared with 8% in the 201 patients without such symptoms. A 50% mortality rate was found in 30 patients with two- or threevessel disease plus congestive heart failure compared with 16% mortality in similar patients without heart failure.
Heart volume as determined by the chest x-ray predicted mortality in patients with two vessel disease (41% in 22 months) as compared with 7% mortality in patients with two-vessel disease and no increase in heart volume determined by a chest x-ray.
Factors contributing to mortality prediction
Seven factors contributed significantly to the prediction of mortality in patients with ischemic heart disease. In order of independent contribution, these included 1) heart size, 2) stenosis of the LAD, 3) evidence of heart failure, 4) tachycardia, 5) stenosis of the left main coronary artery, 6) stenosis of the left circumflex artery and 7) stenosis of the right coronary artery.
Ventricular function and prognosis
The authors also indicated that it was likely that more elegant descriptions of the condition of the ventricles and cardiomegaly or symptoms of heart failure would further increase refinement of these subgroups. Thus, they predicted the prognostic value of ventricular function analysis by either echocardiography or angiography. It is now well known that prognosis following any ischemic event is related to the extent of left ventricular dysfunction.
Randomized clinical trials
They also had the vision to suggest that a comparison of the survival and clinical course of patients in these multiple subgroups assigned at random to medical or surgical treatment is required if clear answers relative to the respective merits of surgical and medical interventions are to be provided. Obviously, these authors were correct, and for the next 25 years, numerous, multicenter, multinational randomized trials were carried out to answer these important questions.
These authors had further insight into the problem of cardiomegaly in patients with ischemic heart disease. They hinted at the patient with hibernating myocardium when they suggested that if there is evidence of ventricular dysfunction or cardiomegaly, especially if there is significant limitation of ordinary activity because of angina, revascularization (coronary artery bypass) is advised.
“Variant” angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Pathogenetic mechanisms, estimated incidence and clinical arteriographic findings in 138 patients
By Maseri, Severi, DeNes, L’Abbate, Chierchia, Marzilli, Ballestra, Parodi, Biagini, and Distante (2)
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 ischemic 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.
Originally published in the The American Journal of Cardiology, December 1978
Many individuals have contributed to the vast amount of accumulated literature on coronary artery spasm, but Maseri et al. have provided the most elegant pathophysiologic investigations in patients presenting with angina at rest. In this report, the investigators described characteristic features of 138 patients with “variant angina.” They provided evidence that coronary vasospasm can result in myocardial ischemia, which can occur in the presence or absence of coronary atherosclerosis of varying degrees with or without a previous myocardial infarction and with or without exertional angina. They also indicated that vasospastic origins of myocardial ischemia can be associated with ST segment depression rather than ST segment elevation, and finally, they indicated that myocardial ischemia secondary to vasospasm can be asymptomatic and in a few instances evolve into a myocardial infarction and sudden cardiac death. Other investigators have subsequently confirmed all of these early observations.
ECG during chest pain
These investigators made a comment that I believe is worthy of repeating to all that have an interest in ischemic heart disease. They found that the percent of patients with demonstrable variant angina increased considerably in 1974 when they introduced the practice of (1) recording a 12 lead electrocardiagram during all episodes of chest pain at rest before the administration of nitroglycerin and (2) submitting patients with brief episodes of chest pain to continuous ECG monitoring. These investigators made the point that you will not find anything if you do not look for it.
Observation during spontaneous myocardial ischemia
Maseri et al. made several important observations in patients with spontaneous episodes of myocardial ischemia. Using electrocardiography, they noted that the duration of ischemia varied from 30 seconds to 20 minutes and that the electrocardiagraphic pattern varied in the number of leads involved, the sequence of T waves and ST segment changes, the direction and magnitude of these changes and the presence or absence of chest pain during typical ST segment changes. It was noted that patients with chest pain experienced the pain 30 seconds to several minutes after the onset of electrocardiographic changes. This was one of the earliest observations that chest pain is one of the last things to occur in patients having acute myocardial ischemia. In addition, the asymptomatic episodes of ST segment depression and ST segment shifts were indistinguishable from those accompanied by chest pain except for their unusually short duration (from 30 seconds to 6 minutes compared with 2 to 20 minutes for episodes with pain). These observations have been repeated many times since these initial findings.
Hemodynamic observations during myocardial ischemia
Many of the patients in this study were monitored hemodynamically, and the findings were the first of their kind. The investigators found no consistent increase in heart rate, blood pressure or dP/dt in any patient before the onset of ST segments elevation or depression or T wave changes. The most typical hemodynamic pattern observed in the initial phase of ST segment elevation with pain was a reduction of relaxation and contraction peak dP/dt of the left ventricle. This change, which slightly preceded or accompanied the onset of ST segment and T wave elevation, was immediately followed by an increase by end-diastolic pressure. These seminal observations have been confirmed many times, particularly in the angiographic suites in which patients are undergoing balloon angioplasty. The precise onset of occlusion of the vessel with the balloon is known, and these electrocardiographic and hemodynamic changes occur as described by Maseri and colleagues many years before angioplasty was performed.
Coronary angiography during myocardial ischemia
Angiographic studies performed during an angina episode occurring spontaneously or induced with ergonovine showed severe reversible coronary vasocontriction in all patients in which it was investigated. Occlusion was the most usual finding by spasm diffusely involving a main vessel and its branches. Delayed filling and run-off but without occlusion was observed at the beginning and during the waning phases of the ischemic episode. It seems that Maseri et al. were of the earliest groups of investigators to describe the “no reflow” or at least a “slow reflow” phenomenon in humans.
Another important observation made by Maseri et al. was that most patients with coronary vasospasm had double- or triple-vessel disease and that the artery involved by the spasm was not consistently less or more severely involved by the atherosclerotic process than the other arteries.
Ventricular arrhythmias or AV block were occasionally observed during episodes of ischemia with or without pain.
Maseri et al. have proved conclusively that all episodes of acute myocardial ischemia can not be due to fixed critical coronary artery stenosis that limits coronary blood flow under conditions of increased myocardial oxygen demand.
The investigation by these authors suggests that for patients with rest angina, studies should be performed to establish whether angina at rest is secondary to the exhaustion of the limited fixed coronary reserve by an excessive increase in demands, or whether it is caused by primary sudden reduction of blood supply or by other mechanisms yet unidentified. The clinical implications of this statement are obvious.
- American College of Cardiology