Increase in myocardial oxygen consumption indexes by exercise training at onset of ischemia in patients with coronary artery disease

It has been unclear whether exercise training of patients with coronary artery disease increases the level of myocardial oxygen consumption, as indicated by heart rate and double product of heart rate and systolic blood pressure, at which electrocardiographic evidence of myocardial ischemia develops. To assess this question we evaluated the experience of 10 patients with coronary artery disease who underwent a modest-level exercise training program for 6 months. All of these subjects had achieved a training effect, had developed electrocardiographic evidence of ischemia during initial exercise testing, had not increased the amount of cardiac medication taken, and had not been taking digoxin. After completion of the training period, the mean heart rate at which electrocardiographic evidence of ischemia developed increased from 107 +/- 19 to 119 +/- 23 beats/min (p less than .05) and the mean double product increased from 166 +/- 18 to 209 +/- 51 X 10(2) mm Hg X beats/min (p less than .05). Eight of the 10 patients demonstrated an increase in heart rate at onset of ischemia (p less than .02), and seven of the eight in whom double product could be assessed manifested an increase in this parameter at onset of ischemia (p less than .05). Thus the rate of myocardial oxygen consumption at which myocardial ischemia develops, as indirectly assessed by heart rate and double product, can be favorably altered by 6 months of moderate-level exercise training.     

Frequent episodes of silent myocardial ischemia after apparently uncomplicated myocardial infarction

Frequent episodes of silent myocardial ischemia were documented in two patients, one with recognized and one with unrecognized prior myocardial infarction. Neither patient had symptoms after the infarction, but both demonstrated silent myocardial ischemia on exercise testing, which prompted further study with 48 hour ambulatory electrocardiographic (Holter) recordings. In each patient, heart rate recorded with the Holter monitor during the ischemic episodes was usually less than that observed during ischemia precipitated by exercise testing. This suggests that increased vasoconstrictive tone may play a role in silent ischemic episodes occurring during daily activities.     

Myocardial ischemia during daily activities: the importance of increased myocardial oxygen demand

The role of increased myocardial oxygen demand in the pathophysiology of myocardial ischemia occurring during daily activities was evaluated in 50 patients with coronary artery disease and exercise-induced ST segment depression. Each patient underwent ambulatory electrocardiographic (ECG) monitoring for ST segment shifts during normal daily activities and symptom-limited bicycle exercise testing with continuous ECG monitoring. All 50 patients had ST depression greater than or equal to 0.1 mV during exercise. A total of 241 episodes of ST depression were noted in the ambulatory setting in 31 patients; only 6% of these were accompanied by angina pectoris. Significant (0.1 mV) ST depression during ambulatory monitoring was preceded by a mean increase in heart rate of 27 +/- 12 beats/min. Patients with ischemia during daily activities developed ST depression earlier during exercise (7.9 +/- 4.4 vs. 14.2 +/- 6.4 min, p less than 0.001) and tended to have significant ECG changes at a lower exercise heart rate and rate-pressure product than did those without ST depression during ambulatory monitoring. In the 31 patients with ischemia during daily activities, the mean heart rate associated with ST depression in the ambulatory setting was closely correlated with the heart rate precipitating ECG changes during exercise testing (r = 0.74, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Improvement of exercise-induced left ventricular dysfunction with oral propranolol in patients with coronary heart disease.

The effect of propranolol on global cardiac function during exercise was analyzed with equilibrium fadionuclide angiography in 10 patients with ischemic heart disease. All patients had angina pectoris and S-T segment depression of more than 0.1 mv during treadmill exercise when not taking propranolol. Each patient was stressed with supine bicycle exercise to the same work load on a maintenance dose of propranolol (120 to 400 mg/day) and on a second occasion without the drug, the two tests being separated by an average of 16 days. The mean heart rate was reduced both at rest and during exercise after propranolol, but propranolol caused no significant reduction of the left ventricular ejection fraction at rest. In the study without administration of propranolol the average ejection fraction during exercise decreased from 0.56 ± 0.09 (standard deviation) to 0.50 ± 0.14. With propranolol, the ejection fraction was improved from the control value in every patient, the average value during peak exercise reaching 0.60 ± 0.15. Thus, the average ejection fraction increased by 22 percent (±12 percent) relative to the value during the same exercise without propranolol (P < 0.001). In 16 other patients with ischemic heart disease who did not take propranolol, reproducibility of the ejection fraction both at rest and at peak exercise on two occasions within 15 days was good (r = 0.95 and 0.97, respectively). It is concluded that oral propranolol therapy in patients with coronary artery disease can ameliorate left ventricular dysfunction induced by exercise and thereby may reduce myocardial ischemia.     

Role of myocardial oxygen demand in the pathogenesis of silent ischemia during daily life.

The role of myocardial oxygen demand in the pathogenesis of silent ambulatory myocardial ischemia was evaluated by reviewing and assessing the methods and results of recent studies. The performance of simultaneous ambulatory electrocardiographic and blood pressure monitoring in 25 men with proven coronary artery disease (CAD) revealed significant increases in heart rate and blood pressure (p < 0.001) preceding most silent ischemic events. By plotting the mean heart rate obtained at 5-minute intervals during the 30 minutes before an ischemic event, the ischemic heart rate was shown to be significantly higher (95 +/- 15 vs 74 +/- 11 beats per minute [bpm]; p < 0.01) than the nonischemic heart rate. The evaluation of heart rate changes during ambulatory ischemia (in patients with CAD and ischemia induced by an exercise test using gradual work load increments) showed a significant heart rate increase (> 10 bpm) at 1-5 minutes preceding the onset of ST-segment depression. Heart rate increases during exercise testing according to the gradual work load increments of the National Institutes of Health protocol were compared with the heart rate preceding ischemic events during daily life monitored by ambulatory electrocardiography and were found to be closely related. In contrast, heart rate increases that occurred during exercise testing using the standard Bruce protocol were higher and correlated less with those preceding ischemia in daily life. Heart rate and blood pressure increased significantly in most silent ischemic episodes, indicating that increased myocardial oxygen demand plays a significant role in the pathogenesis of myocardial ischemia during daily life.     

Shortened platelet survival time and enhanced heart rate responses after abrupt withdrawal of propranolol from normal subjects

Although clinical observations suggest that abrupt discontinuation of propranolol therapy may precipitate myocardial ischemia and infarction in patients with coronary occlusive disease, the physiologic consequences of propranolol withdrawal are not fully understood. Platelet survival times and heart rate responses to exercise, upright tilt and isoproterenol were therefore examined in 14 normal subjects before and after abrupt withdrawal of propranolol. Propranolol, 80 to 240 mg/day, was given for 24 to 79 days; its effect was confirmed by a lower heart rate during exercise and during infusion of isoproterenol. In 10 subjects, the mean survival time of chromium-51-tagged blood platelets decreased from 10.0 days before propranolol to 7.8 days after its withdrawal (p <0.05). One day after withdrawal, the rise in heart rate with exercise or tilt was slightly increased from values before propranolol therapy. Two days after withdrawal of propranolol the mean peak heart rate during exercise (165 beats/min) was 12 beats/min higher (p <0.01) than the value before propranolol. On this same day heart rate increased more after tilt without medication (+6 beats/min, p <0.05) and more after tilt following vagal blockade (+8 beats/min, p <0.02) than before treatment with propranolol. Seven days after propranolol withdrawal, heart rate responses to exercise or tilt remained increased. Isoproterenol-induced heart rate responses (5 to 40 ng/kg per min, n = 14), white blood cell beta receptor function (cyclic adenosine monophosphate production after isoproterenol and ³H-I-dihydroalprenolol binding, n = 9) and plasma norepinephrine values at rest and during exercise (n = 7) were each unaltered after propranolol.The results suggest that abrupt withdrawal of propranolol is accompanied by a shortening of platelet survival and enhancement of sympathetically mediated reflex increases in heart rate. These changes may each play a role in the increased incidence of ischemic episodes observed after withdrawal of propranolol from patients with coronary occlusive disease. However, the number of beta receptors and their sensitivity to adrenergic agonists do not seem to be changed uniformly after abrupt withdrawal of propranolol.     

Quantification of pulmonary thallium-201 activity after upright exercise in normal persons: importance of peak heart rate and propranolol usage in defining normal values

Fifty-nine normal patients (34 angiographically normal and 25 clinically normal by Bayesian analysis) underwent thallium-201 imaging after maximal upright exercise. Lung activity was quantitated relative to myocardial activity and a lung/myocardial activity ratio was determined for each patient. Stepwise regression analysis was then used to examine the influence of patient clinical characteristics and exercise variables on the lung/myocardium ratio. Peak heart rate during exercise and propranolol usage both showed significant negative regression coefficients (p less than 0.001). No other patient data showed a significant relation. Using the regression equation and the estimated variance, a 95% confidence level upper limit of normal could be determined for a give peak heart rate and propranolol status. Sixty-one other patients were studied to validate the predicted upper limits of normal based on this model. None of the 27 patients without coronary artery disease had an elevated lung/myocardial ratio, compared with 1 of 8 with 1-vessel disease (difference not significant), 6 of 14 with 2-vessel disease (p less than 0.005), and 6 of 12 with 3-vessel disease (p less than 0.0001). Thus, lung activity on upright exercise thallium-201 studies can be quantitated relative to myocardial activity, and is inversely related to peak heart rate and propranolol use. Use of a regression analysis allows determination of a 95% confidence upper limit of normal to be anticipated in an individual patient.     

Role of increases in heart rate in determining the occurrence and frequency of myocardial ischemia during daily life in patients with stable coronary artery disease.

OBJECTIVES. The goal of this study was to investigate the role of increases in heart rate in the development of ischemic episodes recorded during ambulatory electrocardiographic (ECG) monitoring in patients with stable coronary artery disease and to establish the importance of such increases in determining the frequency of ambulatory myocardial ischemia. BACKGROUND. The factors that determine the occurrence and frequency of episodes of myocardial ischemia that patients with stable coronary artery disease experience during daily life have not been clearly defined. In particular, the role of increases in heart rate in the development of myocardial ischemia is controversial. METHODS. To address these issues, 54 patients (42 men and 12 women, mean age 60.5 +/- 8 years) with proved coronary artery disease who had > or = 1 mm ST segment depression during exercise testing underwent an exercise treadmill test with use of the National Institutes of Health combined protocol and a 48-h period of ambulatory ECG monitoring. The exercise ischemic threshold was determined as the heart rate at the onset of ST segment depression during exercise testing. RESULTS. During monitoring, 48 (89%) of the 54 patients had at least one episode of ST segment depression (mean +/- SD 6.6 +/- 5 episodes, range 0 to 22). The majority (320 of 359 or 89%) of ischemic episodes were preceded by an increase in heart rate > or = 10 beats/min; the most significant increase (22.3 +/- 10 beats/min) occurred during the 5-min period before the onset of the episode. An ischemic episode occurred 80% of the times the heart rate reached the exercise ischemic threshold. A strong correlation was observed between the number of times the exercise ischemic threshold was reached during monitoring and both the number and the duration of ischemic episodes (r = 0.90 and 0.71, respectively, p < 0.0001). CONCLUSIONS. Increases in heart rate that exceed the exercise ischemic threshold are commonly observed before the onset of episodes of ambulatory myocardial ischemia in patients with stable coronary artery disease. Moreover, such increases constitute an important determinant of the frequency of myocardial ischemia during daily life. These findings may explain the variability observed in the number of ischemic episodes and may have important implications for the mechanisms that contribute to myocardial ischemia in daily life and for the clinical evaluation of patients with coronary artery disease.     

Submaximal exercise testing after acute myocardial infarction: myocardial scintigraphic and electrocardiographic observations.

The relation between global and regional left ventricular function and electrocardiographic signs of ischemia at rest and during submaximal supine exercise was studied in 27 patients 2 to 3 weeks after acute myocardial infarction. Dynamic myocardial scintigraphy was performed at rest and during submaximal exercise utilizing an in vivo method of labeling red blood cells with technetium-99m pertechnetate. Gated radionuclide blood pool scintigrams were obtained in a modified left anterior oblique, and in some patients also in the right anterior oblique projection, to measure left ventricular ejection fraction and segmental wall motion. Electrocardiographic monitoring of heart rate and rhythm was provided during the exercise. The submaximal exercise test was terminated when the patient's heart rate reached 125 beats/min or if angina, malignant ventricular ectopy or electrocardiographic evidence of myocardial ischemia developed before this rate was reached. The data demonstrate that patients with a recent anterior myocardial infarct, in contrast to patients with a recent inferior or nontransmural infarct, manifest a significant reduction in left ventricular ejection fraction with submaximal exercise. Of the eight patients with an anterior infarct, seven had segmental wall motion abnormalities at rest. Four of these eight manifested more severe abnormalities with submaximal exercise; three had abnormalities at rest that did not change with exercise. Four of the eight had a positive electrocardiographic response during exercise (two were taking digoxin). Of these four, only two had more marked wall motion abnormalities with effort. Of the 13 patients with an inferior infarct, 11 had apparently normal wall motion in the modified left anterior oblique projection at rest, including 2 who manifested segmental wall motion abnormalities with submaximal exercise; the 2 remaining patients had wall motion abnormalities at rest that, on exercise, became more marked in one and were unchanged in one. Four of the 13 had a positive electrocardiographic response with exercise (one was taking digoxin); only one of these had a detectably more severe wall motion abnormality with exercise. Of the six patients with a nontransmural infarct, four had no identifiable wall motion abnormalities at rest; in one of these, an abnormality developed with exercise. The remaining two patients had wall motion abnormalities at rest; in one, a positive electrocardiographic ischemic response developed with exercise. Patients with an anterior infarct appear to have a different functional ventricular response to submaximal exercise at the time of hospital discharge than patients with an inferior or nontransmural infarct. To identify ischemic responses with submaximal exercise in these patients one should ideally use both electrocardiographic monitoring and dynamic myocardial scintigraphy.     

Plasma norepinephrine in exercise-induced ventricular tachycardia

The relation between plasma norepinephrine levels and the occurrence of ventricular tachycardia during exercise testing was prospectively evaluated in 17 patients. Ten patients had reproducible ventricular tachycardia exclusively during exercise or recovery, or both; 7 patients had ventricular tachycardia only during ambulatory electrocardiographic monitoring. The two groups did not differ in age, exercise duration, left ventricular ejection fraction at rest, heart rate throughout the exercise protocol, rest QTc interval, change in QTc interval during exercise, the presence of coronary artery disease or exercise-related myocardial ischemia. Furthermore, there was no difference between groups in plasma norepinephrine levels at rest, peak exercise or in the recovery period. Myocardial ischemia was detectable by thallium perfusion scan in only 2 of the 10 patients with exercise-induced ventricular tachycardia. The 10 patients with exercise-induced ventricular tachycardia underwent repeat exercise testing immediately after maximal intravenous beta-adrenergic blockade with propranolol. Although they had no change in exercise duration, ventricular tachycardia did not occur in 9 of these 10 patients. Plasma norepinephrine levels were significantly decreased compared with levels before beta-adrenergic blockade (p less than 0.0002). Thus, plasma norepinephrine levels do not distinguish patients with reproducible exercise-induced ventricular tachycardia from otherwise comparable patients. Propranolol is highly effective in abolishing this arrhythmia and this effect is associated with decreased norepinephrine levels.     

Mechanism underlying the absence of ischemic changes on the exercise electrocardiogram in patients with abnormal exercise thallium-201 imaging and coronary artery disease

Patients with coronary artery disease may have reversible abnormalities on a thallium myocardial perfusion study without simultaneous ischemic changes on the exercise electrocardiogram, but the mechanisms responsible for this disparity have not been fully elucidated. A group of 37 patients with angiographically demonstrated coronary artery disease and abnormal thallium perfusion imaging were divided into two groups on the basis of their exercise electrocardiographic ST segment response. Thirteen patients (Group A) had no significant electrocardiographic changes with exercise, while 24 patients (Group B) had ST changes consistent with ischemia during the test. There were no significant differences in clinical or angiographic characteristics between the two groups. Stress test results showed a similar mean duration of exercise in the two groups (6.2 +/- 1.8 versus 6.7 +/- 2.5 min, p = NS), but the patients in Group A achieved a significantly lower mean maximal heart rate (117 +/- 26 versus 132 +/- 21 beats/min, p less than 0.05) and mean maximal double product (19,650 +/- 5116 versus 22,650 +/- 4871, p less than 0.05). There was no consistent pattern of thallium perfusion abnormality noted in Group A to suggest that a particular region of electrically silent myocardium was responsible for ischemia in the absence of electrocardiographic changes. These results suggest that exercise thallium-electrocardiogram discordance is mediated by the level of myocardial workload achieved. An abnormal perfusion scan accompanying an exercise electrocardiogram which does not demonstrate any ischemic ST change may occur when there is sufficient increase in myocardial oxygen demand to result in differential augmentation of myocardial blood flow, but insufficient imbalance of supply and demand to result in signs of ischemia on the surface electrocardiogram.     

Effect of diltiazem on silent ischemic episodes, plasma bradykinin and prostaglandin metabolism.

Plasma bradykinin and prostaglandin metabolism are related to the anginal pain modulating system in patients with ischemic heart disease. We carried out a placebo controlled single blind test of diltiazem (30 mg three times a day) in 15 patients with chronic stable angina. The effect of diltiazem was evaluated by exercise treadmill testing and 48-h ambulatory electrocardiographic monitoring. Plasma bradykinin, thromboxane B2, and 6-keto-prostaglandin F1 alpha levels were determined by radioimmunoassay prior to and during diltiazem therapy. Diltiazem significantly increased the exercise time and reduced episodes of angina. Diltiazem, however, did not appreciably improve either the frequency of silent myocardial ischemic episodes or the total duration of the silent myocardial ischemic episodes. Diltiazem also tended to decrease plasma bradykinin, thromboxane B2, and 6-keto-prostaglandin F1 alpha levels. When ischemic episodes on ambulatory electrocardiographic monitoring are categorized according to heart rate change at the onset of episode (type A, preceded by heart rate increase > or = 5 beats/min; type B, no preceding heart rate increase), diltiazem was only effective on type A ischemic episodes as well as on symptomatic ischemia. Further, bradykinin was significantly decreased by diltiazem only in patients with exercise-induced silent ischemia or no exercise-induced ischemia, while the thromboxane B2/6-keto-prostaglandin F1 alpha ratio was unaffected by the administration of diltiazem. Thus, silent and symptomatic ischemia may be associated with different bradykinin and prostaglandin responses.     

The effect of timolol vs placebo on angina pectoris

The effect of timolol vs placebo on the frequency of anginal episodes, nitroglycerin consumption and exercise performance was investigated in a double-blind, randomized, crossover study in 23 patients with angina pectoris. The optimal dose of timolol (10-30 mg twice daily) for each patient was titrated by exercise studies. Compared with placebo, timolol decreased the weekly number of anginal attacks and the weekly number of nitroglycerin tablets consumed, reduced the resting heart rate, systolic and diastolic blood pressure, and product of systolic blood pressure times heart rate, decreased the heart rate, systolic and diastolic blood pressure, and product of systolic blood pressure times heart rate at the onset of angina pectoris or marked fatigue, prolonged exercise duration, and diminished electrocardiographic evidence of myocardial ischemia. Timolol is an excellent antianginal agent when prescribed twice daily, with the optimal dose titrated by exercise studies.     

Comparative sensitivity and specificity of exercise electrocardiographic lead systems

A comparison of current exercise electrocardiographic lead systems reveals differences in the sensitivity and specificity of S-T segment shifts diagnostic of obstructive coronary artery disease. The differences are explained in part by differences in population samples, lead systems and criteria for positivity. Multiple electrocardiographic lead recording in symptomatic patients during and after exercise improves sensitivity in detecting S-T segment shifts with only a small decrease in specificity. A review of population screening studies in asymptomatic subjects shows a wide selection of different exercise electrocardiographic lead systems and criteria for a positive test. Few screening studies have compared the prevalence of different S-T segment configurations in individual leads of a simultaneously recorded multiple lead system during or after exercise.

Data from animal studies of myocardial ischemia suggest why 100 percent sensitivity in detecting obstructive coronary disease is unlikely to be obtained with surface electrocardiographic recordings. Additional research is required to identify the optimal set of diagnostic exercise electrocardiographic leads and criteria for positivity so that maximal predictive accuracy can be obtained for different patient subsets.     

Circadian distribution of the characteristics of ischemic episodes in patients with stable coronary artery disease

To determine the circadian distribution of episodes of myocardial ischemia, studies were performed in 111 patients with chronic stable angina pectoris, positive exercise test results and angiographically proven coronary artery disease. During 24 hours of ambulatory electrocardiographic monitoring, 101 symptomatic and 298 asymptomatic ischemic episodes (ST-segment depression greater than 1 mm, duration greater than 1 minute) were observed. The number of ischemic episodes and the cumulative duration of ischemia showed a circadian variation with the highest values between 8 and 10 A.M. and between 4 and 5 P.M. associated with a similar circadian variation of heart rate. Mean duration of ischemic episodes, maximal amplitude of ST-segment depression during ischemic episodes and increase in heart rate before the onset of ischemic episodes showed no significant circadian variation. Heart rate at the onset of ischemic episodes and maximal heart rate during ischemic episodes were lower between midnight and A.M. than during other times of the day. The morning and afternoon increase in ischemic activity is not paralleled by changes reflecting a decrease in myocardial oxygen supply during these periods (heart rate at onset of ischemia, heart rate increase before onset of ischemia), but is paralleled by a similar circadian variation of heart rate. The circadian variation in ischemic activity is predominantly based on a comparable variation in myocardial oxygen requirements.     

Relations between heart rate, ischemia, and drug therapy during daily life in patients with coronary artery disease

BACKGROUND. Previous studies have shown that little if any increase in heart rate occurs 1 minute before the onset of ischemia in ambulant patients with coronary artery disease. This study tested the hypothesis that there are characteristic relations between heart rate and ischemia in ambulant patients with coronary artery disease. METHODS AND RESULTS. Twenty-one patients with proven coronary disease demonstrated 212 episodes of ischemia during 504 hours of continuous monitoring of the electrocardiogram. An important increase in heart rate (from 74 +/- 11 to 90 +/- 14 beats/min, p less than 0.001) occurred between 5 and 30 minutes (not 1 minute) before the onset of ischemia. A significantly higher heart rate at onset of ischemia was seen during Bruce protocol exercise testing than during daily life (117 +/- 12 versus 95 +/- 15 beats/min, p less than 0.01). However, when a less-strenuous, but more prolonged, exercise protocol was used in a subgroup of patients (n = 12), ischemia occurred at a heart rate that was significantly lower than during the Bruce protocol (88 +/- 14 versus 103 +/- 15 beats/min, p less than 0.05) and was not significantly different from the threshold heart rate at onset of ischemia during daily life (88 +/- 14 versus 84 +/- 12 beats/min, p = NS). As part of two placebo-controlled trials, treatment with both propranolol and nitroglycerin altered the distribution of ischemic events by heart rate but in opposite directions. Although propranolol largely eliminated events occurring at high (greater than 100 beats/min) and moderate (80-100 beats/min) heart rates, the number of events at low (less than 80 beats/min) heart rates was increased. In contrast, nitroglycerin reduced episodes at low and moderate heart rates only. CONCLUSIONS. Important increases in heart rate occur before the onset of ischemia during daily life, but this increase occurs much earlier than has been reported. Duration of heart rate increase appears to influence the heart rate threshold for ischemia, and this may contribute to the occurrence of ischemia at lower heart rates during daily life than during standard exercise testing. Last, different classes of drugs appear to have characteristic effects on ischemia occurring at different heart rates that may be useful in planning therapy.     

Symptomatic and silent myocardial ischemia during exercise testing in coronary artery disease

During exercise by patients with coronary artery disease (CAD), electrocardiographic evidence of myocardial ischemia may precede the onset of angina or may be unassociated with angina, even at peak levels of stress. However, neither the precise incidence of silent versus symptomatic ischemic episodes nor their interrelation in this setting has been clearly defined. The prevalence of silent and symptomatic myocardial ischemia during treadmill exercise testing was determined in 92 patients with angiographically documented CAD. The study group comprised 77 men (84%) and 15 women (16%) of mean age 57 years (range 32 to 79). Exercise testing resulted in ischemic ST-segment depression (greater than or equal to 1 mm for greater than or equal to 80 ms) only or in association with delayed (greater than or equal to 1 minute) angina in 39 patients (42%); angina only or in association with delayed ST-segment depression occurred in 42 patients (46%); and simultaneous occurrence of angina and ST-segment depression was noted in 11 patients (12%). Analysis of clinical, exercise and angiographic factors (age, sex, history of myocardial infarction, heart rate, maximal ST-segment depression, extent of CAD and left ventricular ejection fraction) revealed no significant correlation with the frequency of symptomatic and silent myocardial ischemia during exercise. Asymptomatic myocardial ischemia occurred commonly during exercise in patients with CAD, but there were no differences in the characteristics of patients with symptomatic and asymptomatic episodes.     

Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. The ASIS Study Group

Episodes of transient myocardial ischemia during ambulatory activities are common in patients with stable coronary artery disease and who are often asymptomatic. Selection of therapy for episodes of asymptomatic ischemia is limited by a lack of direct comparative studies. To determine the most effective monotherapy for patients with stable angina and a high frequency of asymptomatic ischemic episodes, propranolol-LA (mean daily dose, 293 mg), diltiazem-SR (mean daily dose, 350 mg), nifedipine (mean daily dose, 79 mg) were each compared with placebo, each for 2 weeks, in a randomized, double-blinded, crossover trial. Entry criteria were a positive exercise treadmill test during placebo therapy characterized by 1.0 mm or more ST segment depression and angina pectoris, and six or more episodes of transient ST segment depression of 1.0 mm or more on a 48-hour ambulatory electrocardiogram. One hundred ninety-four patients were screened, 63 were eligible and received randomized therapy, of which 56 patients completed at least two of the four treatment periods and were included in an intent-to-treat analysis. Fifty patients completed all four treatment phases and were included in the protocol-completed analysis. Anti-ischemia efficacy was assessed by 48-hour ambulatory electrocardiographic monitoring, exercise treadmill tests, and anginal diaries. Ninety-four percent of all episodes of ambulatory ischemia were asymptomatic. Compared with placebo, only propranolol was associated with a marked reduction in all manifestations of asymptomatic ischemia during ambulatory electrocardiographic monitoring (2.3 versus 1.0 episodes/24 hr; mean duration of ischemia per 24 hours, 43.6 versus 5.7 minutes; both p less than 0.0001). Diltiazem's reduction of the frequency of episodes compared with placebo (2.3 versus 1.9 episodes/24 hr) was associated with a trend (p = 0.08) in the protocol-completed analysis and with a significant reduction in the intent-to-treat analysis (p = 0.03). Nifedipine had no significant effect on any measured variable of ambulatory ischemia. The dosages of medication used may have been excessive for some patients, and a more beneficial effect may have been evident at a lower dose. In contrast to the marked effects of the active agents on ambulatory asymptomatic ischemia, the effects on exercise performance and angina pectoris were slight. The active agents modestly improved treadmill exercise duration time until 1 mm ST segment depression (3%), and only propranolol and diltiazem had significant effects. Only diltiazem significantly prolonged the total exercise time. Anginal frequency was significantly decreased by both propranolol and diltiazem.(ABSTRACT TRUNCATED AT 400 WORDS)     

Exercise-induced cardiac dysfunction in sickle cell anemia. A radionuclide study

Cardiac performance was studied by radionuclide angiography at rest and during exercise in 22 adolescents with sickle cell (SC) anemia and the results were compared with those in 12 control subjects. At rest, cardiac contractility was normal; cardiac output and end-diastolic volume were increased. At maximal exercise, heart rate, cardiac output response, and work capacity were reduced; the reduction was related to the degree of anemia. Left ventricular end-diastolic volume decreased with exercise most markedly in patients with ischemic exercise electrocardiograms. An abnormal ejection fraction response to exercise occurred in 4 patients; electrocardiographic signs of ischemia developed in all 4, and wall motion abnormalities in 2. Those patients who had electrocardiographic signs of ischemia had a significantly lower heart rate, ejection fraction, and cardiac output response to exercise, and a lower hematocrit level than subjects with normal results on exercise electrocardiography. The increase in cardiac output was not sufficient to maintain a normal level of exercise. The decrease in end-diastolic volume suggests that diastolic function was abnormal during exercise. Cardiac dysfunction was manifested by an abnormal ejection fraction response, wall motion abnormalities, and incomplete left ventricular filling during exercise.     

Detection of silent myocardial ischemia in diabetes mellitus

The prevalence of silent myocardial ischemia and its relation to autonomic dysfunction and pain threshold was studied in 58 men with diabetes mellitus and without cardiac symptoms. All patients underwent 48-hour ambulatory electrocardiographic monitoring and exercise testing after assessment of their autonomic function and pain threshold. Silent myocardial ischemia, defined as greater than or equal to 1 mm of ST-segment depression on either exercise testing or ambulatory electrocardiographic monitoring, was corroborated by exercise-induced reversible defect(s) on tomographic thallium scintigraphy. Autonomic function was assessed by heart rate response to: (1) Valsalva maneuver, (2) deep breathing, and (3) upright posture, as well as by diastolic blood pressure response to sustained handgrip and systolic blood pressure response to upright posture. Autonomic dysfunction was defined as greater than or equal to 2 abnormal responses. Pain threshold measurements were performed using electrical cutaneous stimulation of both forearms. Of the 58 diabetic patients, 21 were found to have autonomic dysfunction (36%). Silent myocardial ischemia was detected in 10 patients (17%), and was significantly more frequent in patients with than without autonomic dysfunction (38 vs 5%, p = 0.003). There was no difference in the electrical pain threshold or tolerance in subjects with and without silent myocardial ischemia. It is concluded that silent myocardial ischemia in asymptomatic diabetic men occurs frequently and in association with autonomic dysfunction, suggesting that diabetic neuropathy may be implicated in the mechanism of silent myocardial ischemia.