Beta-adrenergic blockers in silent myocardial ischemia.

Factors contributing to the development of exercise-induced painful ischemia, such as actions of the central nervous system and catecholamines, have been well identified, but the mechanisms by which nonexercise-related silent episodes of ischemia are provoked are unknown. Possible mechanisms receiving much study in recent years are those having the potential to influence the myocardial oxygen supply-demand relation. Beta-adrenergic receptor stimulations, by increasing myocardial oxygen demand through augmentation of heart rate and contractility (beta 1), may mediate responses that cause ischemia or perpetuate ischemic episodes induced by other means. Other receptors (beta 2) may mediate coronary and peripheral vascular constriction, limiting myocardial oxygen supply and further increasing myocardial oxygen demand. Studies have investigated the effect of beta blockade on ischemic episodes in patients with a variety of clinical forms of coronary heart disease. Beta blockade has been shown to reduce the frequency and duration of silent and painful ischemic episodes in patients with effort angina and rest angina. The data suggest that heart rate and perhaps other changes observed with use of beta blockade play an important role in silent ischemia; heart rate at specific times throughout the day, particularly in the late A.M., and the increase in heart rate seen in conjunction with silent ischemic episodes are all decreased with administration of beta blockade. Results of a recent study focusing only on silent ischemia showed that beta-blocker treatment with metoprolol, compared with placebo, significantly reduced total silent ischemic time (frequency and duration of episodes) in all periods examined.

Low-frequency requirements for recording ischemic ST-segment abnormalities in coronary artery disease.

The objective of this investigation was to determine whether extended low-frequency response is required to record ischemic ST-segment abnormalities in humans. Bipolar electrocardiograms (ECGs) were recorded in 5 men with coronary artery disease using a high-fidelity instrumentation amplifier and FM tape recorder before, during and after erect bicycle exercise. In all patients, ischemic ST-segment abnormalities developed during exercise; 3 patients had angina and 2 remained asymptomatic throughout the test. Using a fast-Fourier transform (FFT) and a variable digitizing rate into a 1,024-point input array, FFT spectra were computed with low-frequency content extending to either 0.20, 0.98 or 1.95 Hz for both a rest and exercise ECG. From these spectra, ECGs were resynthesized using the inverse FFT and compared with the original records. Visual inspection of the original and resynthesized ECGs revealed no obvious differences when low-frequency content extended to 0.20, 0.98 or 1.95 Hz. Numerical comparisons were made by calculating the coefficient of determination (R2) between the original and resynthesized ECGs. The R2 (mean +/- standard deviation) for these comparisons was 0.998 +/- 0.001. It is concluded that the amplitude-response characteristics of electrocardiographic recording equipment do not require extended low-frequency range (such as that found in FM systems) to accurately reproduce ischemic ST-segment abnormalities in humans.

Silent myocardial ischemia during daily activities in asymptomatic men with positive exercise test responses.

The usefulness of prolonged ambulatory electrocardiographic monitoring (AEM) for detecting ischemia was investigated in 17 asymptomatic men who had ischemic-type ST-segment depression (greater than or equal to 2.0 mm) during treadmill exercise testing. No patient took anti-ischemic medications and all patients underwent coronary angiography. A total of 1,154 hours (range 64 to 72 hours/patient) of high-quality AEM recordings was obtained. Silent ischemia (episodes of asymptomatic ischemic-type ST depression of 60 seconds or longer) occurred in 11 patients during daily activity detected by AEM. In 6 other patients, no myocardial ischemic episodes were found. But 1 of these patients withdrew after only 24 hours of AEM and the remaining 5 had no significant coronary artery disease (CAD). All 11 patients who had silent ischemia had significant CAD (at least 50% stenosis) on angiography. There was wide intrapatient variability in the frequency of silent ischemic episodes. Silent ischemia was identified in 6 of these 11 patients after 24 hours of AEM, in 2 after 48 hours and in 3 after 72 hours. Thus, asymptomatic men with positive exercise test responses and CAD have silent ischemic episodes during daily activity. AEM may be useful in helping to predict which patients with asymptomatic positive exercise test responses have CAD; however, extended AEM periods are required.

Effects of titrated beta blockade (metoprolol) on silent myocardial ischemia in ambulatory patients with coronary artery disease.

This study investigates effects of beta-adrenergic blockade on total silent ischemic time assessed by ambulatory electrocardiographic monitoring and its relation to heart rate and time of day in ambulatory men with coronary artery disease. Metoprolol, when titrated to optimal dose in a controlled trial in 9 patients, reduced both total silent ischemic time (from 156 +/- 65 to 20 +/- 15 minutes, p = 0.04) and frequency of silent ischemic episodes (from 8 +/- 2 to 2 +/- 2 episodes, p = 0.03) compared with placebo. Mean daily heart rate was reduced, from 82 +/- 2 beats/min during placebo to 58 +/- 1 beats/min, as was heart rate at onset of 1 mm of ST-segment depression (106 +/- 2 to 74 +/- 4 beats/min, both p less than 0.001). Heart rate increased 10 +/- 1 beats/min during silent ischemia with placebo therapy, but increased only 4 +/- 1 beats/min during metoprolol treatment (p less than 0.03). During placebo administration the largest proportion of silent ischemic time occurred between 0600 and 1200 hours. Metoprolol attenuated this circadian variation in silent ischemia while reducing (p less than 0.05) total silent ischemic time in all periods. Thus, beta-adrenergic blockade reduces the frequency of silent myocardial ischemic episodes and total silent ischemic time, while mean daily heart rate and heart rate at onset of ischemia and maximal ischemia decrease. Metoprolol treatment also attenuates circadian variation of silent ischemia. These data may be interpreted to suggest that beta-adrenergic activation operates in the pathogenesis of silent myocardial ischemia and its circadian variation.

Silent myocardial ischemia during daily activities: studies in asymptomatic patients and those with various forms of angina.

Asymptomatic subjects with proven coronary artery disease, including those with no previous manifestations of coronary heart disease and those with previous myocardial infarction, have silent ischemic episodes during daily activity. Patients with all forms of angina, stable effort and unstable rest angina, and those with coronary artery spasm have very frequent episodes of silent myocardial ischemia during ordinary activity. Characteristics of these episodes and evidence for these findings are reviewed.

Evaluation and treatment of the asymptomatic patient with a positive exercise tolerance test.

A positive exercise study in an asymptomatic patient presents a clinical dilemma. Many of these asymptomatic positive studies are false-positive, but a subset of these patients have silent coronary artery disease. Other noninvasive tests can be used in conjunction with exercise testing to help identify this subset of patients, but coronary angiography is often ultimately necessary to ensure an accurate diagnosis. An algorithm for the evaluation and treatment of the patient with an asymptomatic positive exercise study is proposed.

Detection of silent myocardial ischemia in patients with angina using continuous electrocardiographic monitoring.

In patients with effort angina, ST-segment depression is a reliable indicator of transient myocardial ischemia. Ambulatory electrocardiographic monitoring can detect episodes of ST-segment depression with and without chest pain in patients with coronary heart disease. This test provides valuable information about the presence, frequency, magnitude, and duration of transient myocardial ischemia and associated trigger factors.

Ambulatory ECG (Holter) monitoring in management of acute myocardial ischemia.

Ambulatory ECG monitoring for detection of transient myocardial ischemia is useful because most ischemic episodes that occur outside the exercise laboratory are not accompanied by symptoms. Special considerations, not required for AEM when used for arrhythmia analysis, must be employed. Although many commercially available recorders provide excellent ST-segment reproduction, some playback systems may have a nonlinear phase response resulting in signal distortion, making ST-segment analysis difficult. Conventional Holter-type AEM devices do not allow for patient or physician intervention during acute myocardial ischemia. Considerable cost and time are required to analyze ST-segment data of prolonged monitoring periods from these tape-recorded signals, and human error and fatigue play an important role in diminishing accuracy of ST-segment interpretation. Automated analysis is done with computer and technician interaction but the accuracy and validation of the various systems for ST-segment analysis from tape recordings requires further detailed study. Newer, real-time ambulatory ECG analyzers are designed for prolonged monitoring periods and directed toward ST-segment analysis. Some devices also alert the patient to an acute ischemic or arrhythmic event allowing for intervention immediately. Some real-time systems have undergone some very encouraging validation studies. These recent studies suggest excellent sensitivity and specificity for detection of ischemic-type ST-segment depression. However, more work is needed before the accuracy of other such devices is known with certainty. As the central goal of therapy for patients with coronary artery disease evolves from simply controlling angina to reduction or elimination of ischemic episodes and their consequences, use of AEM devices will play an increasingly important role in management of these patients.

Cumulative effects of quinidine and aspirin on bleeding time and platelet alpha 2-adrenoceptors: potential mechanism of bleeding diathesis in patients receiving this combination.

We observed quinidine-induced prolongation of bleeding time without thrombocytopenia in three subjects. In addition, we noticed a cumulative prolongation of bleeding time by a combination of quinidine and aspirin. We postulated that because both quinidine and aspirin inhibit epinephrine-induced platelet aggregation, a cumulative effect of the two drugs might be responsible for the hemostatic defect. In studies using normal human platelets, we confirmed a marked reduction in epinephrine-induced platelet aggregation by the combination of these two agents. To further study the potential mechanism of this cumulative effect, platelet lysates were incubated with the alpha 2-adrenoceptor antagonist tritiated yohimbine in the presence of quinidine and aspirin. On the basis of the radioligand binding data, the dissociation constant (KD) of alpha 2-adrenoceptors was observed to increase in the presence of quinidine as well as aspirin. The combination of these two agents caused a marked increase in the KD of platelet alpha 2-adrenoceptors without alteration in the number of receptor sites. These data suggest that the cumulative effects of quinidine and aspirin on platelet alpha 2-adrenoceptor KD may relate to the significant reduction in epinephrine-induced platelet aggregation. This phenomenon, coupled with other well-known effects of aspirin on the platelet release reaction and arachidonate metabolism, may lead to bleeding problems in some patients receiving this combination.