Application of time series analysis to circadian rhythms: effect of beta-adrenergic blockade upon heart rate and transient myocardial ischemia.

Circadian variations of transient myocardial ischemia and heart rate have been identified, but the rhythms and their response to beta blockade have not been fully characterized. Time-series analysis, a mathematical technique to describe oscillatory activity occurring within a continuous data set was used, to address these issues. Nine men with coronary artery disease underwent 72 hours of ambulatory electrocardiographic monitoring during therapy with placebo or metoprolol. During administration of placebo, ischemic time and heart rate showed a primary peak with a periodicity of approximately 24 hours with a tight coupling between the 2 variables and a secondary peak with a periodicity of 5 to 8 hours. During metoprolol therapy, heart rate and ischemic variation were reduced and the 24-hour periodicity for heart rate only remained. The 24-hour periodicity for ischemia was eliminated, but the data with 5- to 8-hour periodicity became the major component of the signal.

Influence of beta-adrenergic blockade defined by time series analysis on circadian variation of heart rate and ambulatory myocardial ischemia.

Extended (72-hour) ambulatory electrocardiographic monitoring was used to enable time series analysis of heart rate and asymptomatic ST-segment depression in 9 patients with severe coronary artery disease. The effects of beta 1-adrenergic blockade with optimal dose metoprolol were then assessed. Data were analyzed using Fourier transformation, autocorrelation and cross-correlation to examine possible coupling between heart rate and ischemic electrocardiographic changes. A marked circadian pattern was observed for both heart rate and ambulatory myocardial ischemia, with a period of approximately 24 hours by both Fourier and autocorrelation methods. Cross-correlation revealed heart rate and ischemia to be tightly coupled with a lag of 0 hours during placebo. During beta 1 adrenergic blockade the marked circadian variation in heart rate was diminished, although some periodicity in the 24-hour region remained. Ambulatory ischemia was also markedly diminished during beta 1-adrenergic blockade; however, some residual ischemia remained that was characterized by a peak spectral activity shifted to a period of 5 to 7 hours. Heart rate and ischemia were not coupled during beta 1-adrenergic blockade, as evidenced by lack of significant cross-correlation. Thus, time series analysis suggests close coupling between the variation in heart rate and ambulatory ischemia in patients with severe coronary artery disease. Beta 1-adrenergic blockade can markedly alter the periodic characteristics of and coupling between heart rate and ischemia. Ischemia remaining during beta 1-adrenergic blockade may have different spectral characteristics than that predominating during placebo administration. These differences may be manifestations of the heterogenous pathophysiologic mechanisms responsible for ambulatory ischemia and may have therapeutic implications.

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.

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.

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.

Relation of transient silent ischemic episodes to daily activities.

In patients with coronary disease, asymptomatic ST segment depression during daily life is a reliable indicator of silent myocardial ischemia and is the most frequent form of ischemia in both symptomatic and asymptomatic patients. Silent ischemic episodes usually occur during activities not ordinarily thought to be ischemia provoking, and not necessarily with the same frequency, duration, or magnitude as painful episodes and may be the only type of ischemia detected in some patients. Some features suggest an important reduction in myocardial oxygen supply, in addition to an increase in demand, as a mechanism for silent ischemic episodes occurring during daily life.

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.

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.

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.

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.

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.