Robert E. Kleiger

Frequency domain measures of heart period variability and mortality after myocardial infarction.

BackgroundWe studied 715 patients 2 weeks after myocardial infarction to establish the associations between six frequency domain measures of heart period variability (HPV) and mortality during 4 years of follow-up. Methods and ResultsEach measure of HPV had a significant and at least moderately strong univariate association with all-cause mortality, cardiac death, and arrhythmic death. Power in the lower-frequency bands–ultra low frequency (ULF) and very low frequency (VLF) power–had stronger associations with all three mortality end points than power in the higher-frequency bands-low frequency (LF) and high frequency (HF) power. The 24-hour total power also had a significant and strong association with all three mortality end points. VLF power was the only variable that was more strongly associated with arrhythmic death than with cardiac death or all-cause mortality. In multivariate Cox regression models using a step-up approach to evaluate the independent associations between frequency domain measures of heart period variability and death of all causes, ULF power was selected first (i.e., was the single component with the strongest association). Adding VLF or LF power to the Cox regression model significantly improved the prediction of outcome. With both ULF and VLF power in the Cox regression model, the addition of the other two components, LF and HF power, singly or together, did not significantly improve the prediction of all-cause mortality. We explored the relation between the heart period variability measures and all-cause mortality, cardiac death, and arrhythmic death before and after adjusting for five previously established postinfarction risk predictors: age, New York Heart Association functional class, rales in the coronary care unit, left ventricular ejection fraction, and ventricular arrhythmias detected in a 24-hour Holter ECG recording ConclusionsAfter adjustment for the five risk predictors, the association between mortality and total, ULF, and VLF power remained significant and strong, whereas LF and HF power were only moderately strongly associated with mortality. The tendency for VLF power to be more strongly associated with arrhythmic death than with all-cause or cardiac death was still evident after adjusting for the five covariates. Adding measures of HPV to previously known predictors of risk after myocardial infarction identifies small subgroups with a 2.5-year mortality risk of approximately 50%.

The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction.

We examined the relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality after the occurrence of myocardial infarction in 766 patients who enrolled in a nine-hospital study and underwent two special tests. Frequency and repetitiveness of ventricular premature depolarizations (VPDs) were determined by computer analysis of predischarge 24 hr electrocardiographic recordings. The left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and dichotomized at its optimal value of 30%. Frequency of VPDs was divided into three categories: (1) less than one per hour, (2) one to 2.9 per hour, and (3) three or more per hour. Repetitiveness of VPDs was also divided into three categories: (1) no repetitive VPDs, (2) paired VPDs, and (3) VPD runs. These variables were related, one at a time and jointly, to total mortality and to deaths caused by arrhythmias. The hazard ratios for dying in the higher or highest risk stratum vs the lower or lowest stratum for each variable (adjusted for the effects of the others) were: LVEF below 30%, 3.5; VPD runs, 1.9; and VPD frequency of three or more per hour, 2.0. There were no significant interactions among the three variables with respect to effects on the risk of mortality. There was a suggestion of an interaction between each risk variable and time after infarction. LVEF below 30% was a better predictor of early mortality (less than 6 months) and the presence of ventricular arrhythmias was a better predictor of late mortality (after 6 months).(ABSTRACT TRUNCATED AT 250 WORDS)

Outcomes in Patients with Acute Non–Q-Wave Myocardial Infarction Randomly Assigned to an Invasive as Compared with a Conservative Management Strategy

Background Non–Q-wave myocardial infarction is usually managed according to an “invasive” strategy (i.e., one of routine coronary angiography followed by myocardial revascularization). Methods We randomly assigned 920 patients to either “invasive” management (462 patients) or “conservative” management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia (458 patients), within 72 hours of the onset of a non–Q-wave infarction. Death or nonfatal infarction made up the combined primary end point. Results During an average follow-up of 23 months, 152 events (80 deaths and 72 nonfatal infarctions) occurred in 138 patients who had been randomly assigned to the invasive strategy, and 139 events (59 deaths and 80 nonfatal infarctions) in 123 patients assigned to the conservative strategy (P=0.35). Patients assigned to the invasive strategy had worse clinical outcomes during the first year of follow-up. The numb...

Heart rate variability: A measure of cardiac autonomic tone

Analysis of HRV based on routine 24-hour Holter recordings provides a sensitive, noninvasive measurement of autonomic input to the heart. HRV can be measured in the time or frequency domain. Each frequency domain variable correlates at least r = 0.85 with a time domain variable. Thus time domain measures can be used as surrogates for frequency domain measures which may simplify future studies. Abnormalities of autonomic input to the heart, which are indicated by decreased indices of HRV, are associated with increased susceptibility to ventricular arrhythmias. Decreased indices of HRV are also associated with CHF, diabetes, and alcoholic cardiomyopathy. Decreased indices of HRV are an independent risk factor for mortality post MI and in patients with advanced CHF. Medications can also affect HRV, and that effect may become an important clinical consideration, especially in high-risk patients.

Diltiazem and Reinfarction in Patients with Non-Q-Wave Myocardial Infarction

We performed a multicenter, double-blind, randomized study to evaluate the effect of diltiazem on reinfarction after a non-Q-wave myocardial infarction. Nine centers enrolled 576 patients: 287 received diltiazem (90 mg every six hours) and 289 received placebo. Treatment was initiated 24 to 72 hours after the onset of infarction and continued for up to 14 days. The primary end point, reinfarction, was defined as an abnormal reelevation of MB creatine kinase in plasma within 14 days. Reinfarction occurred in 27 patients in the placebo group (9.3 percent) and in 15 in the diltiazem group (5.2 percent)--a 51.2 percent reduction in cumulative life-table incidence (P = 0.0297; 90 percent confidence interval, 7 to 67 percent). Diltiazem reduced the frequency of refractory postinfarction angina (a secondary end point) by 49.7 percent (P = 0.0345; 90 percent confidence interval, 6 to 73 percent). Mortality was similar in the two groups (3.1 and 3.8 percent, respectively, in the placebo and diltiazem groups), but adverse drug reactions (most of which were mild) were more common in the diltiazem group. Nevertheless, the drug was well tolerated, despite concurrent treatment with beta-blockers in 61 percent of the patients. We conclude that diltiazem was effective in preventing early reinfarction and severe angina after non-Q-wave infarction and that it was also safe and generally well tolerated.

Correlations among time and frequency domain measures of heart period variability two weeks after acute myocardial infarction

Seven hundred fifteen participants from a multicenter natural history study of acute myocardial infarction were studied (1) to determine the correlations among time and frequency domain measures of heart period variability, (2) to determine the correlations between the measures of heart period variability and previously established post-infarction risk predictors, and (3) to determine the predictive value of time domain measures of heart period variability for death during follow-up after acute myocardial infarction. Twenty-four hour electrocardiographic recordings obtained 11 +/- 3 days after acute myocardial infarction were analyzed and 11 measures of heart period variability were computed. Each of 4 bands in the heart period power spectrum had 1 or 2 corresponding variables in the time domain that correlated with it so strongly (r greater than or equal to 0.90) that the variables were essentially equivalent: ultra low frequency power with SDNN* and SDANN index,* very low frequency power and low-frequency power with SDNN index,* and high-frequency power with r-MSSD* and pNN50.* As expected from theoretical considerations, SDNN and the square root of total power were almost perfectly correlated. Correlations between the time and frequency domain measures of heart period variability and previously identified postinfarction risk predictors, e.g., left ventricular ejection fraction and ventricular arrhythmias, are remarkably weak. Time domain measures of heart period variability, especially those that measure ultra low or low-frequency power, are strongly and independently associated with death during follow-up. * Defined in Table II.

Stability over time of variables measuring heart rate variability in normal subjects

Abstract Both time and frequency domain measures of heart rate (HR) variability have been used to assess autonomic tone in a variety of clinical conditions. Few studies in normal subjects have been performed to determine the stability of HR variability over time, or the correlation between and within time and frequency domain measures of HR variability. Fourteen normal subjects aged 20 to 55 years were studied with baseline and placebo 24-hour ambulatory electrocardiograms performed 3 to 65 days apart to assess the reproducibility of the following time domain measures of cycle length variability: the standard deviation of all normal cycle intervals; mean normal cycle interval; mean day normal cycle interval; night/day difference in mean normal cycle interval; root-mean-square successive cycle interval difference; percentage of differences between adjacent normal cycle length intervals that are >50 ms computed over the entire 24-hour electrocardiographic recording (proportion of adjacent intervals >50 ms); and the frequency domain measures of high (0.15 to 40 Hz), low (0.003 to 0.15) and total (0.003 to 0.40) power. The mean and standard deviations of these measures were virtually identical between placebo and baseline measurements and within the studied time range. Variables strongly dependent on vagal tone (high-frequency, low-frequency and total power, root-mean-square successive difference, and percentage of differences between adjacent normal cycle intervals >50 ms computed over the entire 24-hour electrocardiographic recording) were highly correlated (r > 0.8). It is concluded that measures of HR variability are stable over short periods of time. Certain time and frequency domain variables are highly correlated and may serve as surrogates for each other, and no placebo effect on these variables is evident.

Time Domain Measurements of Heart Rate Variability

Assessment of HRV through time domain variables is a simple and practical method of assessing autonomic function. In this capacity its utility has been demonstrated in normal subjects and in diverse cardiac and noncardiac pathologic states. It can be used to assess the effects of drugs and other interventions, including exercise and psychological and physical stress on cardiac autonomic tone. Importantly, decreased HRV is almost uniformly associated with adverse outcome. The prognostic information appears to incorporate both alterations in autonomic tone and longer term components and is best assessed using ambulatory ECG recordings. Defining the clinical applicability and physiologic mechanisms of changes in HRV remain active areas of research.

Correlation of heart rate variability with clinical and angiographic variables and late mortality after coronary angiography

Decreased heart rate (HR) variability is associated with increased mortality after myocardial infarction, but the prognostic value of HR variability in patients without recent myocardial infarction and its correlation with other clinical and angiographic data have not previously been reported. In the present study, detailed clinical assessments and 24-hour ambulatory electrocardiograms were performed prospectively on 100 patients undergoing elective coronary angiography. HR variability was inversely correlated with HR (r = -0.38, p = 0.001), diabetes mellitus (r = -0.22, p = 0.025) and digoxin use (r = -0.29, p = 0.004), but not with left ventricular ejection fraction, extent of coronary artery disease or other clinical, electrocardiographic or angiographic variables. All patients were followed for 1 year. Major clinical events after initial discharge occurred in 10 patients and included 6 deaths and 4 coronary bypass operations. Left ventricular ejection fraction was the only variable that correlated with the occurrence of a clinical event (p = 0.002). Decreased HR variability and ejection fraction were the best predictors of mortality (both p less than 0.01), and the contribution of HR variability to mortality was independent of ejection fraction, extent of coronary artery disease and other variables. Furthermore, 11 patients with HR variability less than 50 ms had an 18-fold increase in mortality compared with patients with HR variability greater than 50 ms (36 vs 2%, p = 0.001). Thus, decreased HR variability is a potent independent predictor of mortality in the 12 months following elective coronary angiography in patients without recent myocardial infarction.

Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease

OBJECTIVE The purpose of this study was to investigate the relationship between depression and heart rate variability in cardiac patients. METHODS Heart rate variability was measured during 24-hour ambulatory electrocardiographic (ECG) monitoring in 40 medically stable out-patients with documented coronary heart disease meeting current diagnostic criteria for major depression, and 32 nondepressed, but otherwise comparable, patients. Patients discontinued beta-blockers and antidepressant medications at the time of study. Depressed patients were classified as mildly (n = 21) or moderately-to-severely depressed (n = 19) on the basis of Beck Depression Inventory scores. RESULTS There were no significant differences among the groups in age, gender, blood pressure, history of myocardial infarction, diabetes, or smoking. Heart rates were higher and nearly all indices of heart rate variability were significantly reduced in the moderately-to-severely versus the nondepressed group. Heart rates were also higher and mean values for heart rate variability lower in the mildly depressed group compared with the nondepressed group, but these differences did not attain statistical significance. CONCLUSION The association of moderate to severe depression with reduced heart rate variability in patients with stable coronary heart disease may reflect altered cardiac autonomic modulation and may explain their increased risk for mortality.