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Familial dysautonomia (FD) is caused by an intronic splice mutation in the IkappaB kinase-associated protein gene (IKBKAP) that leads to partial skipping of exon 20 and tissue-specific reduction of IkappaB kinase-associated protein/elongator protein 1 (IKAP/ELP-1 protein). Kinetin increases IKBKAP mRNA and protein expression in FD cell lines. To determine whether oral kinetin alters IKBKAP splicing in vivo, we administered kinetin to 29 healthy carriers of the major FD mutation for 8 d. Adverse effects, kinetin, and IKBKAP mRNA levels were monitored. In the highest dosing cohorts (23.5 mg/kg/d), the target plasma kinetin level was achieved in 91% of subjects at 2 h. After 8 d, IKBKAP mRNA expression in leukocytes increased as kinetin levels increased. There is a linear association between log plasma kinetin level and corresponding log change from baseline in IKBKAP mRNA expression that allows estimation of IKBKAP mRNA levels because of kinetin ingestion. Adverse effects were transient and mild. This is the first report of in vivo IKBKAP splicing modification and strongly suggests kinetin's therapeutic potential in FD and perhaps in other splicing disorders. Furthermore, our findings support our hypothesis that treatments, which target a particular splicing mutation, can be successfully developed.

The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IkappaB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IkappaB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p < 0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p < 0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP.

Objectives: To compare perceived reasons for continued smoking and withdrawal symptoms between current smokers and quitters in an inner-city adolescent population. To examine the relationship of nicotine dependence, stress, and coping methods between smokers and quitters and, using the Transtheoretical Model of Change, among adjacent smoking cessation stages., Design: A cross-sectional study using a self-administered questionnaire., Participants: The study comprised 354 clinic patients between the ages of 12 and 21 years who reported past or present smoking., Main Outcome Measures: Demographic characteristics, smoking status, perceived reasons for continued smoking, attempts to quit, and withdrawal symptoms, as well as standardized scales assessing nicotine dependence, stress, and coping methods., Results: The overall prevalence of smoking in this population was 26%. Smokers were significantly more likely to report smoking more cigarettes per day as well as higher levels of physical addiction (P<.01), greater levels of perceived stress (P<.02), and less use of cognitive coping methods (P<.02) than quitters (P<.005). However, comparison of consecutive stages revealed a significant difference only between precontemplation and contemplation in cognitive coping methods (P<.01). Three of 20 withdrawal symptoms (cravings, difficulty dealing with stress, and anger) were reported more frequently among current smokers who had attempted to quit in the last 6 months than among former smokers (P<.01)., Conclusion: Interventions for inner-city adolescents who smoke should be designed to target those with the highest levels of nicotine dependence, stress, and decreased use of cognitive coping methods because they are the least likely to quit on their own, rather than developing stage-specific models.

The CABG Patch Trial is testing the hypothesis that prophylactic use of implantable cardiac defibrillators (ICDs) will improve survival in high-risk coronary heart disease patients undergoing CABG surgery. The original design called for 800 patients to be randomized to ICD prophylaxis or to no therapy and followed for 2 to 6.5 years (average, 40 months) to a common termination date. Since the ICD pulse generators used in this trial lasted about 42 months, the original design required ICD replacement in many patients. At its first two meetings in 1993, the Data and Safety Monitoring Board (DSMB) formalized a plan to adjust sample size in October 1994 if the control group mortality rate was lower than expected. In June 1994, an unanticipated and unique event--a subpoena from the Office of the Inspector General (OIG)--made it impossible to replace about half of the ICD generators and threatened to shorten follow-up substantially. If follow-up had been stopped on the date originally planned, but without replacing ICDs, the average follow-up would have fallen from 40 months to about 33 months. Also, in October 1994, the control group mortality rate was found to be somewhat lower than expected. Together, the abbreviated follow-up and lower control group mortality threatened to reduce power substantially. The DSMB reviewed several options for restoring power. Because mortality rates in the first month after CABG surgery were about seven times as high as thereafter and because ICD therapy did not reduce surgical mortality (death during the first 30 days), extending the follow-up benefits power more than does increasing the sample size. However, the limit on extending follow-up was 42 months (the expected battery life of the ICD). Data from the ICD-treated group was not reviewed or considered in making the decision. After reviewing many options for restoring power, the DSMB recommended that the sample size be increased from 800 to 900 patients and that almost all patients be followed for 42 months. This recommendation extended follow-up for 2 years beyond the original termination date planned for the trial and dictated that patients close out after 42 months rather than on a common termination date.

Background: The purposes of the present study were (1) to establish normal values for the regression of log(power) on log(frequency) for, RR-interval fluctuations in healthy middle-aged persons, (2) to determine the effects of myocardial infarction on the regression of log(power) on log(frequency), (3) to determine the effect of cardiac denervation on the regression of log(power) on log(frequency), and (4) to assess the ability of power law regression parameters to predict death after myocardial infarction., Methods and Results: We studied three groups: (1) 715 patients with recent myocardial infarction; (2) 274 healthy persons age and sex matched to the infarct sample; and (3) 19 patients with heart transplants. Twenty-four-hour RR-interval power spectra were computed using fast Fourier transforms and log(power) was regressed on log(frequency) between 10(-4) and 10(-2) Hz. There was a power law relation between log(power) and log(frequency). That is, the function described a descending straight line that had a slope of approximately -1 in healthy subjects. For the myocardial infarction group, the regression line for log(power) on log(frequency) was shifted downward and had a steeper negative slope (-1.15). The transplant (denervated) group showed a larger downward shift in the regression line and a much steeper negative slope (-2.08). The correlation between traditional power spectral bands and slope was weak, and that with log(power) at 10(-4) Hz was only moderate. Slope and log(power) at 10(-4) Hz were used to predict mortality and were compared with the predictive value of traditional power spectral bands. Slope and log(power) at 10(-4) Hz were excellent predictors of all-cause mortality or arrhythmic death. To optimize the prediction of death, we calculated a log(power) intercept that was uncorrelated with the slope of the power law regression line. We found that the combination of slope and zero-correlation log(power) was an outstanding predictor, with a relative risk of > 10, and was better than any combination of the traditional power spectral bands. The combination of slope and log(power) at 10(-4) Hz also was an excellent predictor of death after myocardial infarction., Conclusions: Myocardial infarction or denervation of the heart causes a steeper slope and decreased height of the power law regression relation between log(power) and log(frequency) of RR-interval fluctuations. Individually and, especially, combined, the power law regression parameters are excellent predictors of death of any cause or arrhythmic death and predict these outcomes better than the traditional power spectral bands.

The objective of this study was to characterize the autonomic effects of 2 interventions, head-up tilt and isoproterenol infusion, which alter autonomic balance by different mechanisms but produce the same RR intervals. We compared the effect of head-up tilt with the effect of isoproterenol on autonomic balance as measured by power spectral analysis of RR variability. Fifteen normal subjects had baseline measurements and then underwent head-up tilt. After return to baseline supine values, isoproterenol was infused at a rate of 1 microgram/min (low-dose isoproterenol), which was then increased to 2.1 +/- 0.5 microgram/min (high-dose isoproterenol). All subjects underwent a second tilt during high-dose isoproterenol, and 9 subjects completed this second tilt study. During the experiment, normal RR intervals were recorded and 5-minute segments were used to calculate power spectra. High-frequency (HF) power (0.15 to 0.40 Hz) was used as a measure of vagal activity. The effects of head-up tilt were compared with the effects of low-dose isoproterenol. Despite nearly identical mean RR intervals (784 ms with tilt vs 792 ms with low-dose isoproterenol, p = NS), there was significantly (p < 0.05) less HF power during head-up tilt in the drug-free state (172 ms2) than during low-dose isoproterenol in the supine position (307 ms2). A second head-up tilt was performed during the infusion of high-dose isoproterenol. During high-dose isoproterenol, tilt caused a decrease in RR intervals (from 573 to 491 ms; p < 0.01) and a decrease in HF power (from 68 to 28 ms2; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Background: The purpose of this investigation was to establish normal values of RR variability for middle-aged persons and compare them with values found in patients early and late after myocardial infarction. We hypothesized that presence or absence of coronary heart disease, age, and sex (in this order of importance) are all correlated with RR variability., Methods and Results: To determine normal values for RR variability in middle-aged persons, we recruited a sample of 274 healthy persons 40 to 69 years old. To determine the effect of acute myocardial infarction RR variability, we compared measurements of RR variability made 2 weeks after myocardial infarction (n = 684) with measurements made on age- and sex-matched middle-aged subjects with no history of cardiovascular disease (n = 274). To determine the extent of recovery of RR variability after myocardial infarction, we compared measurements of RR variability made in the group of healthy middle-aged persons with measurements made in 278 patients studied 1 year after myocardial infarction. We performed power spectral analyses on continuous 24-hour ECG recordings to quantify total power, ultralow-frequency (ULF) power, very-low-frequency (VLF) power, low-frequency (LF) power, high-frequency (HF) power, and the ratio of LF to HF (LF/HF) power. Time-domain measures also were calculated. All measures of RR variability were significantly and substantially lower in patients with chronic or subacute coronary heart disease than in healthy subjects. The difference from normal values was much greater 2 weeks after myocardial infarction than 1 year after infarction, but the fractional distribution of total power into its four component bands was similar for the three groups. In healthy subjects, ULF power did not change significantly with age; VLF, LF, and HF power decreased significantly as age increased. Patients with chronic coronary heart disease showed little relation between power spectral measures of RR variability and age. Patients with a recent myocardial infarction showed a strong inverse relation between VLF, LF, and HF power and age and a weak inverse relation between ULF power and age. ULF power best separates the healthy group from either of the two coronary heart disease groups. Differences in RR variability between men and women were small and inconsistent among the three groups., Conclusions: All measures of RR variability were significantly and substantially higher in healthy subjects than in patients with chronic or subacute coronary heart disease. The difference between healthy middle-aged persons and those with coronary heart disease was much greater 2 weeks after myocardial infarction than 1 year after infarction, but the fractional distribution of total power into its four component bands was similar for the healthy group and the two coronary heart disease groups. Values of RR variability previously reported to predict death in patients with known chronic coronary heart disease are rarely (approximately 1%) found in healthy middle-aged individuals. Thus, when measures of RR variability are used to screen groups of middle-aged persons to identify individuals who have substantial risk of coronary deaths or arrhythmic events, misclassification of healthy middle-aged persons should be rare.

Objectives: This study was designed to test the hypothesis that antiarrhythmic drugs that decrease RR variability will predict all-cause mortality during follow-up after myocardial infarction., Background: RR variability, a noninvasive indicator of autonomic nervous system activity, predicts death after acute myocardial infarction independently of other risk predictors and changes substantially in response to some drugs. A previous study in patients with chronic heart disease and frequent ventricular premature complexes reported that flecainide decreased vagal modulation of RR intervals but amiodarone did not. The investigators of that study speculated that changes in RR variability during antiarrhythmic drug therapy predict an increased mortality rate during long-term drug treatment. To explore this hypothesis further, we compared the effects of encainide and flecainide, which increase long-term mortality substantially, on RR variability with the effects of placebo and moricizine, which have no significant effect on mortality during long-term treatment of unsustained ventricular arrhythmias after myocardial infarction., Methods: The 24-h power spectral density was computed from the baseline electrocardiographic recordings and drug evaluation tapes, and six frequency domain measures of RR variability were calculated: ultra-low frequency (< 0.0033 Hz), very low frequency (0.0033 to < 0.04 Hz), low frequency (0.04 to < 0.15 Hz) and high frequency power (0.15 to < 0.40 Hz), plus total power (< 0.40 Hz) and the ratio of low to high frequency power. Changes in power spectral measures were related to drug treatment and to mortality., Results: In the placebo group, values for RR interval and RR variability increased because of recovery from the effects of acute myocardial infarction. Contrasting placebo treatment with all three active antiarrhythmic drug treatments taken together showed that of all the measures of RR variability, only NN50, pNN50 and low frequency power changed significantly during drug treatment (Bonferroni adjusted p value < 0.025); these variables all decreased during drug therapy. Contrasting encainide and flecainide with moricizine, we found that the encainide and flecainide groups taken together showed a larger decrease in dLF than moricizine, but the difference was of borderline significance (Bonferroni adjusted p value < 0.08). Survival was significantly worse in the groups treated with encainide and flecainide than in the groups treated with placebo or moricizine (relative risk > 2.0, adjusted p < 0.05). The antiarrhythmic drug-induced change in measures of RR variability was not a significant predictor of all-cause mortality during a year of follow-up after myocardial infarction., Conclusions: Encainide, flecainide and moricizine all caused a decrease in RR variability in patients studied approximately 1 month after acute myocardial infarction. Encainide and flecainide caused a significant increase in mortality rates; placebo and moricizine did not. Baseline measurements of RR variability also predicted all-cause mortality after myocardial infarction. The decrease in RR variability produced by the three antiarrhythmic drugs did not predict mortality during follow-up.

Background: We studied 715 patients 2 weeks after myocardial infarction to test the hypothesis that short-term power spectral measures of RR variability (calculated from 2 to 15 minutes of normal RR interval data) will predict all-cause mortality or arrhythmic death., Methods and Results: We performed power spectral analyses on the entire 24-hour RR interval time series. To compare with the 24-hour analyses, we selected short segments of ECG recordings from two time periods for analysis: 8 AM to 4 PM and midnight to 5 AM. The former corresponds to the time interval during which short-term measures of RR variability would most likely be obtained. The latter, during sleep, represent a period of increased vagal tone, which may simulate the conditions that exist when patients have a signal-averaged ECG recorded, ie, lying quietly in the laboratory. Four frequency domain measures were calculated from spectral analysis of heart period data over a 24-hour interval. We computed the 24-hour power spectral density and calculated the power within three frequency bands: (1) 0.0033 to < 0.04 Hz, very low frequency power, (2) 0.04 to < 0.15 Hz, low frequency power, and (3) 0.15 to 0.40 Hz, high frequency power. In addition, we calculated the ratio of low to high frequency power. These measures were calculated for 15-, 10-, 5-, and 2-minute segments during the day and at night. Mean power spectral values from short periods during the day and night were similar to 24-hour values, and the correlations between short segment values and 24-hour values were strong (many correlations were > or = 0.75). Using the optimal cutpoints determined previously for the 24-hour power spectral values, we compared the survival experience of patients with low values for RR variability in short segments of ECG recordings to those with high values. We found that power spectral measures of RR variability were excellent predictors of all-cause, cardiac, and arrhythmic mortality and sudden death. Patients with low values were 2 to 4 times as likely to die over an average follow-up of 31 months as were patients with high values. The power spectral measures of RR variability did not predict arrhythmic or sudden deaths substantially better than all-cause mortality., Conclusions: Power spectral measures of RR variability calculated from short (2 to 15 minutes) ECG recordings are remarkably similar to those calculated over 24 hours. The power spectral measures of RR variability are excellent predictors of all-cause mortality and sudden cardiac death.

To test the effects of digitalis and angiotensin-converting enzyme inhibition on the RR interval variability in an electrocardiogram, 20 normal subjects were given digoxin 0.25 mg, enalapril 10 mg, and placebo twice daily in a randomized, double-blind, crossover study. Continuous 24-hour electrocardiographic recordings obtained on day 5 of each treatment were analyzed and several time domain and power spectral measures of heart period variability were calculated. Digoxin markedly increased (up to 51%) indexes of vagal modulation of heart period without changing mean RR interval. Enalapril did not change any measure of heart period variability despite a modest hypotensive effect. To determine the effect of each treatment on the response to orthostatic stress, 10 subjects also underwent 15 minutes of 60 degrees head-up tilt; power spectra were calculated for 15 minutes at 0 degree and at 60 degrees of tilt. Neither active treatment affected the response to head-up tilt.

Objectives: To determine whether spectral measures of heart period (RR) variability predict death when measured late after infarction, we studied patients in the Cardiac Arrhythmia Pilot Study (CAPS) who survived for 1 year and had a 24-h electrocardiographic (ECG) recording made after the CAPS drug was washed out., Background: Four components of the heart period power spectrum--ultra low frequency (< 0.0033 Hz), very low frequency (0.0033 to < 0.04 Hz), low frequency (0.04 to < 0.15 Hz) and high frequency power (0.15 to < 0.40 Hz)--plus total power (1.157 x 10(-5) to < 0.40 Hz) and the ratio of low to high frequency power predict mortality when measured < 30 days after myocardial infarction. However, these variables increase to steady state values by 3 months after infarction and the prognostic significance of recovery values is unknown., Methods: The 24-h power spectral density was computed from ECG recordings made 1 year after infarction using fast Fourier transforms and the six measures listed were calculated. The values were dichotomized at cut points that maximized the association with mortality., Results: Each measure of RR variability had a strong and significant univariate association with mortality; the relative risks for these variables ranged from 2.5 to 5.6. After adjustment for age, New York Heart Association functional class, rales in the coronary care unit, left ventricular ejection fraction and ventricular arrhythmias, some measures of heart period variability still had a strong and significant independent association with all-cause mortality., Conclusions: Spectral measures of heart period variability, measured late after infarction, predict death.

Recruitment and Enrollment Assessment in Clinical Trials (REACT), an NHLBI-sponsored substudy of the Cardiac Arrhythmia Suppression Trial (CAST), was conducted to assess factors associated with enrollment in clinical trials. We report on the relationships of institutional factors at CAST sites to patient enrollment. The proportion of CAST-eligible patients enrolling at each CAST site during the REACT study period was defined as the number of subjects enrolled divided by the sum of (1) the number enrolled plus (2) the number of eligibles who refused plus (3) the number of eligibles whose physicians refused to permit CAST personnel to attempt to enroll them. A questionnaire that included 78 questions regarding factors hypothesized to be associated with enrollment was completed between August 1988 and February 1990 by the nurse coordinators at all 112 CAST sites in the United States and Canada. Sixteen items were unanalyzable, and 37 of the remaining 62 were grouped into seven scales. The remaining items were analyzed individually. Enrollment proportions varied widely across the 112 CAST sites (mean 32.7% SD 22.6). Five variables or scales were included in the final multiple regression model (multiple R2 = .39). The most important of these was the proportion of eligible patients at a site cared for by medical staff other than private attending physicians (multiple R2 for this variable alone, .26). This proportion tended to be high in teaching hospitals. Other variables in this model that were associated with higher enrollment proportions included the number of days per week a nurse coordinator was present at the site, the number of nurse coordinator full-time equivalents at the site, fewer other clinical trials for which the nurse coordinator was responsible, and fewer perceived obstacles to enrollment. These findings indicate that enrollment was more successful at hospitals with higher proportions of eligible subjects cared for by fellows, housestaff, and service attending physicians and at institutions with the committed presence of a nurse-coordinator.

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.

To determine the reproducibility of frequency domain measures of heart period variability in patients with previous myocardial infarction, 2 random samples of 40 patients each (1 from the Cardiac Arrhythmia Pilot Study [CAPS] [unsustained ventricular arrhythmias], and 1 from the Electrophysiologic Studies Versus Electrocardiographic Monitoring [ESVEM] [sustained ventricular arrhythmias] trial) were studied. For each patient, two 24-hour continuous electrocardiographic recordings were analyzed, and the average normal RR interval, total power and 4 components of total power were calculated. Group means and standard deviations for each sample were virtually identical for the pairs of 24-hour recordings. Furthermore, measurements for individual patients were stable from day to day, as measured by the intraclass correlation coefficients and the standard errors of measurement. Reproducibility of heart period variability measurements is excellent in patients with previous myocardial infarction and ventricular arrhythmias, and is comparable to the high stability previously found in a small group of normal subjects. The stability of measures of heart period variability facilitates distinguishing real changes due to progression or regression of cardiac disease or to drug effects from apparent changes due to random variation.

Heart rate variability and heart period variability are important indicators of the functioning of the autonomic nervous system and are strong predictors of survival after myocardial infarction. The standard deviation of a patient's series of normal heart periods (consecutive normal RR intervals) is positively and, in some populations, strongly correlated with the mean period length. This phenomenon has led some investigators to use the coefficient of variation as their measure of variability, because it correlates less strongly with the mean period length. Using data from a multicentre post-infarction natural history study, we show that the standard deviation of the instantaneous heart rates has, like the coefficient of variation, only a modest correlation with the mean period length. Unlike the coefficient of variation, however, this standard deviation is derivable from established statistical principles. We show further that the coefficient of variation, the standard deviation of heart rates, and the standard deviation of heart periods are approximately equally strong predictors of survival after myocardial infarction.

Background: We 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 Results: Each 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., Conclusions: After 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%.

Four components of the heart period power spectrum--ultra low frequency (less than 0.0033 Hz), very low frequency (0.0033 to less than 0.04 Hz), low frequency (0.04 to less than 0.15 Hz) and high frequency power (0.15 to 0.40 Hz)--plus total power (1.157 x 10(-5) to 0.4 Hz for a 24-h electrocardiographic [ECG] recording) all predict mortality after myocardial infarction. To determine the time course and magnitude of recovery for these measures of heart period variability, 68 patients in the Cardiac Arrhythmia Pilot Study (CAPS) placebo group who had 24-h ECG recordings at baseline, 3, 6 and 12 months after myocardial infarction were studied. The 24-h power spectral density was computed with use of fast Fourier transforms and divided into the four components listed previously. The values for the five frequency domain measures of heart period variability in the CAPS patients were similar to those found in 715 patients who participated in the Multicenter Post Infarction Program (MPIP), indicating that the CAPS sample is generally representative of postinfarction patients with respect to these measures. The values for the five measures were one third to one half of those found in 95 normal persons of similar age and gender. There was a substantial increase in all measures of heart period variability between the baseline 24-h ECG recording and the 3-month recording (p less than 0.001). Between 3 and 12 months, the values were quite stable for the group as a whole, as well as for individual patients (intraclass correlation coefficients greater than or equal to 0.66).(ABSTRACT TRUNCATED AT 250 WORDS)

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 greater than 50 ms computed over the entire 24-hour electrocardiographic recording (proportion of adjacent intervals greater than 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 greater than 50 ms computed over the entire 24-hour electrocardiographic recording) were highly correlated (r greater than 0.8). It is concluded that measures of HR variability are stable over short periods of time.(ABSTRACT TRUNCATED AT 250 WORDS)

Several time and frequency domain measures of heart period variability are reduced 1 to 2 weeks after myocardial infarction, and a reduced standard deviation of normal RR intervals over a 24 h period (SDNN) is associated with increased mortality. The predictive accuracy of heart period variability may be reduced by drugs used to treat patients after myocardial infarction. Accordingly, a randomized, three period, placebo-controlled, crossover (Latin square) design was used to determine the effect of atenolol and diltiazem on time and frequency measures of heart period variability calculated from 24 h continuous electrocardiographic recordings during treatment with atenolol, diltiazem and placebo in 18 normal volunteers. During atenolol treatment, the 24 h average normal RR (NN) interval increased 24% (p less than 0.001). The three measures of tonic vagal activity were significantly increased (p less than 0.001) during atenolol treatment: percent of successive normal RR intervals greater than 50 ms = 69%, root mean square successive difference of normal RR intervals = 61% and high frequency power in the heart period power spectrum = 84%. Low frequency power also increased 45% (p less than 0.01), indicating that this variable also is an indicator of tonic vagal activity over 24 h. Diltiazem had no significant effect on the 24 h average NN interval or on any measure of heart period variability. The decreased mortality rate after myocardial infarction associated with beta-adrenergic blocker but not calcium channel blocker therapy may be attributed in part to an increase in vagal tone caused by beta-blockers.

This study examined the relations among beta-adrenergic blocker use, various correlates of left ventricular function and the chance of developing congestive heart failure in patients after myocardial infarction. The study was performed with the placebo group of the Multicenter Diltiazem Post-Infarction Trial. Ejection fraction data were available in 1,084 patients; of these, 557 were receiving a beta-blocker and 527 were not. In addition to ejection fraction, other correlates of left ventricular function included the presence or absence of pulmonary rales, chest X-ray film evidence of pulmonary congestion and the presence of an S3 gallop. Beta-blocker use was less frequent in patients with an ejection fraction less than 30%, rales, an S3 gallop and pulmonary congestion on chest X-ray film. Twenty-one percent of patients with an ejection fraction less than 30%, 42% of patients with rales, 28% of patients with an S3 gallop and 28% of patients with pulmonary congestion were receiving beta-blocker therapy. For every correlate of left ventricular function, the chance of developing congestive heart failure was greater in patients with diminished left ventricular function than in those without. For each level of left ventricular function, the chance of developing congestive heart failure requiring treatment was greater in patients not taking a beta-blocker.(ABSTRACT TRUNCATED AT 250 WORDS)

The a priori hypothesis that diltiazem would reduce the frequency and repetitiveness of ventricular arrhythmias was tested 3 months after myocardial infarction in patients participating in the Multicenter Diltiazem Postinfarction Trial. After 3 months of follow-up, 1,546 of the 2,466 patients enrolled had a 24-hour continuous electrocardiographic recording that contained greater than or equal to 12 hours of analyzable data. They were similar to the patients who survived 3 months but chose not to have a 24-hour electrocardiographic recording (i.e., they were representative of the entire group that survived 3 months). After 3 months of follow-up, there were no significant differences between the diltiazem and placebo groups in the prevalence of atrioventricular block, the frequency of atrial arrhythmias or the frequency or repetitiveness of ventricular arrhythmias. Heart rate was significantly lower (67 +/- 12 vs 71 +/- 12 beats/min) and there was a significantly greater proportion of patients with sinus pauses greater than or equal to 2 seconds in duration in the diltiazem group (6%) than in the placebo group (3%). Comparison with placebo revealed no evidence either for an anti- or proarrhythmic effect of diltiazem. There was no reduction in sudden or arrhythmic death attributable to diltiazem treatment; the fraction of total deaths that were arrhythmic by the Hinkle classification was 41% in the placebo group and 42% in the diltiazem group. It may be that the lack of effect of diltiazem on ventricular arrhythmias is partially responsible for its lack of effect on mortality 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)

A 24-hour continuous electrocardiographic recording was made 11 +/- 3 days after acute myocardial infarction (AMI) in 820 of the 867 participants in the Multicenter Post-Infarction Program. Ninety patients (11%) had unsustained ventricular tachycardia (VT) and 2 (0.2%) had sustained VT (more than 15 seconds). In 53 of the 92 patients (58%) with VT, only 1 episode of VT was in the recording. In 26 patients the longest episode of VT was 3 consecutive complexes (28%); in 56 patients (61%) it was 4 to 10 complexes; and in only 10 patients (11%) were there more than 10 consecutive complexes. The average rate of VT was 121 +/- 34 complexes per minute (range 75 to 240). Most episodes of VT started well after the T wave. Occurrence of VT was strongly related to the frequency of ventricular premature complexes in the 24-hour recording; 46% of the patients with at least 100 ventricular premature complexes per hour had VT. The 92 patients who had VT were compared to the 728 who did not with respect to relevant clinical characteristics. Several variables were significantly (p less than 0.05) more common in the VT group: age older than 60 years, previous AMI, history of angina pectoris, occurrence of VT or ventricular fibrillation in the coronary care unit, left ventricular ejection fraction less than 30%, rales greater than bibasilar in the coronary care unit, and use of antiarrhythmic drugs, digitalis or diuretics at the time of discharge from hospital. Based on Kaplan-Meier survival curves, the cumulative probability of surviving 3 years was 0.67 for patients with VT and 0.85 for patients without VT (p less than 0.001). There were no statistically significant associations between individual VT characteristics and mortality. However, patients with longer runs of VT tended to have a higher mortality rate, and both patients with sustained VT died in the first month after the index infarct. VT had a strong and statistically significant association (p less than 0.05) with all-cause and arrhythmic mortality independent of other risk variables that were associated with VT. Adjusted for other risk indicators, VT nearly doubled the risk of dying during an average follow-up of 31 months.

Left ventricular (LV) dysfunction, ventricular arrhythmias, and ischemic jeopardy independently determine outcome after recovery from acute myocardial infarction. Because death and reinfarction are most common early after hospital discharge, predischarge assessment of risk is optimal. Noninvasive methods can adequately detect LV dysfunction and ventricular arrhythmias, but coronary angiography is needed to assess ischemic risk in several subsets of patients. Management should be guided by the magnitude and functional nature of risk factors.

There is still no consensus on which arrhythmias should be treated in the 6- to 12-month high-risk period after acute myocardial infarction. To examine this question, we analyzed 24-hour ECG recordings in 430 patients who survived for at least 2 weeks after myocardial infarction and studied these patients for at least 1 year. During the year after infarction, 63 cardiac deaths occurred. High ventricular premature depolarization (VPD) frequency increased the risk of dying; 26% of the patients had greater than or equal to 10 VPDs/hr and were 2.6 times as likely to die within a year as those with lower frequencies. Repetitive VPDs (pairs or ventricular tachycardia) also were strongly associated with mortality. Thirty-one percent had repetitive VPDs, and these patients were 3.2 times as likely to die as those who lacked this characteristic. Frequent or repetitive VPDs were strongly associated with many other important postinfarction risk factors (e.g., left ventricular dysfunction or digitalis treatment). Nevertheless, frequent or repetitive VPDs contributed significantly to death in the first year after infarction independent of other risk factors; about 90% of these arrhythmias can be controlled satisfactorily with antiarrhythmic drugs. As yet, no definitive trial has been conducted to show whether controlling frequent or repetitive VPDs will significantly reduce the mortality in the first year after infarction. The principal design features for such a trial are discussed.

This prospective study of 100 patients evaluated the sensitivity and specificity of the repetitive ventricular response and ventricular tachycardia induced by programmed electrical stimulation for identifying patients with spontaneous ventricular tachyarrhythmias. The influence of underlying heart disease on such sensitivity and specificity was also evaluated. The repetitive ventricular response was sensitive (92 percent) for detecting patients with prior spontaneous ventricular tachyarrhythmias, but lacked specificity (57 percent); the rate of false positive responses was 43 percent. Inducible ventricular tachycardia was less sensitive (65 percent) but more specific (98 percent); the rate of false positive responses was only 3 percent. Among the 100 patients, 71 had heart disease, 29 did not. The presence of underlying heart disease had no significant effect on the sensitivity and specificity of repetitive ventricular responses or ventricular tachycardia induced by programmed stimulation; it did not increase the rate of false positive responses. It is concluded that (1) ventricular tachycardia induced with programmed ventricular stimulation is an excellent basis for guiding the management of clinically significant ventricular tachyarrhythmias, regardless of underlying heart disease; and (2) the repetitive ventricular response is not useful for this purpose because of its high rate of false positive responses among patients with or without significant heart disease.

We enrolled 250 patients with acute myocardial infarction after they had been discharged from the cardiac intensive care unit. Among 236 patients who performed a low-level exercise test just before hospital discharge, 52 (22%) had exercise-induced ST depression of at least 0.1 mV in ECG lead V5, 102 (43%) had ventricular arrhythmias, and 121 (51%) had an exercise capacity of shorter than 6 minutes. We used multiple logistic regression analysis to investigate the association of exercise variables with 1-year cardiac mortality. Exercise duration and ventricular premature depolarizations (VPDs) were significantly associated with 1-year mortality after acute myocardial infarction, both with and without control of the influence of other exercise variables statistically; the association of exercise-induced ST depression with 1-year cardiac mortality was not statistically significant. Standardized regression coefficients showed that the variables ranked in the following order in terms of predictive value: exercise duration, VPD frequency and ST depression. Jackknife techniques showed that multiple logistic regression using the three exercise variables was highly accurate in predicting 1-year mortality.

A 24 hour electrocardiographic recording was performed before hospital discharge in 430 patients who survived the cardiac care unit phase of acute myocardial infarction. Fifty patients (11.6 percent) had ventricular tachycardia, that is, three or more consecutive ventricular complexes. In 25 (50 percent) of these 50 patients, there was only one episode of ventricular tachycardia and, in 15 patients (30 percent), the longest run of ventricular tachycardia was only three consecutive ventricular premature depolarizations. The average rate of tachycardia was 119/min. Tachycardia rarely started with R on T ventricular premature complexes (4 of 1,370 episodes in 50 patients). There was no difference between the groups with and without ventricular tachycardia with respect to age and sex, but the patients with tachycardia had a significantly greater prevalence of previous myocardial infarction, left ventricular failure in the cardiac care unit, atrial fibrillation, ventricular tachycardia or ventricular fibrillation in the cardiac care unit and significantly more frequent use of digitalis and diuretic and antiarrhythmic drugs at the time of hospital discharge. The group with tachycardia had a 38.0 percent 1 year mortality rate compared with the rate of 11.6 percent in the group without tachycardia. Ventricular tachycardia had a strong association with 1 year mortality (odds ratio = 4.7). Although ventricular tachycardia had a significantly association with many other postinfarction risk factors, it was still significantly associated with the 1 year mortality (p less than 0.05) when other important risk variables were controlled statistically using a multiple logistic regression model. The 36 month cumulative mortality rate was 54.0 percent in the group with ventricular tachycardia compared with 19.4 percent in the group without tachycardia.

In animals, baroreflex sensitivity is inversely related to the likelihood of ventricular fibrillation during myocardial ischemia. After myocardial infarction in human patients, reduced baroreflex sensitivity is associated with increased mortality. A reduced standard deviation of normal RR intervals over a 24 h period is also associated with reduced survival after myocardial infarction. Therefore, 32 normotensive men who had survived their first myocardial infarction were studied to define the relation between baroreflex sensitivity assessed with phenylephrine injection and three Holter electrocardiographic measures of tonic vagal activity: the percent of successive normal RR intervals greater than 50 ms, the root mean square successive difference of normal RR intervals and the power in the high frequency energy of the normal RR interval power spectrum. Correlations among the Holter measures of heart period variability were greater than or equal to 0.94, indicating that these measures are so strongly correlated that any one of them can be used to represent the others. Baroreflex sensitivity showed weaker correlations with the three Holter variables (0.57 to 0.63), indicating that the Holter measures did not accurately predict baroreflex sensitivity. Baroreflex sensitivity showed a stronger correlation with the three Holter variables during the night than during the day. Baroreflex sensitivity and tonic vagal activity reflected by Holter variables were reduced more in patients with inferior myocardial infarction than in those with anterior infarction. The relative utility of baroreflex sensitivity and Holter measures of tonic vagal activity in predicting sudden cardiac death after myocardial infarction needs to be evaluated in a large prospective study.

A high degree of heart rate (HR) variability is found in persons with normal hearts, whereas low HR variability can be found in patients with severe coronary artery disease, congestive heart failure and diabetic neuropathy. Two weeks after acute myocardial infarction, low HR variability predicted reduced long-term survival even after adjusting for clinical risk indicators, left ventricular ejection fraction, HR and ventricular arrhythmias. The present study elucidated the causes of differences in HR and HR variability between patients with low and high HR variability. In a matched-pair study, 10 patients with low HR variability (24-hour standard deviation of N-N intervals less than 50 ms) were randomly selected. For each of these 10 patients, a control patient with high HR variability (24-hour standard deviation of N-N intervals greater than or equal to 100 ms), matched for age, left ventricular ejection fraction and rales in the coronary care unit was selected. Patients who were taking either digitalis or beta-adrenergic blocking drugs were excluded. Analysis of 24-hour electrocardiograms showed that for the low HR variability group compared with the high: (1) the daytime and nighttime average HR was faster; (2) the difference between daytime and nighttime HR was less; (3) the proportion of differences greater than 50 ms between successive N-N intervals was smaller; and (4) the number of HR "spikes" per day (increase in HR greater than or equal to 10 beats/min, lasting from 3 to 15 minutes) was less.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether treatment with digitalis is associated with decreased survival after acute myocardial infarction (AMI), data from 504 patients who were enrolled in a postinfarction natural history study were analyzed. At the time of discharge, 229 patients (45%) were taking digitalis. After 3 years of follow-up, the cumulative survival rate for patients discharged on a regimen of digitalis was 66%, compared with 87% for those not treated (p less than 0.001). Univariate analysis showed that statistically significant differences existed between the 2 groups with respect to age, previous AMI, left ventricular failure in the coronary care unit, atrial fibrillation in the coronary care unit, peak creatine kinase levels, enlarged heart and pulmonary vascular congestion on the discharge chest x-ray, ventricular arrhythmias and treatment with diuretic, antiarrhythmic and beta-blocking drugs. Survival analysis using Cox's regression model showed that the association between digitalis and decreased survival was of borderline significance after adjustment for atrial fibrillation and left ventricular failure. Serum digoxin concentration was measured in 83% of the patients who took digitalis. Survival was inversely and significantly related to serum digoxin, i.e., the higher the serum digoxin concentration, the lower the long-term survival rate. After adjusting for atrial fibrillation and left ventricular failure, serum digoxin was not significantly related to survival. Taken together with the results of 3 other large, nonrandomized studies of digitalis treatment after AMI, this study suggests that digitalis treatment may have adverse effects on survival during follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)