Heart rate variability in cocaine-exposed newborn infants.

BACKGROUND: Infants born to cocaine-using mothers have a 3- to 8-fold increase in sudden infant death syndrome. Its underlying cause, in part, may be attributed to abnormal autonomic function. We proposed to study heart rate variability, reflecting autonomic control of the heart, in cocaine-exposed infants. METHODS: From 1997 to 2000, we studied 217 asymptomatic, term infants, of whom 68 had intrauterine cocaine exposure (group I). Their data were compared with infants exposed to drugs other than cocaine (group II, n = 77) and no drugs (group III, n = 72). Twenty-four-hour heart rate variability was measured within 72 hours of birth. RESULTS: Cocaine-exposed infants, as compared with the 2 control groups, had an overall significant decrease (P <.05) in global heart rate variability and a lower standard deviation of all valid N-N intervals in the recording (41.9 +/- 1.4 ms vs 47.6 +/- 1.3 ms and 46.9 +/- 1.3 ms, respectively). Vagal parameters such as high-frequency power and the square root of the mean of the squared differences between adjacent N-N intervals were also lower in newborns with heavy in utero cocaine exposure. CONCLUSIONS: Decreased heart rate variability was seen in cocaine-exposed infants. Whether low heart rate variability is a marker for increased risk of sudden death in infants (as it is in adults with structural heart disease) is unknown and requires further investigation.

Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: experience in 101 related family members.

INTRODUCTION: Previous studies showed that diagnosing congenital long QT syndrome (LQTS) is difficult due to variable penetrance and genetic heterogeneity, especially when subjects from multiple families with diverse mutations are combined. We hypothesized that a combination of clinical and ECG techniques could identify gene carriers within a single family with congenital LQTS. METHODS AND RESULTS: One hundred one genotyped members of a family with LQTS, including 26 carriers of a HERG mutation, underwent history and ECG analysis. Forty-eight family members also underwent exercise testing with QT and T wave alternans (TWA) analysis and 24-hour Holter monitoring with QT and heart rate variability analysis. A logistic regression model, which included age, gender, QTc, and QTc by age, provided the best prediction of gene carrier status, although there was substantial overlap (78%) of QTc among subjects with and without the mutation. QTc was not helpful as a discriminator in children < or = 13 years. TWA (observed infrequently) did not add significantly to the model's ability to predict abnormal genotype. CONCLUSION: Even in this homogeneous LQTS population, the phenotype was so variable that clinical and detailed ECG analyses did not permit an accurate diagnosis of gene carrier status, especially in children. Sustained microvolt TWA was a specific (100%) but insensitive (18%) marker for LQTS. Its ability to predict risk of arrhythmia in this population remains to be determined. Genetic testing serves an essential role in screening for carriers of LQTS.

A comparison of T-wave alternans, signal averaged electrocardiography and programmed ventricular stimulation for arrhythmia risk stratification.

OBJECTIVES: The goal of this study was to compare T-wave alternans (TWA), signal-averaged electrocardiography (SAECG) and programmed ventricular stimulation (EPS) for arrhythmia risk stratification in patients undergoing electrophysiology study. BACKGROUND: Accurate identification of patients at increased risk for sustained ventricular arrhythmias is critical to prevent sudden cardiac death. T-wave alternans is a heart rate dependent measure of repolarization that correlates with arrhythmia vulnerability in animal and human studies. Signal-averaged electrocardiography and EPS are more established tests used for risk stratification. METHODS: This was a prospective, multicenter trial of 313 patients in sinus rhythm who were undergoing electrophysiologic study. T-wave alternans, assessed with bicycle ergometry, and SAECG were measured before EPS. The primary end point was sudden cardiac death, sustained ventricular tachycardia, ventricular fibrillation or appropriate implantable defibrillator (ICD) therapy, and the secondary end point was any of these arrhythmias or all-cause mortality. RESULTS: Kaplan-Meier survival analysis of the primary end point showed that TWA predicted events with a relative risk of 10.9, EPS had a relative risk of 7.1 and SAECG had a relative risk of 4.5. The relative risks for the secondary end point were 13.9, 4.7 and 3.3, respectively (p < 0.05). Multivariate analysis of 11 clinical parameters identified only TWA and EPS as independent predictors of events. In the prespecified subgroup with known or suspected ventricular arrhythmias, TWA predicted primary end points with a relative risk of 6.1 and secondary end points with a relative risk of 8.0. CONCLUSIONS: T-wave alternans is a strong independent predictor of spontaneous ventricular arrhythmias or death. It performed as well as programmed stimulation and better than SAECG in risk stratifying patients for life-threatening arrhythmias.

Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome.

Hereditary long QT syndrome (hLQTS) is a heterogeneous genetic disease characterized by prolonged QT interval in the electrocardiogram, recurrent syncope, and sudden cardiac death. Mutations in the cardiac potassium channel HERG (KCNH2) are the second most common form of hLQTS and reduce the delayed rectifier K(+) currents, thereby prolonging repolarization. We studied a novel COOH-terminal missense mutation, HERG R752W, which segregated with the disease in a family of 101 genotyped individuals. When the mutant cRNA was expressed in Xenopus oocytes it produced enhanced rather than reduced currents. Simulations using the Luo-Rudy model predicted minimal shortening rather than prolongation of the cardiac action potential. Consequently, a normal or shortened QT interval would be expected in contrast to the long QT observed clinically. This anomaly was resolved by our observation that the mutant protein was not delivered to the plasma membrane of mammalian cells but was retained intracellularly. We found that this trafficking defect was corrected at lower incubation temperatures and that functional channels were now delivered to the plasma membrane. However, trafficking could not be restored by chemical chaperones or E-4031, a specific blocker of HERG channels. Therefore, HERG R752W represents a new class of trafficking mutants in hLQTS. The occurrence of different classes of misprocessed channels suggests that a unified therapeutic approach for altering HERG trafficking will not be possible and that different treatment modalities will have to be matched to the different classes of trafficking mutants.

Influence of heart rate and sympathetic stimulation on arrhythmogenic T wave alternans.

We determined the temporal stability of T wave alternans (TWA) during constant rate stimulation and the dependence of alternans on heart rate (HR) and beta-adrenergic stimulation. Although it is established that exercise can provoke microvolt-level TWA in patients at risk for reentrant ventricular arrhythmias, the mechanisms underlying TWA in humans are not well understood. Specifically, the temporal stability of alternans at any given HR and the influence of HR vs. sympathetic activation on alternans remain unclear. TWA was measured during prolonged fixed-rate atrial pacing at multiple cycle lengths (CLs) in 10 subjects referred for electrophysiological testing and in 14 additional subjects in whom atrial pacing was performed at identical pacing CLs with and without isoproterenol. During constant CL stimulation, TWA amplitude oscillated significantly over time (typically by 10 microV) in a quasiperiodic fashion with periodicity of approximately 2-3 min. Alternans amplitude was strongly dependent on HR but not on adrenergic stimulation. There was a patient-specific threshold HR over which alternans appeared. At higher HR, alternans amplitude increased and oscillations were less prominent. Adrenergic stimulation was required to produce TWA that was not already elicited by moderate elevation of HR in only 2 of 14 (14%) patients. In conclusion, TWA 1) fluctuates spontaneously over 2-3 min and 2) increases monotonically with increased HR (without a major adrenergic contribution in most patients). These data suggest that increased HR rather than sympathetic activation is responsible for arrhythmogenic microvolt-level TWA measured during exercise.

Passive head-up tilt and actively standing up produce similar overall changes in autonomic balance.

The primary objective of this study was to compare, in normal subjects, the average change in autonomic balance during a 5-minute period by using two methods of changing posture: actively standing up and passive head-up tilt. We hypothesized that the average effect of these two methods of changing posture on autonomic balance would not significantly differ. After collecting supine baseline measurements, subjects were first tilted head up to 60 degrees for 15 minutes, then returned to the supine position for 5 minutes, before they stood up for 5 minutes. Comparing the average (over a 5-minute period) autonomic response to head-up tilt with that of standing, there were no significant differences in the decrease in average R-R intervals (-18% vs -18%, p = not significant), the drop in high-frequency power (-73% vs -69%, p = not significant), or the increase in the low-frequency/high-frequency ratio (+252% vs +298%, p = not significant). The changes in autonomic balance that occur during the first 5 minutes of passive 60-degree head-up tilt are nearly identical to the change in autonomic balance that occurs during the first 5 minutes of quiet standing.

The relationship of autonomic function to age-related changes in left ventricular filling in normal subjects.

Heart rate and age are independent variables associated with the pattern of normal left ventricular filling. Since heart rate variability also varies with age, the relationship between these and left ventricular filling in normal subjects was assessed. In 31 subjects (age range 21 to 71 years), power spectral analysis of heart rate variability was determined from 24 h Holter tapes, and left ventricular filling was assessed by Doppler echocardiography. Relationships between heart rate variability and left ventricular filling were assessed by univariate and multivariate regression analyses. Total, low frequency and high frequency power each significantly correlated with the peak filling velocity with atrial systole (A) (r = -0.70, P < 0.0001; r = -0.69, P < 0.0001; r = -0.54, P < 0.01, respectively), but did not correlate with measures of early diastolic left ventricular filling. Although age and A were related (r = 0.46, P < 0.010), age was no longer a significant variable when measures of heart rate variability were included in the multivariate regression model for A. Thus, the variability in measures of early diastolic filling in normal subjects appears to be independent of measures of heart rate variability, whereas, A is significantly associated with these measures.

Effects of digoxin and enalapril on heart period variability and response to head-up tilt in normal subjects.

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.