Effects of low dose transdermal scopolamine on heart rate variability in acute myocardial infarction.

OBJECTIVES: We hypothesized that by enhancing parasympathetic activity, low dose transdermal scopolamine would increase heart rate variability after myocardial infarction. BACKGROUND: Low heart rate variability is associated with increased mortality after acute myocardial infarction. METHODS: Conventional time domain heart rate variability was measured from 24-h Holter recordings of 61 consecutive male patients (mean age 58 +/- 10 years, left ventricular ejection fraction 44.7 +/- 15.5%) 6 days (median) after acute myocardial infarction. Patients were then randomly assigned to wear one patch of transdermal scopolamine or a matching placebo patch for 24 h, during which their 24-h heart rate variability was remeasured. RESULTS: Compared with placebo, transdermal scopolamine caused a significant increase in time domain measures of 24-h heart rate variability by 26% to 35% above baseline. Transdermal scopolamine was well tolerated. CONCLUSIONS: Low dose transdermal scopolamine safely increases cardiac parasympathetic activity and short-term heart rate variability after acute myocardial infarction. Whether the effect of transdermal scopolamine on heart rate variability is a reasonable surrogate for improvement of long-term morbidity and mortality requires an appropriate designed investigation.

Conventional heart rate variability analysis of ambulatory electrocardiographic recordings fails to predict imminent ventricular fibrillation.

OBJECTIVES: The purpose of this report was to study heart rate variability in Holter recordings of patients who experienced ventricular fibrillation during the recording. BACKGROUND: Decreased heart rate variability is recognized as a long-term predictor of overall and arrhythmic death after myocardial infarction. It was therefore postulated that heart rate variability would be lowest when measured immediately before ventricular fibrillation. METHODS: Conventional indexes of heart rate variability were calculated from Holter recordings of 24 patients with structural heart disease who had ventricular fibrillation during monitoring. The control group consisted of 19 patients with coronary artery disease, of comparable age and left ventricular ejection fraction, who had nonsustained ventricular tachycardia but no ventricular fibrillation. RESULTS: Heart rate variability did not differ between the two groups, and no consistent trends in heart rate variability were observed before ventricular fibrillation occurred. CONCLUSIONS: Although conventional heart rate variability is an independent long-term predictor of adverse outcome after myocardial infarction, its clinical utility as a short-term predictor of life-threatening arrhythmias remains to be elucidated.

A reduction in the correlation dimension of heartbeat intervals precedes imminent ventricular fibrillation in human subjects.

Reduced reflexive control of heartbeat intervals occurs with advanced heart disease and is an independent risk factor for mortality. Based on a previous study of experimental myocardial infarction in pigs, we hypothesized that a deterministic measure of heartbeat dynamics, the correlation dimension of R-R intervals (D2), may be a better predictor of risk than a stochastic measure, such as the standard deviation (SD). We determined the point estimates of the heartbeat D2 (i.e., PD2s) in Holter electrocardiographic recordings from 11 high-risk patients who manifested ventricular fibrillation (VF) during the recording and in high-risk controls having only nonsustained ventricular tachycardia (14 patients) or premature ventricular complexes (13 patients). We found that PD2 reduction (i.e., PD2s < 1.2) precedes lethal arrhythmias by hours, but is not reduced in high-risk controls (p < 0.001; sensitivity, 91%; specificity, 85%). Heartbeat SD did not discriminate among the patients. Thus PD2 of heartbeat intervals may provide an important diagnostic test and early warning sign of VF.

Accumulation and assembly of myosin in hypertrophic cardiomyopathy with the 403 Arg to Gln beta-myosin heavy chain mutation.

The sarcomeric proteins and organization of cardiac myofibrils appeared intact in multiple unrelated patients with hypertrophic cardiomyopathy. In two subjects demonstrating the missense mutation at position 403 (Arg to Gln) in the beta-myosin heavy chain gene, total myosin and immunoreactive beta-myosin heavy chain levels were similar to those found in other patients with hypertrophic cardiomyopathy and various disease control subjects. No alteration in expression of the cardiac alpha-myosin heavy chain gene was observed. These results are consistent with the examined myosin heavy chain mutation, permitting proper accumulation and assembly of myosin while primarily impairing contractile function. The characteristic myocyte disarray would appear likely to be a secondary consequence of the mutations.

Human cardiac and skeletal muscle spectrins: differential expression and localization.

We describe multiple human cardiac and skeletal muscle spectrin isoforms. Cardiac muscle expresses five erythroid alpha,beta spectrin-reactive isoforms with estimated MR's of 280, 274, 270, 255, and 246 kD, respectively. At least one nonerythroid alpha-spectrin of MR 284 kD is expressed in heart. While skeletal muscle shares the 280, 270, and 246 kD erythroid spectrins, it expresses an immunologically distinct 284 kD nonerythroid alpha-spectrin isoform. The 255 kD erythroid beta-spectrin isoform is specific for cardiac tissue. By immunocytochemistry, both erythroid beta- and nonerythroid alpha-spectrins are localized to costameres, the plasma membrane, and the neuromuscular junctional region.

Application of chaos theory to biology and medicine.

The application of "chaos theory" to the physical and chemical sciences has resolved some long-standing problems, such as how to calculate a turbulent event in fluid dynamics or how to quantify the pathway of a molecule during Brownian motion. Biology and medicine also have unresolved problems, such as how to predict the occurrence of lethal arrhythmias or epileptic seizures. The quantification of a chaotic system, such as the nervous system, can occur by calculating the correlation dimension (D2) of a sample of the data that the system generates. For biological systems, the point correlation dimension (PD2) has an advantage in that it does not presume stationarity of the data, as the D2 algorithm must, and thus can track the transient non-stationarities that occur when the systems changes state. Such non-stationarities arise during normal functioning (e.g., during an event-related potential) or in pathology (e.g., in epilepsy or cardiac arrhythmogenesis). When stochastic analyses, such as the standard deviation or power spectrum, are performed on the same data they often have a reduced sensitivity and specificity compared to the dimensional measures. For example, a reduced standard deviation of heartbeat intervals can predict increased mortality in a group of cardiac subjects, each of which has a reduced standard deviation, but it cannot specify which individuals will or will not manifest lethal arrhythmogenesis; in contrast, the PD2 of the very same data can specify which patients will manifest sudden death. The explanation for the greater sensitivity and specificity of the dimensional measures is that they are deterministic, and thus are more accurate in quantifying the time-series. This accuracy appears to be significant in detecting pathology in biological systems, and thus the use of deterministic measures may lead to breakthroughs in the diagnosis and treatment of some medical disorders.

Effects of transdermal scopolamine on heart rate variability in normal subjects.

A decrease in cardiac parasympathetic tone is a recognized finding in patients with ischemic heart disease, sudden cardiac death and heart failure, correlating closely with disease severity and overall survival. To study the clinical potential of vagomimetic intervention, the effect of transdermal scopolamine on fluctuations in heart rate was studied in 32 healthy adult subjects using both time-domain (mean RR interval, standard deviation of the mean RR interval, mean of the differences between consecutive RR intervals) and frequency-domain measures (spectrum analysis of 128 consecutive RR intervals) of heart rate variability. After an exposure of 24 hours, transdermal scopolamine resulted in a significant increase in all indexes tested. The increase was most pronounced in the 0.25-Hz respiratory peak of the RR interval power spectrum, compatible with a strong vagomimetic mode of action of transdermal scopolamine. Results indicate that transdermal scopolamine may have potential merit as a selective vagotonic agent in certain patients with myocardial infarction, heart failure or ventricular arrhythmias.

Effect of passive tilt on sympathetic and parasympathetic components of heart rate variability in normal subjects.

Decreased heart rate (HR) variability has been shown to be an independent predictor of poor outcome after acute myocardial infarction. Presumably, both reduced parasympathetic activity and increased sympathetic activity contribute to this observed HR variability response. To elucidate the physiologic contributions of the sympathetic and parasympathetic nervous systems to HR variability, the effect of passive head-up tilt (+70 degrees) was investigated on 4 indexes of HR variability in 17 healthy subjects. The standard deviation of the mean of 512 consecutive RR intervals, a traditional marker of HR variability and a purported index of cardiac parasympathetic neural tone, was compared with the mean difference of 512 consecutive RR intervals, with the maximal expiratory RR interval to minimal inspiratory RR interval ratio (respiratory RR ratio) and with the low- and high-frequency components of the power spectrum of 512 consecutive RR intervals. Passive tilt produced a nonsignificant decrease in the standard deviation of RR intervals. There was, however, a highly significant decrease in the mean difference of consecutive RR intervals and the high-frequency component of the RR-interval spectrum. Both the respiratory RR ratio and the low-frequency component of the RR-interval spectrum increased with tilt. It was concluded that the mean difference of consecutive RR intervals and the high-frequency component of the RR-interval spectrum are potentially superior indexes of "pure" parasympathetic neural tone and may be preferable for future use in cardiovascular studies of autonomic dysfunction.