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Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and mortality. Timely diagnosis of the arrhythmia, particularly transient episodes, can be difficult since patients may be asymptomatic. In this study, we describe a robust algorithm for automatic detection of AF based on the randomness, variability and complexity of the heart beat interval (RR) time series. Specifically, we employ a new statistic, the Turning Points Ratio, in combination with the Root Mean Square of Successive RR Differences and Shannon Entropy to characterize this arrhythmia. The detection algorithm was tested on two databases, namely the MIT-BIH Atrial Fibrillation Database and the MIT-BIH Arrhythmia Database. These databases contain several long RR interval series from a multitude of patients with and without AF and some of the data contain various forms of ectopic beats. Using thresholds and data segment lengths determined by Receiver Operating Characteristic (ROC) curves we achieved a high sensitivity and specificity (94.4% and 95.1%, respectively, for the MIT-BIH Atrial Fibrillation Database). The algorithm performed well even when tested against AF mixed with several other potentially confounding arrhythmias in the MIT-BIH Arrhythmia Database (Sensitivity = 90.2%, Specificity = 91.2%).

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1. Are arterial blood pressure fluctuations buffered or reinforced by respiratory sinus arrhythmia (RSA)? There is still considerable debate about this simple question. Different results have been obtained, triggering a discussion as to whether or not the baroreflexes are responsible for RSA. We suspected that the measurements of different aspects of arterial pressure (mean arterial pressure (MAP) and systolic pressure (SP)) can explain the conflicting results. 2. Simultaneous recordings of beat-to-beat MAP, SP, left cardiac stroke volume (SV, pulsed ultrasound Doppler), heart rate (HR) and respiration (RE) were obtained in 10 healthy young adults during spontaneous respiration. In order to eliminate HR variations at respiratory frequency we used propranolol and atropine administration in the supine and tilted positions. Respiration-synchronous variation in the recorded variables was quantified by spectral analysis of the recordings of each of these variables, and the phase relations between them were determined by cross-spectral analysis. 3. MAP fluctuations increased after removing heart rate variations in both supine and tilted position, whereas SP fluctuations decreased in the supine position and increased in the head-up tilted position. 4. RSA buffers respiration-synchronous fluctuations in MAP in both positions. However, fluctuations in SP were reinforced by RSA in the supine and buffered in the tilted position.

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BACKGROUND: In low doses, scopolamine paradoxically enhances parasympathetic outflow to the heart. The mechanisms which mediate this action are not fully understood. Moreover, there are conflicting data regarding the potential role of sympathetic activity. This study in 17 healthy individuals was designed to characterize the influence of low dose transdermal scopolamine on the gain of the baroreflex and respiratory heart rate reflex and to determine the role of sympathetic activity. METHODS: The effect of scopolamine was analyzed in the time and frequency domain by computing heart rate variability indices. The gains of the respiratory heart rate reflex and the baroreflex were estimated simultaneously by means of a cardiovascular system identification approach using an optimized autoregressive moving average algorithm. Measurements were repeated in the upright posture to assess the influence of enhanced sympathetic activity. In six subjects ambulatory ECGs were recorded to determine whether there are diurnal variations of the effect of scopolamine. RESULTS: Scopolamine enhances vagal modulation of heart rate through both the respiratory-heart rate reflex and the baroreflex, as the gains of both were augmented by the drug in the supine and in the upright postures. CONCLUSIONS: Scopolamine increases parasympathetic cardiac control by augmenting the gain of the respiratory-heart rate and baroreflex. This action is not attenuated in the upright posture when sympathetic tone is increased.

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INTRODUCTION: Beat-to-beat adaptation of ventricular repolarization duration to cardiac cycle length and autonomic activity has not been previously characterized in the spontaneously beating human heart. METHODS AND RESULTS: The ECG of 14 healthy subjects was recorded from the supine and upright positions. Autonomic blockade was accomplished by atropine and propranolol. RR and RT intervals were measured by a computer algorithm, and the impulse response (h) from RR to RT computed. In the supine position the maximal adjustment of the RT interval occurred in the first beat following a change in cycle length (hpeak = 17.8 +/- 1.6 msec/sec), but continued to be detectable for 3.8 seconds (2.9-4.7 sec). Propranolol attenuated the peak impulse response to 15.8 +/- 4.0 msec/sec (P = NS). In the standing position the peak impulse response was increased to 25.2 +/- 5.0 msec/sec (P = 0.004 vs supine), and the impulse response duration (hdur) shortened to 1.4 seconds (1.3-1.6). This was reversed by beta blockade (hpeak = 10.7 +/- 3.6 [P = 0.005 vs standing]; hdur = 5.5 sec [4.8-6.1]). Parasympathetic and combined autonomic blockade resulted in too little residual heart rate variability to estimate the impulse response accurately. The slope of the regression of delta RT and delta RR in the supine position was 0.0177 +/- 0.0016, which was closely correlated with the peak impulse response (r = 0.91). CONCLUSIONS: System identification techniques can assist in characterizing the cycle dependence of ventricular repolarization and may provide new insights into conditions associated with abnormal repolarization.

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Statistical criteria for suppression and aggravation of ventricular arrhythmia were defined by means of 50 short-term drug tests performed in 24 patients. Each patient's spontaneous variability (SV) was evaluated by linear regression analysis of hour-to-hour changes in ectopy during 24- to 48-hour Holter monitoring. The response to a single oral dose of disopyramide, 300 mg, flecainide, 200 mg, and propafenone, 450 mg, was measured during a trial lasting 4 hours. Lidocaine was administered intravenously in incremental doses of up to 4 mg/min and was evaluated over 3 hours. Threshold values of ventricular arrhythmia corresponding to 95% confidence limits were calculated from baseline recordings and were used to ascertain the likelihood of a true drug effect. The minimum decrease in hourly ectopy indicating arrhythmia suppression averaged 90.9%, while an increase of at least 947% was required for a proarrhythmic effect. When these efficacy criteria were applied, 16 of 50 short-term tests revealed no drug effect. In contrast, when a 70% threshold derived from studies of daily variability was employed, only 7 of 50 trials were negative. Thus individual determination of hourly arrhythmia variability yields more stringent criteria than extrapolation from day-to-day spontaneous variation.

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Day to day variability of ventricular ectopic activity was analyzed in 45 patients with a history of malignant ventricular tachyarrhythmias who underwent two successive 24 h periods of ambulatory electrocardiographic (ECG) monitoring in the absence of antiarrhythmic drugs; 26 were male and 19 female, with a mean age of 56 years (range 15 to 76). The total number of single ventricular premature beats, couplets and ventricular tachycardia beats and runs on days 1 and 2 demonstrated a consistent overall correlation (r = 0.76 to 0.84). Individual variability was evaluated by regression analysis with determination of 95% confidence limits. The minimal decrease in arrhythmia density necessary to distinguish true drug effect from spontaneous variability was 64% for single ventricular premature beats, 83% for couplets, 90% for ventricular tachycardia runs and 93% for ventricular tachycardia beats. To meet the criteria for arrhythmia aggravation, the arrhythmia density had to increase by 400, 877, 1,500 and 2,400%, respectively. Multivariate analysis disclosed an inverse relation between day to day arrhythmia variability and baseline arrhythmia density and age. Variability was more pronounced in patients with coronary artery disease but was not influenced by the type of presenting arrhythmia or left ventricular function. The diurnal distribution of arrhythmias and heart rate followed a distinct circadian pattern. These data indicate that, despite good group reproducibility, spontaneous arrhythmia variability in individuals is substantial, necessitating standards to define both drug effect and arrhythmia aggravation.

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Brain serotoninergic neurons are known to participate in cardiovascular regulation. Administration of the serotonin precursor 5-l-hydroxytryptophan in conjunction with the monamine oxidase inhibitor phenelzine and the selective peripheral l-amino acid decarboxylase inhibitor carbidopa has been shown to raise the repetitive extrasystole threshold in the canine heart. The present investigation demonstrates that this drug regimen increases the cerebrospinal fluid concentration of serotonin and its major metabolite, 5-hydroxyindoleacetic acid, by 330 and 830%, respectively. By contrast, cerebrospinal fluid concentrations of norepinephrine and its major brain metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate, and of dopamine's metabolite, 3, 4-dihydroxyphenylacetic acid, were not significantly altered. Concomitantly, the ventricular fibrillation threshold was elevated by 42% and the effective refractory period prolonged by 7%. Efferent sympathetic neural activity was suppressed in the normal heart (from 7.9 +/- 1.3 to 3.9 +/- 1.1 impulses/s). The surge in sympathetic activity associated with acute myocardial ischemia was markedly attenuated. These results indicate that enhancement of central serotoninergic neurotransmission can reduce the susceptibility to ventricular fibrillation mediated through a decline in sympathetic neural traffic to the heart.

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The relationship between arrhythmia density observed during ambulatory monitoring, left ventricular ejection fraction (EF), and response to antiarrhythmic drug therapy was evaluated in 94 patients presenting with ventricular fibrillation (VF) (n = 20) or ventricular tachycardia (VT) (n = 74). Following baseline studies, an average of 4.9 antiarrhythmic drugs were tested singly in each patient. Univariate and multivariate analyses revealed that the density of VT on baseline ambulatory monitoring and initial left ventricular EF were independent predictors of drug efficacy. The 45 patients with an EF less than or equal to 35% responded to 34 +/- 29% of drugs tested, whereas the 49 with an EF greater than 35% had arrhythmia suppression with 46 +/- 28% of agents (p less than 0.038). Patients exhibiting VT during greater than or equal to 50% of monitoring hours responded to 32 +/- 26% of drugs, whereas those with VT during less than 50% of hours showed arrhythmia suppression with 48 +/- 29% of antiarrhythmic agents tested (p = 0.009). During a mean follow-up period of 12.9 months, the annual sudden death mortality for all patients was 9.3%. However, 8 of the 55 patients responding to less than 50% of drugs tested died suddenly and 17 had recurrent VT. By contrast, only 1 of the 39 patients responding to greater than or equal to 50% of the antiarrhythmic drugs tested died suddenly and two experienced recurrent VT (p = 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)

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To examine the impact of hypokalemia on cardiac electrical stability, the thresholds for repetitive extrasystole and ventricular fibrillation were determined before and after potassium depletion in 15 chloralose-anesthetized dogs. A reduction in serum potassium concentration from 3.6 to 2.1 mEq/L induced by hemodialysis decreased the repetitive extrasystole threshold by 30% and the ventricular fibrillation threshold by 25% (p less than 0.01). The increase in ventricular vulnerability following acute coronary occlusion was markedly augmented by concomitant potassium depletion. Thus, hypokalemia enhances the propensity for ventricular fibrillation in the normal as well as in the ischemic canine heart. These findings shed light on clinical observations of enhanced susceptibility to life-threatening arrhythmias during acute myocardial ischemia in hypokalemic patients.

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Calcium channel antagonists differ in their effects on myocardial excitable properties. This study examines whether tiapamil (100 micrograms/kg/min intravenously) is capable of reducing the susceptibility to ventricular fibrillation (VF) during acute occlusion and reperfusion of the left anterior descending coronary artery. During occlusion, tiapamil elevated the VF threshold to 17.5 +/- 8.2 mA compared to a control of 8.6 +/- 5.9 mA (2p less than 0.01). However, no significant effect was noted upon reperfusion of the vessel. Adrenergic stimulation with norepinephrine, 0.5 microgram/kg/min, lowered the VF threshold by 32% (2p less than 0.02), and by 6% (N.S.) when tiapamil was infused concurrently. Thus, tiapamil protects the heart against VF during coronary occlusion, but not during reperfusion. This appears to be mediated in part by an antiadrenergic action of the drug.

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Tocainide was administered to 228 patients referred for treatment of recurrent ventricular tachyarrhythmias that were refractory to therapy with conventional antiarrhythmic drugs. After baseline studies, 1200 to 2400 mg tocainide/day was given for 4 days. Tocainide was effective in 49% of 180 patients evaluated with monitoring and exercise testing and in 35% of 48 patients undergoing electrophysiologic testing. No clinical parameter predicted the response to tocainide, although there was a correlation with the effect of lidocaine. Tocainide was selected for long-term treatment in 73 patients who were followed for an average of 26.4 months (range 1 to 92 months). The incidence of sudden death was 4.3% per year and two patients had nonfatal recurrence of arrhythmia. It is concluded that tocainide is effective and well tolerated during long-term use if therapy is evaluated carefully and is individualized.

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To assess the incidence of adverse effects associated with long-term amiodarone therapy, we reviewed the records of 217 consecutive patients who were treated for refractory arrhythmia. After an average of 11.8 months of therapy, one or more side effects occurred in 113 patients (52%). These were considered clinically significant in 42 patients (19.3%), mandating discontinuation of amiodarone in 18 (8.3%). The untoward reactions requiring discontinuation of amiodarone included thyroid dysfunction, visual disturbances, pulmonary infiltrates, ataxia, cardiac conduction abnormalities, and drug interactions. The mild side effects included corneal microdeposits, skin rashes, and gastrointestinal symptoms. There was a weak correlation between blood levels of amiodarone, the daily dose, and the cumulative dose (r = 0.23, p = 0.015). Drug levels were higher in symptomatic patients (p less than 0.03), although they received lower doses of amiodarone. While amiodarone is associated with frequent side effects, they are generally mild and do not necessitate drug discontinuation. Careful monitoring of therapy is essential to detect the potentially serious adverse reactions which are encountered in nearly 20% of patients.

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Beta-adrenergic blocking agents differ considerably in their effects on myocardial excitable properties. The possibility that intrinsic sympathomimetic activity might contribute to such differences has not been adequately explored. This study examined the influence of intrinsic sympathomimetic activity on the electrophysiologic effects of three agents with varying degrees of such activity. Intravenous propranolol (0.5 mg/kg), oxprenolol (0.5 mg/kg) and pindolol (0.05 mg/kg) were administered in 16 anesthetized dogs. The effects of the drugs on ventricular vulnerability were studied over a 2 hour period. Propranolol and oxprenolol raised the ventricular fibrillation threshold by 42 and 56%, respectively. In contrast, pindolol resulted in an elevation of only 25%. After depletion of endogenous norepinephrine stores using reserpine, pindolol led to a decrease of the ventricular fibrillation threshold, which was reversed by propranolol. These data indicate that intrinsic sympathomimetic activity of beta-adrenergic blocking agents substantially alters their ultimate effect on myocardial excitable properties.

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Partial coronary stenosis produces cyclical changes in coronary blood flow (CBF) which are the result of spontaneous aggregation and disaggregation of platelet plugs at the site of occlusion. The possible influence of the autonomic nervous system on this phenomenon has not been hitherto determined. The present study was performed in 20 chloralose-anesthetized dogs in which the effects of bilateral vagotomy and stellectomy were examined during partial stenosis of the left circumflex coronary artery. Vagotomy reduced the frequency of CBF oscillations from 11.5 +/- 2.1 to 5.0 +/- 2.1 cycles/hr (p less than 0.05). The magnitude of the flow changes was reduced from 13.8 +/- 4.0 to 9.7 +/- 3.0 ml/min (NS). Bilateral cervical stellectomy reduced the frequency of CBF changes from 7.8 +/- 2.7 to 3.7 +/- 1.3 cycles/hr (p less than 0.025) and their magnitude from 10.6 +/- 2.5 to 5.6 +/- 1.8 ml/min (P less than 0.05). In five dogs in which cyclical CBF changes were reduced or abolished by decentralizing the stellate ganglia, electrical stimulation of the main body of the left ganglion evoked or enhanced the oscillations in two dogs, had no distinct effect in two dogs, and elicited no response in one dog. A 5-minute infusion of 0.5 microgram/kg/min and 0.75 microgram/kg/min epinephrine (four dogs) provoked the CBF changes in all animals for a period of 5 to 10 minutes. Blockade of muscarinic receptors by 0.2 mg/kg atropine resulted in a significant attenuation of flow changes, which may at least in part have been due to a direct effect of atropine on platelets. We conclude that cardiac sympathetic tone significantly influences the CBF pattern during critical coronary stenosis. While the afferent limb of the vagus may in part mediate this effect via a reflex increase of adrenal medullary catecholamines, the role of the efferent vagus awaits further clarification.

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The effects of sulfinpyrazone were studied in 33 chloralose-anesthetized dogs. Ventricular fibrillation thresholds, mid diastolic thresholds and duration of the effective refractory period were determined in the normal heart after intravenous administration of sulfinpyrazone, 30 mg/kg body weight. The drug significantly raised the ventricular fibrillation threshold by 24 percent and the mid diastolic threshold by 36 percent and prolonged the effective refractory period by seven percent. The influence of sulfinpyrazone during acute myocardial ischemia was evaluated before and during a 10 minute occlusion of the left anterior descending coronary artery and after abrupt release of the occlusion. Although the drug afforded significant protection during coronary occlusion, it had no effect on the ventricular fibrillation threshold after reperfusion. Because potent cardiocardiac reflexes are elicited during ischemia, the influence of sulfinpyrazone on the ventricular fibrillation threshold was studied during norepinephrine infusion. Sulfinpyrazone attenuated the reduction of the ventricular fibrillation threshold during sympathetic humoral stimulation. Its effect was additive to beta adrenergic blockade with practolol and membrane stabilization with lidocaine. This investigation suggests that sulfinpyrazone exerts significant effects on ventricular vulnerability of both the normal and the ischemic myocardium. Further studies are needed to elucidate its precise mechanism of action.

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The possibility of beta-adrenoreceptor hypersensitivity after abrupt withdrawal of long-term therapy (8-18 months) with the slow-release (SR) formulation of oxprenolol (160-320 mg/day) was assessed in six patients with uncomplicated essential hypertension. The chronotropic dose 25 of isoproterenol (the dose that increases the resting heart rate by 25 beats/min), plasma concentration of catecholamines, triiodothyronin and thyroxin, plasma renin activity and aldosterone, hemoglobin, hematocrit and oxyhemoglobin dissociation were measured on the last day of oxprenolol SR intake and 1, 2, 3, 6 and 13 days after abrupt replacement by identical placebo tablets. The chronotropic dose 25 of isoproterenol (microgram/m2), which was greater than 25.6 in all patients on the last day of oxprenolol SR, fell to 4.83 +/- 2.03 on the second day and to 3.50 on the third day after its abrupt withdrawal and reached a minimal value on the thirteenth day (2.78 +/- 0.30). Throughout the study, plasma concentrations of catecholamines, triiodothyronin and thyroxin and oxyhemoglobin dissociation remained unchanged. Plasma renin activity and plasma aldosterone, which were suppressed during oxprenolol administration, rose significantly during placebo, coinciding with a significant fall in hematocrit and hemoglobin. No major subjective symptoms were reported by the patients. Thus, hypersensitivity of beta-adrenoreceptor-mediated responses was not demonstrated after sudden withdrawal of oxprenolol SR.

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The effect of the beta-blocking drug acebutolol on the severity of cardiac arrhythmias and the incidence of exercise-induced arrhythmias was studied in 15 patients with chronic coronary artery disease using ambulatory Holter monitoring and bicycle ergometry. We found a significantly lower grading of arrhythmias both on long-term ECGs and during and after exercise. Furthermore, there was a significant decrease in the incidence of VPBs during and after exercise (18.15 +/- 7.7 on placebo vs. 3.46 +/- 1.7 on acebutolol). It is concluded that acebutolol favorably influences the incidence and severity of ventricular arrhythmias in patients with chronic coronary artery disease.

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