Psychologic stress and threshold for repetitive ventricular response.

A psychologically stressful environment reduced the threshold of the dog's ventricle for repetitive response. Elicitation of such a response indicates the presence of electrical instability and a predisposition to ventricular fibrillation, the mechanism of sudden death.

Tyrosine administration decreases vulnerability to ventricular fibrillation in the normal canine heart.

Intravenous infusion of tyrosine (1, 2, or 4 milligrams per kilogram) for 20 to 30 minutes caused dose-dependent increases in the ventricular fibrillation threshold in normal dogs. Administration of valine, a neutral amino acid that competes with tyrosine for uptake at the blood-brain barrier, in a dose equimolar to the most effective dose of tyrosine, slightly decreased the ventricular fibrillation threshold when given alone and significantly blocked elevation of the ventricular fibrillation threshold after tyrosine infusion. Hence, tyrosine, presumably acting in the central nervous system, can protect against certain ventricular arrhythmias.

Propafenone: a new agent for ventricular arrhythmia.

Propafenone, a new antiarrhythmic agent, was utilized in 30 patients with diverse heart disease who presented with sustained hemodynamically unstable ventricular arrhythmia. Drug efficacy was judged by means of ambulatory electrocardiographic monitoring and exercise testing. Nine patients additionally had invasive electrophysiologic studies. Seventeen patients (57%) responded to therapy as judged by monitoring and 21 patients (70%) responded to therapy as judged by exercise testing. When both methods were considered, 16 patients (53%) responded. The acute drug test predicted the result of maintenance therapy in 91% of patients. Seven of nine patients who had electrophysiologic testing responded based on this technique, and in all cases the results were concordant with the noninvasive evaluation. Serum blood levels did not correlate with antiarrhythmic effect. In patients with myocardial impairment, echocardiographic assessment of left ventricular function indicated a decrease in ejection fraction during propafenone therapy (32 versus 24%, p less than 0.05), while no change was observed in patients with normal left ventricular function. Side effects occurred in nine patients and included exacerbation of congestive heart failure, development of conduction abnormalities and aggravation of arrhythmia, each occurring in two patients. Ten patients who continued on long-term propafenone therapy for an average of 10 months (range 3 to 13) have remained free of arrhythmia and side effects. Propafenone needs to be employed with caution in patients with congestive heart failure or evidence of conduction system disease.

Intrinsic sympathomimetic activity and the effects of beta-adrenergic blocking drugs on vulnerability to ventricular fibrillation.

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.

Lorcainide in patients with refractory ventricular tachyarrhythmia.

Lorcainide, a new antiarrhythmic agent with local anesthetic or membrane-stabilizing properties similar to those of quinidine, was tested in 76 patients with diverse types of heart disease and recurrent ventricular tachycardia or ventricular fibrillation. Lorcainide was administered for 72 to 96 hours in a dose ranging from 200 to 400 mg daily. Evaluation of drug efficacy involved ambulatory monitoring and exercise stress testing in 60 patients who had high grade ventricular arrhythmia. Invasive electrophysiologic testing was carried out in the remaining 16 patients who exhibited infrequent ventricular ectopic activity during control studies. Lorcainide was effective in 21 (38%) of 56 patients evaluated for suppression of ventricular ectopic activity and in 6 (40%) of 15 who had invasive testing. In five patients, the drug was discontinued because of toxic reactions. Thus, 27 (38%) of the 71 patients who completed the drug study responded to lorcainide. Side effects, reported by 42 patients (55.3%), consisted primarily of insomnia and gastrointestinal symptoms; 7 experienced aggravation of arrhythmia. Fifteen patients were discharged while receiving lorcainide therapy, but in four the treatment was discontinued after 2 months because of side effects. Three patients died, one suddenly. It is concluded that lorcainide is of value in a small subset of patients with life-threatening ventricular arrhythmias who have proven refractory to conventional drugs. Its usefulness is limited by the high frequency of insomnia.

Congestive heart failure induced by six of the newer antiarrhythmic drugs.

The incidence of drug-induced congestive heart failure with several newer antiarrhythmic agents including encainide, ethmozine, lorcainide, mexiletine, propafenone and tocainide was determined in a group of 407 patients who underwent 1,133 drug tests. The incidence rate ranged from 0.7% with lorcainide to 4.7% with propafenone. Congestive heart failure was present in 167 patients (41%) who underwent 491 drug trials. Congestive failure was induced in 15 (9%) of these 167 patients and involved 19 (3.9%) of the 491 tests. Left ventricular ejection fraction was 20 +/- 8% in patients who developed congestive failure, in contrast to 39 +/- 19% in those who did not (p less than 0.001). It is concluded that each of the six antiarrhythmic drugs examined has the potential to aggravate congestive heart failure in patients with reduced left ventricular ejection fraction or a history of congestive heart failure, but the incidence rate is low and its occurrence unpredictable.

Spontaneous variability and circadian distribution of ectopic activity in patients with malignant ventricular arrhythmia.

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.

Mexiletine and tocainide: does response to one predict response to the other?

Mexiletine and tocainide were administered to 79 patients to determine whether the response to one of these drugs would predict the effect of the other. In 57 patients, the two agents were evaluated noninvasively with monitoring and exercise testing, and efficacy was judged by the suppression of spontaneous ventricular arrhythmia. In the remaining 22 patients, electrophysiologic testing was performed and efficacy was defined as the inability to induce more than two repetitive ventricular premature beats. An equal number of patients responded to mexiletine and tocainide (38 versus 39%). However, in only 42 patients (53%) were the results concordant. There was no difference in concordance when the results were analyzed by method of drug evaluation, left ventricular ejection fraction or etiology of presenting arrhythmia. It is concluded that mexiletine and tocainide have different clinical effects and must be evaluated individually.

Is amiodarone good for heartburn?

Three cases are reported in which resolution of severe esophagitic dyspepsia followed amiodarone therapy for cardiac arrhythmias. This effect has proved long lasting. The mechanism of amiodarone action may be related to its calcium antagonist or nitratelike properties that reduce lower esophageal sphincter tone. An alternate hypothesis calls attention to structural similarities between amiodarone and the histamine antagonist ranitidine, and suggests a previously unrecognized action of amiodarone on histamine receptors.

The effect of caffeine on ventricular ectopic activity in patients with malignant ventricular arrhythmia.

We evaluated the effect of caffeine on ventricular ectopic activity in a group of 50 consecutive patients with malignant ventricular arrhythmia. The clinical arrhythmia in these patients (mean age, 61 years) was recurrent ventricular tachycardia in 21 (42%), ventricular fibrillation in three (6%), and symptomatic nonsustained ventricular tachycardia in 26 (52%). Forty-two (84%) had either ischemic heart disease or cardiomyopathy. Each patient underwent two short-term drug trials on successive days, receiving either decaffeinated coffee mixed with 200 mg of caffeine or the decaffeinated drink alone. Continuous electrocardiographic recordings were made during the 30-minute control period, the three-hour observation period, and the hourly bicycle exercise tests. Forty-five patients (90%) exhibited ventricular couplets and 29 patients (58%) had salvos of ventricular tachycardia during the testing. However, no differences between the caffeine and decaffeinated trials were observed in either individual or group data on total or repetitive ventricular arrhythmia. Serum catecholamine levels reflected the average increase in serum caffeine level but were not associated with enhanced arrhythmia. We found no evidence that a modest dose of caffeine is arrhythmogenic, even among patients with known life-threatening arrhythmia.

Coronary occlusion before, during, and after strenuous exercise.

Groups of dogs were exercised immediately before, and immediately after occlusion of the left anterior descending coronary artery. Coronary occlusion by a staged procedure resulted in a low mortality and rare ventricular ectopic beats. The combination of simultaneous exercise with coronary occlusion reproducibly provoked ventricular fibrillation (VF). Exercise before and after occlusion frequently produced ventricular tachycardia but no VF. The risk of major arrhythmias was related to the peak heart rate resulting from the exercise.

Effects of adrenergic and muscarinic receptor stimulation on serum potassium concentrations and myocardial electrical stability.

The influence of adrenergic and muscarinic receptor activation on cardiac electrical stability and on serum potassium concentrations was studied in 23 anaesthetised dogs. The ventricular fibrillation threshold was assessed using the single stimulus technique. Adrenaline (1.0 microgram X kg-1 X min-1) caused a brief rise and a subsequent prolonged fall in serum potassium concentration, which was accompanied by a decline in ventricular fibrillation threshold when baroreceptor activation was prevented. After pretreatment with the beta1 adrenoceptor blocking agent metoprolol (0.5 mg X kg-1), adrenaline did not alter vulnerability to ventricular fibrillation but still elicited hypokalaemia. In contrast, selective beta2 adrenoceptor blockade (ICI 118551, 100 micrograms X kg-1) prevented the adrenaline induced lowering of serum potassium concentration but not of ventricular vulnerability. Muscarinic receptor activation by methacholine (3.0 micrograms X kg-1 X min-1) had no effect on serum potassium concentration but increased the ventricular fibrillation threshold by 30%. When methacholine was administered concomitantly with adrenaline the decline in serum potassium concentration persisted, but the increase in ventricular vulnerability was completely prevented. It is concluded that in the normal canine myocardium adrenaline produces an increase in vulnerability that is mediated through beta 1 adrenoceptors and that the beta 2 adrenoceptor mediated hypokalaemia is dissociated from electrophysiological effects of adrenaline. Parasympathetic nervous system activation does not influence serum potassium concentrations but opposes the effects of adrenaline on susceptibility to ventricular fibrillation.

Decreased vulnerability to ventricular fibrillation by vasodilator-induced baroreceptor sensitisation.

Vulnerability to ventricular fibrillation (VF) is affected by changes in systemic arterial blood pressure which are mediated through the sympathetic nervous system. We determined that small doses of a vasodilator drug can abolish the enhanced ventricular vulnerability induced by norepinephrine infusion. Noradrenaline (0.5 micrograms X kg-1 X min-1) caused a fall in ventricular fibrillation threshold from 30 to 20 mA (P less than 0.001). Pretreatment with prostaglandin E1, I2 or nitroglycerin at doses which reduced mean arterial blood pressure by 0.7 to 1.3 kPa (5 to 10 mmHg) abolished the enhanced vulnerability produced by noradrenaline. Following baroreceptor denervation, these agents no longer afforded protection against the profibrillatory action of noradrenaline. We conclude that small doses of vasodilator agents can augment ventricular electrical stability. The mechanism for this protective action appears to be a decrease in cardiac sympathetic tone resulting from vasodilatation of baroreceptor areas.

Protective effect of verapamil on vulnerability to ventricular fibrillation during myocardial ischaemia and reperfusion.

The effects of verapamil on vulnerability to ventricular fibrillation were studied in 55 chloralose-anaesthetised dogs. Ventricular fibrillation threshold was measured before and during a 10 min period of left anterior descending coronary artery occlusion and following abrupt release of occlusion. The action of intravenous verapamil (0.01 mg.kg-1.min-1, following a 0.1 mg.kg-1 bolus) on vulnerability to fibrillation was examined before and during coronary artery occlusion and reperfusion. While the infusion of verapamil did not alter the ventricular fibrillation threshold in the nonischaemic myocardium, the vulnerable period threshold was raised and the incidence of spontaneous ventricular fibrillation was reduced both after coronary artery occlusion and release. Since cardiocardiac sympathetic reflexes are elicited in response to coronary artery occlusion, the effect of verapamil on vulnerability during left stellate ganglion stimulation and during noradrenaline infusion was investigated. Verapamil completely prevented the reduction in vulnerable period threshold during sympathetic nerve stimulation or noradrenaline infusion. This study suggests that the antifibrillatory action of verapamil during coronary artery occlusion may be, in part, related to antagonism of enhanced adrenergic input to the heart, while the mechanism of protection during reperfusion is as yet uncertain.

Reduction in vulnerability to ventricular fibrillation by bromocriptine, a dopamine agonist.

The effect of a dopamine agonist, bromocriptine, on ventricular fibrillation (VF) threshold was studied in anaesthetised dogs. Bromocriptine produced an increase of 50% in VFT. Pretreatment with the dopamine antagonist haloperidol abolished the effects of bromocriptine on VF threshold as did pretreatment with the peripheral dopamine antagonist, domperidone. It is concluded that bromocriptine reduces vulnerability of the nonischaemic canine ventricle to fibrillation. This effect is most probably mediated by peripheral presynaptic stimulation of dopaminergic receptors, thereby inhibiting noradrenaline release.

Influence of autonomic nervous system stimulation on the protective zone.

The effect of sympathetic and parasympathetic stimulation on the vulnerable period threshold and the protective zone was studied in chloralose-anaesthetised dogs. Sympathetic stimulation substantially decreased the repetitive extrasystole threshold and shifted the timing of the protective zone earlier into diastole. Vagus nerve excitation exerted the opposite effect on both electrophysiological properties. During concurrent sympathetic nerve stimulation, the changes produced by vagal activation were accentuated. These findings suggest that parasympathetic influences on the protective zone are due, in part, to an antagonism of adrenergic effects on ventricular electrical properties.

Protective effect of the vagotonic action of morphine sulphate on ventricular vulnerability.

Administration of morphine sulphate to 16 anaesthetised dogs resulted in significant reduction in ventricular vulnerability to fibrillation. The repetitive extrasystole threshold was used as an index of vulnerability to ventricular fibrillation. In 14 dogs, atropine or vagotomy abolished this response. This suggests that central vagal activation by morphine sulphate may be protective against ventricular fibrillation.

Incremental bias in Finapres estimation of baseline blood pressure levels over time.

Finapres finger blood pressure monitoring appears to provide a reliable alternative to intra-arterial blood pressure measurement under many circumstances. However, few studies have focused on the limitations of Finapres assessment. In a previous pilot investigation, we observed that Finapres pressure following mental stressors failed to return to initial resting levels. Our objectives in the present study were to (1) replicate earlier findings, (2) examine whether local changes in the measured finger were responsible for the observed drift, and (3) test a method to facilitate the return of pressure to systemic baseline levels. We studied two groups of healthy subjects who underwent a protocol consisting of two mental stressors preceded and followed by baseline periods. In the control group, the Finapres continuously monitored pressure on a single finger for the entire protocol. The intervention group periodically had the Finapres cuff removed and the measured finger exercised to prevent local changes that might influence Finapres estimation of blood pressure. Comparisons indicated a group x baseline interaction effect for systolic and diastolic pressures (P < .0004 and P < .003, respectively). The group with the exercise intervention showed much greater recover during the final baseline than the control group. Recovery of pressures in the control group but not the intervention group was inversely related to the stress level of blood pressure (r = .86, P < .0002), indicating a relationship between blood pressure rise and the degree of distortion of subsequent baseline values. On the basis of our results, we propose that in prolonged protocols, the measurement finger be exercised to facilitate accurate measurements of finger pressure with the Finapres.

Psychophysiologic factors in sudden cardiac death.

Sudden cardiac death due to ventricular fibrillation is the leading cause of fatality in the industrially developed world. A considerable body of evidence indicates that the higher nervous system modifies electrical activity of the heart and may trigger sudden death. The evidence for increased risk for ventricular fibrillation due to psychophysiologic factors is supported predominantly by animal studies, but increasing evidence is forthcoming from human studies. The involvement of psychiatrists, psychologists, and cardiologists in a multidisciplinary approach to managing patients at risk for sudden death from ventricular fibrillation is yielding significant insights and prolonging their lives.

Unrecognized organic mental disorders in survivors of cardiac arrest.

Long-term survivors of cardiac arrest may suffer from mild cerebral impairment manifested primarily by personality changes and behavioral symptoms that can be mistaken for emotional responses to illness. The authors report six cases that illustrate the clinical problem of differentiating depression from organic brain dysfunction in this population. The diagnosis is facilitated by observation over time and by information from the spouse on baseline and current function. Chronicity, dysinhibition, apathy, and disturbances of judgment and insight indicate cerebral dysfunction. The accurate diagnosis of cerebral impairment after cardiac arrest is essential to the rehabilitation process.