Steven D. Nelson

Identification and catheter ablation of a zone of slow conduction in the reentrant circuit of ventricular tachycardia in humans

Three patients who had incessant ventricular tachycardia and in whom a zone of slow conduction was identified are presented. Each patients tachycardia was refractory to multiple antiarrhythmic drugs and was being treated with amiodarone at the time of the electrophysiologic study. The ventricular tachycardia cycle length was 500 to 580 ms. In Patients 1 and 2, a single site at the posterolateral wall or low septum in the left ventricle was identified at which overdrive pacing during ventricular tachycardia resulted in ventricular capture with a stimulus to QRS interval of 280 to 400 ms and with little or no change in the configuration of the QRS complexes during pacing as compared with during ventricular tachycardia. In Patient 3, the same phenomenon was observed at two areas in the left ventricle: at the inferior wall, overdrive pacing during ventricular tachycardia resulted in a stimulus to QRS interval of 440 to 470 ms, whereas at the posterolateral wall, the stimulus to QRS interval was 320 to 360 ms. Transcatheter shocks of 100 to 240 J delivered at the pacing sites have been successful in preventing recurrences of ventricular tachycardia over a follow-up period of 10 to 11 months. These observations may be explained by the pacing site being located within a reentrant circuit in a zone of slow conduction bounded by inexcitable tissue between the pacing site and the exit site of the reentrant circuit. In Patient 3, the variable stimulus to QRS intervals are explained by variable proximity of the pacing sites within the slow conduction zone to the exit site of the reentrant circuit.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic effects of epinephrine in humans

The electrophysiologic effects of circulating epinephrine in humans were examined in four study groups of 10 subjects each. In 10 subjects without structural heart disease (Group 1) and in 10 patients with coronary disease or dilated cardiomyopathy (Group 2) epinephrine infusion at 25 and 50 ng/kg body weight per min for 14 min resulted in an elevation of the plasma epinephrine concentration in the physiologic range. In both groups it produced a dose-dependent decrease in the effective refractory period of the atrium, atrioventricular (AV) node and ventricle and improvement in AV node conduction. Epinephrine facilitated the induction of sustained ventricular tachycardia in 3 of the 20 subjects. In Group 3, a beta-adrenergic blocking dose of propranolol was added to the infusion of 50 ng/kg per min of epinephrine. Propranolol not only reversed the effects of epinephrine, but also lengthened these variables compared with baseline values. In Group 4, propranolol was administered first, followed by 50 ng/kg per min of epinephrine. Propranolol alone slowed AV node conduction and mildly prolonged the refractory periods. In the presence of beta-blockade, epinephrine had no effect on AV node properties but resulted in a lengthening of the atrial and ventricular effective refractory periods. In conclusion, epinephrine in physiologic doses shortens the effective refractory period of the atrium, AV node and ventricle, improves AV node conduction and may facilitate the induction of sustained ventricular tachycardia. The overall electrophysiologic effects of epinephrine result from stimulation of beta-receptors. Stimulation of alpha-receptors by epinephrine has no effect on the AV node but prolongs the effective refractory period of the atrium and ventricle, partially offsetting the shortening of refractory periods mediated by beta-receptor stimulation.

Accentuated antagonism between beta-adrenergic and vagal effects on ventricular refractoriness in humans.

The purpose of this study was to determine whether there is accentuated antagonism between sympathetic and vagal effects on ventricular refractory periods (VRPs) in humans. The effects of 0.04 mg/kg of atropine on the right ventricular effective and functional refractory periods were determined in the setting of beta-adrenergic blockade by propranolol (0.15 mg/kg loading dose, then 0.1 mg/min continuous infusion, group 1) and in the setting of beta-adrenergic stimulation by 25 or 50 ng/kg/min isoproterenol (groups 2 and 3, respectively). Groups 4 to 6 served as control groups. In group 4, VRPs were determined on three occasions separated by 10 min each in the absence of drug. VRPs also were determined on two occasions after infusion of propranolol (group 5) or 25 ng/kg/min of isoproterenol (group 6). Groups 1 to 4 consisted of 10 subjects each, and groups 5 and 6 consisted of five subjects each. VRPs were determined with the use of basic drive cycle lengths of 600, 500, 400, and 350 msec. Because of sinus tachycardia, sufficient data for comparison of groups 1 to 3 were available only at drive cycle lengths of 400 and 350 msec. Atropine significantly shortened the VRPs in groups 1 to 3, but the magnitude of atropines effects in group 3 (5.3% to 5.8% shortening at drive cycle length of 350 msec) was significantly greater than in group 1 (2.6% to 3.0% shortening, p less than .05) Data from the control groups demonstrated that there was no effect of time on measurement of VRPs either in the drug-free state or in the presence of propranolol or isoproterenol. The results of this study indicate that cholinergic tone lengthens VRPs in the absence of background sympathetic activity and that this lengthening of VRPs may become accentuated during beta-adrenergic stimulation.

Effect of flecainide acetate on prevention of electrical induction of ventricular tachycardia and occurrence of ischemic ventricular fibrillation during the early postmyocardial infarction period: Evaluation in a conscious canine model of sudden death

The antiarrhythmic and antifibrillatory effects of flecainide acetate during the early postinfarction period were evaluated in a conscious canine model of sudden cardiac death. Ventricular tachycardia remained inducible early after infarction in eight of nine dogs receiving an intravenous loading dose of flecainide (2.0 mg/kg body weight) and seven of eight dogs receiving saline vehicle. In both the drug and vehicle groups, there was no significant change in the ventricular refractory period or in the cycle length of the induced ventricular tachycardia. With a maintenance intravenous infusion of flecainide, 1.0 mg/kg per h for 4 hours, the subsequent occurrence of acute posterolateral ischemia resulted in the development of ventricular fibrillation and sudden death in seven of eight flecainide-treated and eight of eight vehicle-treated dogs. Seven additional postinfarction dogs with noninducible tachycardia during pretreatment programmed stimulation, and thereby considered to be at low risk for the development of ischemic ventricular fibrillation, were also given flecainide in an intravenous loading and maintenance dosing regimen. The subsequent occurrence of posterolateral ischemia resulted in the development of ventricular fibrillation in three of these seven dogs. These findings suggest that flecainide acetate may not possess pharmacologic properties useful in managing ventricular tachycardia or in preventing ischemic ventricular fibrillation in the presence of recent myocardial damage.

Antagonism of quinidine's electrophysiologic effects by epinephrine in patients with ventricular tachycardia

The purpose of this study was to determine whether pharmacologically induced elevations in the plasma epinephrine concentration within reported physiologic limits alter the response to quinidine during electropharmacologic testing. Twenty-one patients with coronary artery disease and a history of unimorphic ventricular tachycardia were found to have inducible sustained unimorphic ventricular tachycardia that was suppressed by treatment with oral quinidine gluconate. Epinephrine was then infused at a rate of either 25 or 50 ng/kg per min and testing was repeated. These infusion rates of epinephrine were previously demonstrated to result in elevations of the plasma epinephrine concentration in the range of concentrations that occur during a variety of stresses. Quinidine significantly lengthened the ventricular refractory periods and the QRS duration at a ventricular pacing cycle length of 350 ms, which was used as an index of intraventricular conduction. Epinephrine partially or completely reversed the effects of quinidine on ventricular refractory periods, but had no effect on QRS duration. During electropharmacologic testing of quinidine, no ventricular tachycardia was inducible in 12 patients, and only nonsustained ventricular tachycardia, 8 to 48 beats in duration, was inducible in 9 patients. Retesting during infusion of epinephrine demonstrated inducible sustained unimorphic ventricular tachycardia in 2 of the 12 patients in whom quinidine had completely suppressed the induction of ventricular tachycardia and in 8 of the 9 patients in whom only nonsustained ventricular tachycardia had been inducible during testing of quinidine. In conclusion, physiologic elevations in the plasma epinephrine concentration may reverse quinidine-induced prolongation of ventricular refractoriness but not intraventricular conduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Significance of ST segment depression during paroxysmal supraventricular tachycardia

During paroxysmal supraventricular tachycardia, patients frequently experience chest pain and marked ST segment depression suggesting acute myocardial ischemia. The purpose of this study was to assess whether ST depression during supraventricular tachycardia is caused by myocardial ischemia as reflected by net myocardial lactate production. Twenty-five patients (14 men, 11 women) who had a history of paroxysmal supraventricular tachycardia and a mean age (+/- SD) of 38 +/- 14 years underwent electrophysiologic testing. Twenty-four of these patients had no evidence of coronary disease, whereas one patient had undergone previous coronary bypass surgery. Nineteen patients had orthodromic and six patients had atrioventricular node reentrant tachycardias. A 12 lead electrocardiogram and simultaneous femoral artery and coronary sinus blood samples for lactate determinations were obtained at baseline and at 5 and 10 min of supraventricular tachycardia. Mean baseline heart rate of 83 +/- 12 beats/min increased to 180 +/- 25 beats/min during supraventricular tachycardia. All patients had 1 to 8 mm of ST segment depression in 1 to 9 of the 12 leads. Chest pain occurred in 64% of patients during supraventricular tachycardia. Baseline myocardial lactate extraction was 28 +/- 13% with no significant change at 5 or 10 min of tachycardia. In contrast, in a comparison group of seven patients with known coronary artery disease, atrial pacing at 168 +/- 26 beats/min in five patients resulted in greater than or equal to 1 mm ST depression in 2 to 7 of the 12 leads and a change in lactate extraction from a baseline of 29 +/- 13% to -27 +/- 20% (p less than 0.05) indicating net myocardial lactate production.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the Mechanism of the Acute Antihypertensive and Vasodilator Actions of Several β-adrenoceptor Antagonists

Summary Several new β-adrenoceptor antagonists (sulfinalol, MK 761, and prizidilol) have been reported to possess direct vasodilator activity in addition to blocking β-receptors. The mechanism of the hypotensive and vasodilator actions of these agents was examined and compared to that of pindolol and hydralazine. Intraarterial injection of each agent increased blood flow in the sympathetically denervated hindlimb of anesthetized dogs. Doses increasing flow by 50 ml/min (ED50) were 0.48, 0.24, 331, 0.3, and 51 μg for sulfinalol, MK 761, prizidilol, pindolol, and hydralazine, respectively. Intravenous injection of each agent reduced blood pressure of anesthetized, ganglion-blocked dogs. Vasodilation and hypotension to sulfinalol, MK 761, and pindolol, but not prizidilol or hydralazine were attenuated by propranolol pretreatment. Oral administration of sulfinalol (2.5 mg/kg), MK 761 (2.5 mg kg), prizidilol (10 mg/kg), pindolol (0.1 mg/kg), and hydralazine (2.5 mg/kg) reduced pressure of conscious spontaneously hypertensive rats. Antihypertensive actions of sulfinalol and pindolol, but not MK 761, prizidilol, and hydralazine were inhibited by propranolol pretreatment (25 mg/kg. p.o.). With the exception of hydralazine, each agent demonstrated effective β-adrenergic blockade at the antihypertensive dose tested as judged by inhibition of the chronotropic responses to sympathetic stimulation and isoproterenol in pithed rats. These data suggest that the acute vasodilator and blood pressure lowering effects of sulfinalol, MK 761, and pindolol, but not prizidilol and hydralazine, are mediated, at least in part, through activation of vascular β-receptors.

Mechanisms of ventricular arrhythmia during amitriptyline toxicity

Summary: The ventricular tachycardia (VT) caused by high-dose tricyclic antidepressants has been hypothesized to be due to a quinidinelike effect with generation of repolarization abnormalities and afterdepolarizations. To test this hypothesis further, we infused amitriptyline in a graded fashion (0.5-1 mg/kg/min) in 23 chloraloseanesthetized dogs during endocardial monophasic action potential (AP) recording and continuous hemodynamic monitoring. Three groups of dogs were studied: group A (n=5), crushed sinus node and fixed atrial pacing at 100 beats/min; group B (n=12), crushed sinus node and fixed atrial pace plus intermittent accelerated pacing to mimic group C; and group C (n=6) intact sinus node and unimpeded sinus tachycardia. Amitriptyline infusion induced VT in no (0 of 5) group A dogs, all (12 of 12) group B dogs during accelerated pacing, and 83% (5 of 6) of group C dogs. Dogs with VT had significantly higher heart rates (HR 184.8 ± 39.3 beats/min) as compared with dogs without VT (115.2 ± 12.5 beats/min, p=0.0015). There was a strong positive correlation between the last RR coupling interval to the first VT interval (r=0.85; p=0.0033). Amitriptyline infusion caused rate-dependent QRS prolongation in each group, especially group C (p<0.001). Action potential duration at 50% and 90% of repolarization (APD50, APD90) showed a biphasic response with progressive shortening followed by prolongation as amitriptyline serum concentrations increased. Afterdepolarizations were not detected from any monophasic AP recording, even in dogs with VT. Unlike the proarrhythmia observed with quinidine, amitriptyline-induced VT is tachycardic dependent, possibly owing to triggered activity, without significant prolongation of APD or development of early afterdepolarizations (EADs). Interventions that prevent sinus tachycardia may also prevent VT in this canine model

A prospective comparison of programmed ventricular stimulation with triple extrastimuli versus single and double extrastimuli during infusion of isoproterenol

This prospective study compared the yield of programmed ventricular stimulation with single and double extrastimuli during an infusion of isoproterenol with that of programmed stimulation with triple extrastimuli. The subjects of this study were 58 patients who underwent programmed stimulation and did not have inducible ventricular tachycardia (VT) with single or double extrastimuli at two basic drive cycle lengths and at two right ventricular sites; 17 patients had a history of uniform VT unrelated to exercise, and 41 had no history of documented or suspected VT or ventricular fibrillation (VF). Programmed stimulation was performed with triple extrastimuli at both right ventricular sites. Isoproterenol was infused as a dose titrated to increase the sinus rate by 25% or to a rate of 100 beats/min, whichever was greater, and stimulation then was repeated with single and double extrastimuli. Among the 17 patients with a history of uniform VT, the clinical VT was induced by three extrastimuli in five patients (29%) and by two extrastimuli during isoproterenol infusion in six patients (35%, p greater than 0.05). Among the total study population of 58 patients, nonclinical multiform VT or VF was induced by three extrastimuli in 29 patients (50%), and by two extrastimuli during isoproterenol infusion in 15 patients (26%, p less than 0.05). Therefore stimulation with two extrastimuli during isoproterenol infusion has the same probability of inducing a clinical form of VT as does stimulation with extrastimuli, but the former has a significantly lower probability of inducing nonclinical multiform VT and VF.

Electrophysiologic actions and antifibrillatory efficacy of subacute left stellectomy in a conscious, post-infarction canine model of ischemic ventricular fibrillation

The autonomic nervous system appears to modulate ventricular arrhythmias associated with acute myocardial ischemia. This study investigated the electrophysiologic effects and antifibrillatory actions of subacute left stellectomy in a conscious, post-infarction canine model of sudden cardiac death. Twenty-two dogs with a previous anterior wall myocardial infarction and inducible ventricular arrhythmias were randomized to undergo either left stellectomy (n = 12) or remain as sham-denervated controls (n = 10). Five to 7 days post left stellectomy, there were no significant changes in heart rate, electrocardiographic intervals or ventricular refractoriness compared to sham-denervated controls. Acute posterolateral ischemia was produced in left stellectomy and sham-denervated dogs by anodal current-induced thrombosis via a previously positioned electrode in the left circumflex coronary artery. Ventricular fibrillation developed within 1 hour of the onset of ischemia (early ventricular fibrillation) in 3/12 (25%) left stellectomy dogs versus 8/10 (80%) sham-denervated controls (P less than 0.05). However, 24-hour mortality rate was 5/12 (42%) after left stellectomy versus 8/10 (80%) after sham denervation (P = 0.072). Small differences in regional myocardial norepinephrine content, which is a marker for neuronal integrity, occurred in the mid-posterolateral and mid-anteroseptal regions of the left ventricle after left stellectomy. Overall norepinephrine concentration after left stellectomy was 409.70 +/- 9.90 ng/g vs 428.07 +/- 10.84 ng/g in sham controls (P = NS). In summary, subacute left stellectomy significantly reduces the incidence of ventricular fibrillation occurring within 1 hour of the onset of acute posterolateral ischemia at a distance to a previous myocardial infarction in conscious dogs, and tends to reduce the ischemic post-infarction mortality at 24 hours after the onset of ischemia. This protective effect of left stellectomy is not due to any alteration in cardiac electrophysiologic parameters measured prior to the development of acute posterolateral ischemia, nor is it related to regional denervation as determined by myocardial tissue concentration of residual norepinephrine.