Mark E. Josephson

The electrophysiology of propranolol in man

Abstract The effects of intravenous propranolol (0.1 mg. per kilogram) on the electrophysiologic properties of the A-V conducting system were studied in 16 patients using His-bundle electrograms and the extrastimulus method. The drug was infused at a rate of 1 mg. per minute without significant side effects. Sinus cycle length was slowed in 15 out of 16 patients (average, 128 msec.). AVN conduction time was increased in 13 out of 16 patients (average, 10 msec.) during sinus rhythm and in all patients during atrial pacing. AVN Wenckebach block occurred at slower paced rates in 14 patients. Corrected QT interval was shortened in 9 out of 16 patients (average, 24 msec.). The functional and effective refractory periods (ERP) of the AVN were prolonged in 14 out of 14 patients (average, 29 msec.) and 9 out of 9 patients (average, 24 msec.), respectively. No significant changes were seen in His-Purkinje system (HPS) conduction time, ERP of the atrium, relative refractory period or ERP of the HPS, or ERP of the ventricle in all patients in whom these variables could be muasured. Mean end-study blood level was 13.6 ng. per milliliter. Effects on the AVN explain the efficacy of propranolol in (1) controlling the ventricular rate in atrial fibrillation and flutter and (2) the treatment and prophylaxis of re-entrant supraventricular tachycardias. Its lack of effects on the HPS make its use relatively safe in patients with infra-His conduction disturbances.

Electrophysiologic studies in the syndrome of short P-R interval, normal QRS complex☆

Eighteen subjects with a short P-R interval (<0.12 second) and normal QRS complex were studied by means of His bundle recordings and programmed atrial premature depolarizations. Eight subjects had a history of supraventricular tachycardia. During sinus rhythm, the A-H interval was less than or at the lower limits of normal values (45 to 80 msec), and the H-V interval was normal (30 to 50 msec). Atrial pacing at rates of up to 160/min produced 3 types of responses. Thirteen subjects showed a progressive increase in A-H interval similar to that of normal subjects but to a lesser degree. Three subjects showed an initial increase at low pacing rates, followed by a plateau response and further increase at higher rates. Two subjects showed no significant increase in the A-H interval. In 6 of 8 subjects with supraventricular tachycardia, atrial premature depolarizations produced atrial echo beats and sustained supraventricular tachycardia in 4, indicating atrioventricular (A-V) nodal reentry as the mechanism for the supraventricular tachycardia. In 10 subjects, refractory periods of the various components of the A-V conducting system were found to be similar to those of subjects with a normal P-R interval. The data suggest the following possible explanations for the short P-R interval: (1) total or partial bypass of the A-V node; (2) an anatomically small A-V node; (3) a short or rapidly conducting intranodal pathway; or (4) isorhythmic A-V dissociation.

Electrophysiologic properties of procainamide in man

Abstract The electrophysiologic properties of procainamide were studied in 16 patients and correlated with plasma levels. Procainamide caused a minimal prolongation of atrioventricular (A-V) nodal conduction in 11 of 16 patients during sinus rhythm, but His-Purkinje conduction time was significantly prolonged in 15 of 16 patients. The effective refractory period of the atrium was prolonged by procainamide in 14 of 16 patients. The effective refractory period of the A-V node decreased in 8 of 9 patients. This may have been due to (1) anticholinergic properties of procainamide, (2) production of an A-V nodal “gap” by procainamide, or (3) an apparent A-V nodal block that actually represented decremental conduction in the His bundle; procainamide then caused delay in the A-V node allowing improved intra-His conduction and ventricular depolarization. The relative refractory period of the His-Purkinje system was prolonged in 10 of 11 patients. The effective refractory period was prolonged in one patient, unchanged in a second and apparently shortened in a third. In this third patient, procainamide produced a marked delay in proximal His-Purkinje conduction allowing a distal area of refractoriness to recover, thus causing apparent shortening of the effective refractory period. Plasma levels averaged 7.1 mg/ liter at the end of the study; no toxicity was noted.

Effect of Atrial Stimulation Site on the Electrophysiological Properties of the Atrioventricular Node in Man

The electrophysiological properties of the atrioventricular conduction system were compared in 16 patients using stimulation of the high right atrium (HRA) and a site within the coronary sinus (CS). The site of atrial stimulation significantly altered A-V nodal conduction time and refractoriness in eight patients (Group A) and did not change A-V nodal properties in the remaining patients. His-Purkinje conduction time and refractoriness were not affected by changing the atrial stimulation site. The atrial stimulation site may influence A-V nodal function by changing the site and/or mode of entry of the impulse into the A-V node.

Effects of lidocaine on refractory periods in man

Abstract The effect of lidocaine on the refractory periods of the atrium, A-V node, and His-Purkinje system were studied using His bundle recordings and the extrastimulus method. This method provides a safe and systematic approach to the evaluation of electrophysiological properties of drugs in man. In usual therapeutic doses, the present study demonstrated no consistent effect of lidocaine on the ERP of the atrium or the A-V node. However, in these doses it shortened the ERP and the RRP of the His-Purkinje system. These results explain the effectiveness of lidocaine in the management of ventricular arrhythmias and its inconsistency in the treatment of supraventricular rhythm disturbances. The potential for lidocaine toxicity in the presence of heart failure and/or liver disease is noted.

The electrophysiological effects of intramuscular quinidine on the atrioventricular conducting system in man

Abstract The electrophysiological effects of intramuscular quinidine were evaluated using His bundle electrograms and the extrastimulus method. The mean mid-study plasma quinidine level was 4.6 mg. per liter. Our results show that quinidine tends to shorten A-V nodal conduction time while it routinely prolongs His-Purkinje and intraventricular conduction time. The refractory periods of the atrium and His-Purkinje system were prolonged by quinidine while the effective refractory period of the A-V node was consistently shortened. Those patients with evidence of infra-His conduction disturbances manifested no difference in their response to quinidine from the group as a whole. These studies suggest quinidine has antivagal properties which are of clinical significance. In addition, the effects of quinidine on His-Purkinje conduction and refractoriness may lead to the ventricular tachyarrhythmias implicated in “quinidine syncope” by a re-entrant mechanism.

Electrophysiologic effects of atropine on atrioventricular conduction studied by his bundle electrogram

The electrophysiologic effects of atropine were studied with His bundle recordings in 14 patients. Administration of atropine, 0.5 mg intravenously, produced a moderate degree of sinus acceleration in all patients (average increase 20 percent over control rate). Atrioventricular (A-V) nodal conduction was enhanced during both sinus rhythm and at various paced atrial rates after administration of atropine. The paced atrial rates at which the A-V nodal Wenckebach phenomenon occurred were significantly higher after administration of the drug than before. Similar effects on retrograde conduction were observed during ventricular pacing. Atropine shortened both the functional and effective refractory periods of the A-V node but appeared to have no direct effect on either His-Purkinje conduction time or refractoriness. However, aberrant ventricular conduction and block within the His-Purkinje system increased during premature atrial stimulation after atropine administration. This was the result of shortening of the functional refractory period of the A-V node by atropine, which produced significantly shorter H1–H2 intervals. The effect of atropine on the electrophysiologic properties of the A-V conducting system was important in interpreting the conversion of a type I gap in A-V conduction to a type II gap.

Sinus node re-entrant tachycardia in man

Sinus node re-entry (SNR) usually appears as a single beat. Tachycardias (SNRT) consistent with sustained SNR were seen in six patients and were initiated by premature stimulation of the high right atrium (six patients) and coronary sinus (four patients), and after continuous pacing from the high right atrium (four patients) or right ventricle (one patient) at rates of 130 to 200 per minute. During SNRT: (1) atrial beats exhibited a high-to-low atrial activation sequence, (2) the P-waves were similar in morphology to P-waves during sinus rhythm, and (3) re-entry in the A-V node or at the site of stimulation could be excluded. The cycle length of SNRT ranged from 625 to 320 msec. and SNRT either terminated spontaneously (six patients) or after premature atrial capture and/or vagal maneuvers (two patients). The electrophysiologic characteristics of SNRT and differentiation of SNRT from A-V nodal re-entry are discussed.

Electrophysiologic Properties of Diphenylhydantoin

The electrophysiologic properties of diphenylhydantoin (DPH) (5-10 mg/kg) intravenously was studied in 14 subjects using His bundle recordings and correlated with blood levels. Conduction through the A-V conducting system (AVCS) was studied at various paced atrial rates and refractory periods determined using programmed atrial premature depolarization within 10 min of drug administration. In 11 of 14 subjects the sinus cycle length was shortened by an average of 110 msec, lengthened in three (average 116 msec). Conduction through the A-V node (AVN) was shortened in seven subjects (average 10 msec), lengthened in one (5 msec), and unchanged in the remaining six. Conductinged by 5 msec). Prior to DPH, the longest mained constant in all but two subjects (proloengthened in four, and was unchanged in the re-refractory period of the AVCS was in the AVN in nine subjects, the atrium in four and the HPS in one. After DPH, the following effects were noted: (1) the effective refractory period (ERP) of the atria shortened in four subjects, lengthened in four, and was unchanged in the remaining six; (2) the ERP of the AVN shortened in 6/9 subjects, lengthened in 3/9; (3) functional refractory period of AVN shortened in six, prolonged in three subjects, and remained unchanged in five subjects; (4) the relative refractory period (RRP) of the HPS shortened in 7/7 subjects; (5) ERP of HPS in 1/1 subject shortened. Thus, DPH showed varied effects on A-V nodal conduction, inconsistent effect in the atrium, and consistent shortening of the refractory period of the HPS. The data suggest DPH differs from other antiarrhythmic drugs such as quinidine and procaine amide.

Gap in A-V conduction in man: Types I and II☆

Abstract The mechanism of the “gap” phenomenon in A-V conduction was studied in man during premature atrial stimulation studies using His bundle recordings. Previous reports have demonstrated that while relatively late premature atrial impulses are blocked within the His-Purkinje system, earlier premature atrial impulses may successfully propagate to the ventricle if they encounter sufficient A-V nodal delay to allow recovery of the distal area of refractoriness (Type I “gap”). In the present report, an analogous mechanism of the “gap” is described which is due to delay within the His-Purkinje system (Type II “gap”). Relatively late premature atrial impulses were noted to block within the His-Purkinje system, similar to the findings in Type I. Conduction resumed in Type II, however, when earlier premature atrial impulses encountered delay in a relatively proximal area of the His-Purkinje system, allowing more complete recovery of the distal area of refractoriness. Both types of gap phenomena represent examples of apparent supernormal conduction.