Robert F. Gilmour

Cellular Electrophysiologic Abnormalities of Diseased Human Ventricular Myocardium

Using standard microelectrode techniques, the cellular electrophysiologic features of ventricular myocardium resected from 8 patients with refractory arrhythmias were studied in vitro. Action potentials from damaged myocardium compared with normal myocardium had reduced resting membrane potential, amplitude, and maximal upstroke velocity. Tetrodotoxin, but not verapamil, suppressed 3 action potentials with resting potentials of -60 to -64 mV and Vmax less than 70 V/s. Verapamil, but not tetrodotoxin, suppressed 4 action potentials with resting potentials of -44 to -57 mV and Vmax less than 20 V/s. Unidirectional block, Wenckebach block, and summation occurred in damaged zones. Exit block from and frequency-dependent entrance block into an ectopic focus were noted. Subthreshold responses in the focal area induced by action potentials in the surrounding myocardium and by subthreshold current pulses injected through the recording microelectrode altered the spontaneous discharge rate of the focus, as previously described for modulated parasystole. Pulses early in the spontaneous cycle delayed the next expected discharge, and later pulses accelerated the subsequent discharge. Pulses injected at the singular point completely suppressed automaticity (annihilation). Tetrodotoxin and verapamil suppressed automaticity in some fibers. Single action potentials induced in quiescent fibers triggered and terminated sustained rhythmic activity. These data suggest that depressed fast responses, slow responses, and subthreshold potentials can generate and modulate ectopic activity in damaged human ventricle and that fast- and slow-channel blocking agents and single premature stimuli can terminate such activity.

Depressant effect of magnesium on early afterdepolarizations and triggered activity induced by cesium, quinidine, and 4-aminopyridine in canine cardiac Purkinje fibers.

Magnesium chloride has been shown to terminate torsades de pointes in some patients with the acquired long QT syndrome. The mechanism for this effect is unknown. Recently early afterdepolarizations (EADs) and triggered activity (TA) have been proposed as causes of torsades de pointes. The purpose of the present study was to examine whether magnesium suppressed EADs that were initiated in vitro by different agents and if so its mechanism of action. TA arising from EADs was induced by quinidine (1 to 4 mumol/L, n = 5) at high temperature (38.5 to 40 degrees C), cesium chloride (5 to 12 mmol/L, n = 6), and 4-aminopyridine (1.5 to 5 mmol/L, n = 7) in canine cardiac Purkinje fibers superfused with modified Tyrodes solution (KCI = 2.7 mmol/L). MgCl2 (2 to 7 mmol/L) reversibly abolished TA and suppressed EADs. Tetrodotoxin (TTX; 1 to 5 mumol/L) also abolished TA elicited by 4-aminopyridine (n = 6). We then examined the effects of MgCl2, TTX, and verapamil on depolarization-induced automaticity by means of a single sucrose gap technique to gain insight into the mechanism of action of magnesium. MgCl2 (5 mmol/L) abolished automaticity arising from membrane potentials more negative than -70 mV and prolonged the spontaneous cycle length at less negative membrane potentials. The effects of TTX (1 to 5 mumol/L) resembled those of MgCl2. Verapamil (1 mumol/L) prolonged the cycle length of the initial automatic response at high levels of membrane potential and progressively reduced the amplitude of the subsequent automatic potentials. It abolished automaticity arising from less negative membrane potentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of the Autonomic Nervous System on the Genesis of Cardiac Arrhythmias

The purpose of this report is to present a brief overview of the concepts concerned with the potential effects of the autonomic nervous system on the genesis of cardiac arrhythmias. First, we present data indicating the functional importance of presynaptic and postsynaptic vagaJ modulation of adrenergic neurotransmission on electrical activity in sinus and A‐V nodes, and contractile activity of canine cardiac Purkinje fibers. Second, we indicate the possible intraventricular adrenergic and vagal pathways to the ventricles, suggesting that sympathetic fibers travel in the epicardium while vagal fibers appear to cross the A‐V groove in the epicardium but then take an intramural route for part of their course. Finally, we demonstrate that a lesion such as a myocardial infarction can interrupt neural fibers traveling through the infarction to affect nominfarcted myocardium distal to the infarction. These factors may play a role in the genesis of some cardiac arrhythmias.

Overdrive suppression of conduction at the canine Purkinje-muscle junction.

We have shown previously that overdrive suppression of conduction in depolarized His-Purkinje tissue requires conduction asymmetry. In this study we examined whether overdrive suppression of conduction can occur at the Purkinje-muscle junction, where natural asymmetry of conduction exists. Canine Purkinje-muscle preparations were superfused with hyperkalemic Tyrodes solution (KCl 8 to 12 mM), and action potentials were recorded from Purkinje, junctional, and muscle cells. Initially, the Purkinje fiber was paced at the shortest cycle length at which 1:1 anterograde Purkinje-muscle conduction occurred. The papillary muscle then was paced for 10 to 50 beats at shorter cycle lengths during which, because of conduction asymmetry at the Purkinje-muscle junction, 1:1 retrograde muscle-Purkinje conduction also occurred. After overdrive papillary muscle pacing, Purkinje fiber pacing at the same cycle length that previously resulted in 1:1 conduction now produced transient Purkinje-muscle conduction block (overdrive suppression of conduction). The degree and duration of overdrive suppression of conduction were proportional to the rate and duration of overdrive pacing. After overdrive pacing, Purkinje cell action potential amplitude and Vmax recovered within 300 msec, yet conduction block persisted for up to 7 sec. In contrast, excitability in papillary muscle cells near the Purkinje-muscle junction increased continuously after overdrive pacing. These data suggest that rapid activation of Purkinje cells during overdrive pacing was not required for overdrive suppression of conduction and that restoration of conduction after overdrive pacing was determined primarily by recovery of excitability in papillary muscle cells. Transient Purkinje-muscle conduction block after periods of rapid ventricular rates might account for overdrive-induced conduction disturbances normally attributed to bundle branch block.

Overdrive suppression of conduction in the canine His-Purkinje system after occlusion of the anterior septal artery.

The purpose of these experiments was to determine whether overdrive suppression of conduction (OSC), i.e., transient worsening of conduction or development of atrioventricular block after cessation of rapid pacing, could be produced in the canine His-Purkinje system damaged by ligation of the anterior septal coronary artery and to investigate the responsible mechanism. We found that OSC occurred in vivo after rapid ventricular and His bundle pacing but not after atrial pacing, and that it occurred in vitro after rapid pacing from the left bundle branch but not after pacing from the proximal His bundle. OSC was related to the duration and cycle length of pacing. Lidocaine increased while verapamil reduced the duration of OSC in vivo. The mechanism responsible for the unidirectionality of OSC is not clear but is probably related to the geometry of the atrioventricular junction and the anterograde versus the retrograde activation sequence. Changes in regional myocardial blood flow, autonomic tone, hemodynamic variables, or ventricular function do not appear to be required to produce OSC, based on the demonstration of the phenomenon in vitro. The data suggest a time- and rate-dependent change in factors affecting conduction such as excitability or cell-to-cell coupling, possibly due to accumulation of intracellular cations such as calcium.

Pathophysiology of Cardiac Arrhythmias

Normal cardiac rhythm occurs when spontaneous electrical impulses generated in the sinoatrial (SA) node are transmitted via the specialized conducting pathways to working myocardium. This orderly progression of impulse formation and propagation ensures a synchronous sequence of contraction in atrial and ventricular myocardium. Myocardial disease, cardioactive drugs, neurotransmitters, and other interventions can disrupt cardiac rhythm by altering spontaneous activity in the sinus node and other potential pacemaker regions in the heart and by impairing impulse propagation. Significant abnormalities of automaticity or conduction precipitate rhythm disturbances that compromise cardiac function, often to the point of producing clinical symptoms or death.

Management of arrhythmias with "calcium antagonists".

From the Krannert Institute of Cardiology, the Departments of Medicine and Pharmacology, Indiana University School of Medicine, and from the Veterans Administration Medical Center, Indianapolis, IN. Supported in part by the Herman C. Krannert Fund; by Grants HL-06308, HL-07182 and HL-18795 from the National Heart, Lung and Blood Institute, National Institutes of Health; and by the American Heart Association, Indiana Affiliate, Inc. Introduction