Albert K. Dawson

Electrophysiologic Actions of High Plasma Concentrations of Propranolol in Human Subjects

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (greater than 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 +/- 17 ng/ml) and at high concentrations (472 +/- 68 ng/ml). Significant (p less than 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p less than 0.05). At high concentrations, there was significant (p less than 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period. In summary, the concentration-response relations for atrioventricular conductivity and sinus node automaticity were flat above concentrations of 150 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

The QRS complex during transient myocardial ischemia: studies in patients with variant angina pectoris and in a canine preparation.

We made continuous electrocardiographic recordings on magnetic tape during 15 episodes of ischemia in five patients with variant angina to determine the characteristics of the QRS changes. Orthogonal leads were used and the electrocardiograms were analyzed visually and by digital computer. Changes were quantified by subtracting baseline electrocardiograms from those obtained during ischemia. Large changes in the QRS occurred during ischemia but the waveform quickly returned to baseline when the episode subsided. In all patients there was prolongation of the QRS duration and an increase in QRS voltage during the terminal 40 msec of the waveform in the lead(s) showing the most marked ST displacement. The increase in the terminal QRS could be represented by a vector directed toward the ischemic zone. In a given patient the amplitude of ST displacement varied between episodes, presumably because of variation in the intensity of ischemia, but the QRS changes were directionally similar in each episode. In two patients there was also a smaller change involving the initial 40 msec of the QRS that could be represented by a vector directed away from the ischemic zone. To determine the possible mechanism for the electrocardiographic changes, ischemic episodes of 120 to 150 sec were produced in seven dogs and electrocardiographic recording and analysis techniques similar to those used in patients were employed. Myocardial conduction velocity was measured in three directions in the ischemic zone and was correlated with simultaneous electrocardiographic recordings from the body surface. The electrocardiographic changes in the dog preparation were virtually identical to those in the patients and strongly correlated with a fall in myocardial conduction velocity. We conclude that the QRS changes during variant angina result from the altered excitation pattern produced by conduction delay in the ischemic zone. The probable cause for the increase in terminal QRS voltage is delayed (and uncancelled) activation of the ischemic zone.

Electrophysiologic actions of O-demethyl encainide: an active metabolite.

Differences between the electrophysiologic actions of the antiarrhythmic agent encainide have been reported after short-term intravenous and oral administration. Only prolongation of the HV interval and QRS duration have been described immediately after short-term intravenous administration of encainide in dogs and man. However, during oral therapy or more prolonged infusions, prolongation of the AH interval and atrial and ventricular effective refractory periods have also occurred. In most patients receiving encainide therapy, metabolites (O-demethyl encainide and 3-methoxy-O-demethyl encainide) accumulate during prolonged therapy to concentrations greater than those of the parent drug. We compared the electrophysiologic action of O-demethyl encainide with that of saline in anesthetized dogs to determine if this metabolite has pharmacologic activity and whether its electrophysiologic effects could account for the disparities noted between effects of intravenous and oral encainide therapy. An initial pharmacokinetic evaluation allowed design of a series of loading and maintenance infusions that produced plasma concentrations similar to those seen during encainide therapy in man (concentration after first maintenance dose, 149 +/- 27 ng/ml [+/- SE] and after second maintenance dose, 230 +/- 45 ng/ml). Significant increases in atrial effective refractory period and ventricular refractoriness, and prolongation of AH interval and HV conduction time were observed. These effects are similar to those reported after prolonged oral encainide therapy but are substantially different from those seen after short-term infusions of encainide. These findings indicate that the difference between the electrophysiologic actions of intravenous and oral encainide may be due to pharmacologic effects of at least one encainide metabolite, O-demethyl encainide.

Differential effects of O-demethyl encainide on induced and spontaneous arrhythmias in the conscious dog☆

Encainide is highly effective in suppressing most nonsustained ventricular arrhythmias, but there is evidence that the drug is less effective and may worsen some arrhythmias, particularly in patients with sustained ventricular tachycardia. In most patients it is likely that the major antiarrhythmic effects of encainide are mediated through a potent metabolite, O-demethyl encainide. The effects of infusions of saline solution or O-demethyl encainide on spontaneous ventricular ectopic activity and ventricular fibrillation (VF) threshold were compared in 25 dogs with a mottled myocardial infarct produced by transient coronary occlusion. Plasma levels of the metabolite above 100 ng/ml suppressed (greater than 92%) the spontaneous ventricular ectopic activity that occurred 48 hours after MI, whereas saline solution had no effect. In 15 dogs treated with O-demethyl encainide, the VF threshold decreased an average of 23%, from a baseline level of 23 +/- 8 mA to 18 +/- 9 mA (p less than 0.05). There was a concentration-dependent fall in VF threshold with plasma concentrations of O-demethyl encainide above 150 ng/ml. In 2 dogs with very high plasma concentrations of the metabolite (greater than 1,000 ng/ml), VF was induced by right ventricular pacing alone (S1S1 300 ms). No change in VF threshold was observed in the 8 dogs treated with saline solution, and in each of these dogs VF could be terminated by the countershock protocol. However, in 7 of the 17 dogs treated with O-demethyl encainide, VF could not be terminated by the countershock protocol.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effects of placebo and encainide on programmed electrical stimulation and ventricular arrhythmia frequency

Abstract Encainide is an investigational antiarrhythmic agent that is very effective in the treatment of nonlife-threatening ventricular arrhythmias. Because of its marked efficacy and short half-life it has been possible to manipulate the dose and dosing interval to produce repeatedly and predictably episodes of arrhythmia abolition followed by arrhythmia recurrence. This study examined the results of programmed electrical stimulation during periods of arrhythmia suppression and recurrence induced by encainide. Eight patients with chronic ventricular arrhythmias who had suppression of ventricular arrhythmia as assessed by ambulatory monitoring during 6 months of outpatient treatment with encainide underwent programmed electrical stimulation testing in a drug-free state. Patients were then randomly assigned to receive placebo or encainide. Thereafter, electrophysiologic testing was performed twice daily immediately before and 1 hour after administration of either placebo or encainide. In patients receiving encainide, the repetitive ventricular response was neither consistently absent during periods of arrhythmia suppression nor consistently present during periods of arrhythmia recurrence. Furthermore, four patients showed increased ease of inducibility of the repetitive ventricular response during periods when encainide had suppressed the spontaneous ventricular arrhythmias. Indeed, in one of these patients programmed electrical stimulation (single extrastimulus) in the presence of encainide elicited ventricular fibrillation. Three of four patients randomly assigned to placebo therapy initially manifested a repetitive ventricular response: However, over a period of time the zone in diastole in which the repetitive ventricular response was observed progressively diminished and became absent for at least 1 day in all patients. Indistinguishable changes over a period of time were seen in the patients treated with encainide. Time-dependent variations in cardiac electrophysiologic measurements must be taken into account when programmed electrical stimulation at a single electrode site is used to evaluate drug therapy. In this study the presence or absence of the repetitive ventricular response bore no relation to arrhythmia frequency as encainide was administered or withdrawn. Programmed electrical stimulation in the presence of encainide may elicit potentially lethal ventricular arrhythmias.

Effect of Fluosol-DA on infarct morphology and vulnerability to ventricular arrhythmia

Although the blood substitute perfluorochemical Fluosol-DA has been shown to reduce experimental myocardial infarct size, the electrophysiologic properties of the surviving myocardium have not been assessed. Twenty-six dogs underwent closed-chest occlusion of the proximal left anterior descending coronary artery. Prior to infarction animals were randomly assigned to one of three treatment groups: groups receiving blood exchange with either Fluosol-DA (F = 9) or autologous heparinized blood (H = 8), given 30 minutes following occlusion over the next 30 minutes (these animals were ventilated with 100% oxygen for 6 hours), or a control group (C = 9) receiving no exchange transfusion and ventilated with room air. On the third postmyocardial infarction day the animals underwent programmed stimulation. The area at risk was defined by injecting different colored microvascular dyes into the three coronary beds, and the area of necrosis was defined by sectioning ventricular slices and staining with Mallorys trichrome stain. Infarct size was significantly reduced in the Fluosol-DA-treated group as compared to the heparin-treated and control groups when expressed as a percentage of the area at risk (F = 53.3 +/- 10, H = 67.2 +/- 12.8, C = 73.6 +/- 11.4: F vs H p less than 0.05; F vs C p less than 0.01). Ventricular tachycardia was inducible and sustained in 16 animals (3F, 6H, and 7C), and there was morphologic correlation with greater endocardial necrosis and smaller viable epicardial regions. In the 10 animals (6F, 2H, and 2C) without sustained ventricular tachycardia, there was greater epicardial viability and sparing of the endocardial regions with irregularity of the borders between viable and necrotic myocardium. We conclude that Fluosol-DA not only decreases infarct size but also modifies infarct morphology to reduce electrical instability.

Electrophysiology of O-demethyl encainide in a canine model of sustained ventricular tachycardia

The antiarrhythmic agent encainide produces marked suppression of ventricular arrhythmias in most patients. However, in some with sustained ventricular tachycardia, worsening of clinical arrhythmias can occur. Since the effects of this agent are mediated by its O-demethyl metabolite in most patients, we have evaluated the effects of O-demethyl encainide in dogs susceptible to the induction of ventricular tachycardia. Nonsedated animais were studied 3–5 days after 90-min left anterior descending coronary artery occlusions. Electrophysiologic evaluations were carried out at baseline, and then during a series of infusions of O-demethyl encainide that achieved low (58 ± 5 ng/ml) (&OV0335; ± SE), moderate (190 ± 16 ng/ml), and high (758 ± 98 ng/ml) plasma concentrations compared with the range seen in patients (50–300 ng/ml). Ventricular tachycardia induction was unaffected by the drug. Effective refractory period was prolonged in a doserelated fashion at both normal and infarcted epicardial sites. However, local electrogram duration was prolonged only in the infarcted zone. We conclude that O-demethyl encainide exerted no consistent effect on susceptibility to induction of ventricular tachycardia in this study. This agent appears to alter infarcted zone conduction disproportionately.

Sequential QRS vector subtractions in acute myocardial infarction in humans. Time course and relationship to serial changes in serum CK-MB concentration.

We used an automated recording system and computer analysis to perform hourly QRS subtractions on ECG signals obtained with dipolar leads in 14 patients admitted within 6 hours of the onset of symptoms of acute myocardial infarction (AMI). The resulting changes in QRS time-voltage area were expressed as a difference vector (QRSMD) which was found to have a simple time course that was similar for infarcts in different locations and closely fit the equation: QRSMD(t) = α (1 − eβ(t − t)) where to is the time of admission, t is the time of each measurement, β is the exponential development rate, and α is the asymptotic value for QRS«D. QRSMD changes rapidly and essentially linearly during the initial 10 hours and the changes were 90% complete at 13 ± 2 hours. When a was computed from data obtained after hospital entry, it correlated poorly with infarct size estimated from CK-MB analysis. Extrapolations to correct for changes assumed to have occurred prior to entry did not significantly improve the correlation. The exponential development rate, β, and the initial growth rate, αβ, were also poor predictors of infarct size estimated by the CK-MB method. The QRSMD and the integral of serum CK-MB release had a similar time course, with the QRSMD changes preceding the changes in CK-MB concentration by approximately 10 hours. It is concluded that the QRS difference vector measured during the AMI has a characteristic time course that is independent of anatomical location and has similarities to the integrated CK-MB release course. However, the rate of change of QRSMD and various functions of the maximum QRS difference are poor predictors of infarct sire as determined by the CK- MB method. The apparent inability of QRSMP to predict infarct size may be due to the lack of a preinfnrction control ECG recording, to slowly developing changes in the ECG that were completed after the period of observation in our study, or to distortion of the QRS complex by injury currents associated with ST segment elevation.