Michael J. Reiter

The electrophysiologic basis and management of symptomatic recurrent tachycardia in patients with ebstein's anomaly of the tricuspid valve

Twenty-two patients with Ebsteins anomaly were evaluated because of recurrent tachycardia. A total of 30 accessory pathways were present in 21 of the 22 patients. Twenty-six accessory pathways were of the atrioventricular (A-V) type while four were Mahaim fibers. Multiple accessory pathways were present in eight patients. Twenty-five of the 26 accessory A-V pathways were right-sided, either in the posterior septum (12 pathways) or the posterolateral free wall (13 pathways); one patient with corrected transposition of the great arteries had a left-sided accessory A-V pathway in a lateral free wall location. Patients with accessory A-V pathways had a long minimal ventriculoatrial (V-A) conduction time during reciprocating tachycardia (192 +/- 47 ms) and usually showed a persistent complete or incomplete right bundle branch block morphology. At surgery, preexcitation was invariably localized to the atrialized ventricle. The long V-A conduction time during reciprocating tachycardia appeared to consist of late activation of the local ventricle in the region of the accessory pathway with a further delay occurring before excitation of adjacent atrium presumably due to conduction over the accessory pathway. Accessory A-V pathways were successfully sectioned with no deaths in 13 of 15 patients. On the basis of these data, certain electrocardiographic findings encountered in the study of patients with recurrent tachycardia should point to the possibility of associated Ebsteins anomaly: morphology of the surface electrocardiogram suggesting preexcitation of the right posterior septum or right posterolateral free wall as well as the combination during reciprocating tachycardia of a long V-A interval and right bundle branch block.

Clinical Spectrum of Ventricular Tachycardia With Left Bundle Branch Morphology

Twenty-nine patients with apparent ventricular tachycardia (VT) of left bundle branch block (LBBB) morphology were evaluated. Tachycardia was associated with an organic basis in 24 of 29 patients: 7 had Mahaim fibers of the nodoventricular type, 7 had arrhythmogenic right ventricular dysplasia, 5 had coronary heart disease, 3 had biventricular cardiomyopathy, and 2 had associated congenital heart disease. In many patients the underlying cardiac disease was not readily apparent. In the patients with a Mahaim fiber, the electrocardiogram taken during sinus rhythm was frequently normal. A reentry tachycardia with anterograde conduction over the nodoventricular fiber could mimic VT as diagnosed by the usual criteria; nodoventricular fibers were, therefore, often unsuspected before electrophysiologic evaluation. In patients with arrhythmogenic right ventricular dysplasia, cineangiography demonstrated abnormalities of the right ventricle, but only minor or no abnormalities of the left ventricle. Clinical and electrocardiographic features were not distinctive. Of the 29 patients, 22 had serious symptoms accompanying the tachyarrhythmia or had required cardioversion. Patients were followed up for an average of 20 months: 4 patients died. Thus, VT exhibiting an LBBB morphology is not uncommon and is frequently associated with organic heart disease, serious symptoms, and significant mortality. Right ventricular angiography and electrophysiologic study may clarify the diagnosis in these patients.

Verapamil plasma binding: Relationship to α1‐acid glycoprotein and drug efficacy

The relationship between α1‐acid glycoprotein (AAG) plasma concentration and plasma verapamil binding was examined in samples obtained 15 minutes after 10 mg IV verapamil to 15 subjects. There was a good correlation (r = 0.83) between the binding ratio and AAG concentration, suggesting that AAG could bind verapamil. This was confirmed in vitro by the addition of AAG to an albumin solution, which resulted in a strong correlation between binding ratio (r = 0.99) and AAG concentration. The relationship between both free and total plasma concentrations and the effects of verapamil on the PR interval was also examined several times after 10 mg IV verapamil in seven of the subjects. While there was a correlation between log of both concentrations and the percent prolongation in PR interval (P < 0.001), the correlation was stronger with free drug concentration (r2 = 0.58) than with total plasma concentration (r2 = 0.36). The range of free concentrations associated with a given effect (220%) was also narrower than that for total concentration (300%). While these data indicate that AAG is responsible for most of the variability in plasma verapamil binding, which in turn contributes somewhat to variation in effectiveness of a given total plasma concentration, neither of these causes of individual variations is likely to have a major clinical impact in patients who, apart from arrhythmia, are otherwise healthy.

Comparison of intravenous and oral verapamil dosing.

To compare the effects of intravenous and oral verapamil we examined the prolongation of the PR interval in 11 patients after (1) a single 10 mg IV bolus given over 2 min, (2) a single oral dose of 120 mg, and (3) a sustained concentration‐maintaining infusion. Maximal PR interval prolongation was delayed relative to peak plasma verapamil concentration in all patients after the bolus and in seven of 11 patients after oral dosing. In all 11 patients oral verapamil was less potent than a single intravenous bolus of verapamil; the plasma verapamil concentration corresponding to a 10% prolongation of the PR was 39.5 ± 21.7 ng/ml after the bolus and 146.3 ± 75.1 ng/ml after the oral dose (P = 0.001). However, there was no such difference between oral verapamil and an infusion in six patients. The plasma verapamil concentration corresponding to a 10% PR prolongation was 35.7 ± 24 ng/ml after the bolus, 132.5 ± 80.8 ng/ml after the oral dose, and 85.2 ± 29.9 ng/ml after the infusion. Maximum PR prolongation (drug efficacy) was comparable for the three methods of administration. There was no evidence of tachyphalaxis during prolonged infusions. We conclude that both oral doses and infusions of verapamil are less potent than bolus doses, but that drug efficacy at the concentrations reached is equivalent for the three. Plasma verapamil concentrations determined after bolus doses appear to underestimate effective plasma concentration when the drug is given by the oral or infusion methods.

Life-table methods for evaluating antiarrhythmic drug efficacy in patients with paroxysmal atrial tachycardia☆

Spontaneous variability in the occurrence of paroxysmal arrhythmias has made it difficult to apply objective and quantitative methods to describe their clinical course. In this study of paroxysmal atrial tachycardia, the tachycardia-free interval was used as a quantitative measure of drug efficacy during treatment with oral verapamil. The tachycardia-free interval is the time a patient remains free from an episode of tachycardia after drug treatment is begun. We documented recurrent tachycardia by telephone transmission of the electrocardiogram. Improvement caused by increasing the drug dose (360 versus 480 mg/day) or by comparing verapamil with placebo treatment was demonstrated by upward shifts in the cumulative tachycardia-free interval curves. The tachycardia-free interval is an easily measured clinical variable that has substantial promise in the study of paroxysmal arrhythmias.

Pharmacokinetics of verapamil: Experience with a sustained intravenous infusion regimen

Disappearance kinetic characteristics of verapamil were determined in 9 patients after a single intravenous dose. From the pharmacokinetic variables determined, we designed an intravenous regimen to maintain a plasma verapamil concentration of 150 ng/ml consisting of (1) a loading bolus (10 mg over 2 minutes), followed by (2) a rapid loading infusion (0.375 mg/min) for 30 minutes, and finally (3) a maintenance infusion (0.125 mg/min). We tested this regimen in 7 patients for 2 to 12 hours, and found it to be safe and to produce stable prolongation of the P-R interval. Verapamil concentration was highest immediately after the bolus administration and was prevented from falling below 67 ng/ml by the rapid infusion. Maintenance concentration remained between 77 and 156 ng/ml for all patients, and averaged 122 ng/ml. Transient and slight decreases in brachial blood pressure and sinus cycle length occurred coincident with the maximum verapamil concentration. Maximum P-R prolongation lagged behind peak plasma concentration but was sustained for the duration of the infusion. Prolongation of the P-R interval was not significantly different at the end of the infusion from that 90 minutes after the start of the regimen. No patient demonstrated significant side effects, arrhythmia, or clinically important hypotension. Although the specified regimen produced a final concentration averaging 125 ng/ml, it is predicted that infusion regimens producing other plasma concentrations can be similarly devised by changing the bolus, rapid loading infusion, and maintenance infusion doses in proportion to the desired final plasma concentration.

Pirmenol kinetics and effective oral dose

The oral form of pirmenol has not been administered to man. Pirmenol was given by mouth to eight patients with chronic, stable premature ventricular beats (PVBs) to determine effective dose and kinetics. The patients were evaluated with a dose‐ranging protocol followed by a double‐blind, crossover, placebo‐controlled study of doses that were effective during dose ranging. Oral doses of 150 to 250 mg induced at least 90% suppression of PVBs 18 of the 19 times they were administered during both protocols. During the double‐blind experiment, a single oral dose of pirmenol suppressed 95 ± 8% PVBs/hr (mean ± SD) for 3 consecutive hr, while placebo suppressed 4 ± 42% PVBs/hr (P < 0.01). A 90% or greater reduction in PVBs persisted for a median of 6 hr (range 1 to 8 hr). The range of plasma pirmenol concentrations associated with an at least 90% reduction in PVBs was 0.7 to 2.0 μg/ml. Median half‐life (t½) was 9.3 hr (range 6.0 to 12.4) with 86.6 ± 2.4% protein binding and 82.6 ± 23.6% bioavailability. At peak drug level there was lengthening of the QTc interval (0.036 sec, P <0.05), but no change in heart rate, blood pressure, PR interval or QRS duration, or symptoms. In this single‐dose study, pirmenol effectively reduced PVBs, had a relatively long t½, and was minimally toxic.

Bystander Accessory Pathway During AV Node Re‐entrant Tachycardia

Between 1970 and July 1980, wide QRS tachycardia due to re‐entryconfined to the AV node with bystander involvement of an accessory atrioventricular pathway (AAV) was documented in three of 290 patients with the Wolff‐Parkinson‐White syndrome studied at Duke Medical Center. In each of the patients, at least one transition between wide and narrow QRS morphology was recorded without change in either the cycle length of tachycardia or the atrial activation sequence. Two of the three patients had a single left‐sided AAV (lateral, posterolateral) showing antegrade conduction only. The third patient had two right‐sided AAVs (free wall, septal), each capable of bidirectional conduction. Initiation and termination of repetitive concealed conduction into the ventricular insert of an AAV appeared to be one mechanism determining bystander AAV participation. Documentation of the retrograde sequence of atrial activation during tachycardia, and examination of the effects of interpolated premature depolarizations from both the ventricle and midline atrium are the most helpful features in resolving the differential diagnosis of wide QRS tachycardia in patients with W‐P‐W syndrome.

Efficacy, safety, and pharmacokinetics of a concentration-maintaining regimen of intravenous pirmenol☆

A 3-stage, concentration-maintaining intravenous infusion regimen of pirmenol, a new antiarrhythmic agent, was tested for efficacy and safety in 8 subjects with chronic, stable premature ventricular beats. The regimen, which consisted of (1) a priming bolus of 50 mg over 2 minutes, followed by (2) a rapid loading infusion of 2.5 mg/min for 1 hour, and (3) a maintenance infusion of 0.25 mg/min, rapidly achieved and maintained stable plasma pirmenol levels from 0.94 to 2.75 micrograms/ml, during infusions lasting up to 48 hours. Therapeutic efficacy was evaluated during 4-hour infusions in 5 patients utilizing a randomized, double-blind, placebo-controlled study design. Pirmenol suppressed average premature ventricular beat frequency 93 +/- 6% compared with control values (p = 0.03). Pirmenol infusions were unassociated with toxicity. There were slight but significant increases in diastolic blood pressure, QRS duration, and corrected Q-T interval. No significant changes occurred in systolic blood pressure, heart rate, P-R interval, or laboratory variables. Pirmenol is a promising therapeutic agent that warrants further evaluation. The 3-stage infusion satisfactorily achieves and maintains therapeutic plasma pirmenol levels.

A system for the analysis of long-term electrocardiographic studies in clinical research and training

A computer system has been developed for the analysis of data from long-term electrocardiographic studies in the context of an institution committed to clinical research and training. The major characteristics required of such a system are intelligence, flexibility, friendliness, and maintainability. These attributes are achieved by a user interface which consists of menus and interactive graphics, and by the use of highly modular software developed in a high-level programming language. The system has been used in studies of the effects of drugs on cardiac arrhythmias and has been easy to learn and convenient to use.