Leonard N. Horowitz

Flecainide: Its proarrhythmic effect and expected changes on the surface electrocardiogram

The proarrhythmic potential and electrophysiologic effect of flecainide acetate, a potent class IC anti-arrhythmic agent, are considered in this report. Although the definition of a proarrhythmic effect is arbitrary, several such definitions are discussed and applied to data on flecainide. In patients with chronic ventricular arrhythmias, an increase in VPC frequency developed in 0 to 4% of patients, compared with 1 to 8% of patients who received quinidine and 2% who received encainide, another class IC agent. In patients with acute hemodynamically significant ventricular arrhythmias, the proarrhythmic effects were noted in 5 to 12%. Proarrhythmic effects appear to be more common in patients with left ventricular dysfunction and life-threatening ventricular arrhythmias. The depression of atrioventricular conduction produced by flecainide is similar to that seen with other class IC agents. Increases in PR and QRS intervals are related to dose and plasma concentration and are approximately 25% at therapeutic levels. These changes in the electrocardiographic intervals do not appear to carry important clinical implications and do not require discontinuation of flecainide. QT prolongation is absent or minimal with flecainide. Guidelines for management of patients with flecainide are suggested.

Use of amiodarone in the treatment of persistent and paroxysmal atrial fibrillation resistant to quinidine therapy

The efficacy of amiodarone was assessed in 38 patients with atrial fibrillation resistant to quinidine and an effort made to identify factors correlated with amiodarone response. The study group included 29 patients with and 9 without organic heart disease and either persistent (n = 11) or paroxysmal (n = 27) atrial fibrillation. All patients were treated with amiodarone and followed up in a research clinic. Efficacy was classified as excellent (no recurrent symptomatic atrial fibrillation) in 15 (55%) of 27 patients with paroxysmal and 5 (45%) of 11 patients with persistent atrial fibrillation. Efficacy was poor (no effect on atrial fibrillation) in 5 (19%) of 27 patients with paroxysmal and 6 (55%) of 11 patients with persistent atrial fibrillation. Efficacy was good (amelioration but not total suppression) in 7 (26%) of 27 patients with paroxysmal atrial fibrillation. Efficacy was related to echocardiographic left atrial dimension, left ventricular ejection fraction and, in patients with persistent atrial fibrillation, the duration of the arrhythmia. During the follow-up period of 15 months (range 1 to 36), overall efficacy (considering response and toxicity) was 67% in the 27 patients with paroxysmal and 45% in the 11 patients with persistent atrial fibrillation. It is concluded that amiodarone offers an additional therapeutic alternative in quinidine-resistant atrial fibrillation and that certain clinical factors are correlated with amiodarone response.

Electrophysiologic testing in patients at high risk for sudden cardiac death. I. nonsustained ventricular tachycardia and abnormal ventricular function

Nonsustained ventricular tachycardia, although usually asymptomatic, is associated with a high risk of sudden cardiac death in patients with depressed left ventricular function. To test the vulnerability of such patients to symptomatic and potentially life-threatening arrhythmias, complete electrophysiologic studies were performed in 58 patients with clinically documented nonsustained ventricular tachycardia (greater than or equal to three complexes but less than 15 seconds of self-terminating ventricular tachycardia by 24 hour ambulatory electrocardiographic [Holter] or telemetric monitoring) and abnormal left ventricular function (ejection fraction less than 50% by radionuclide angiography). All patients had nonsustained ventricular tachycardia in the absence of antiarrhythmic drugs, acute ischemia, long QT syndrome, recent infarction or electrolyte abnormalities. The stimulation protocol for each patient included the introduction of single, double and triple ventricular extrastimuli at three cycle lengths (sinus, 600 and 450 ms) and two right ventricular sites (apex and outflow tract). A sustained ventricular tachyarrhythmia was induced in 23 patients (40%) and a nonsustained ventricular tachycardia in 14 patients (24%). Induction of sustained tachycardia correlated with the presence of akinesia or aneurysm, or both, by radionuclide angiography, but not with ejection fraction or presence or absence of coronary artery disease. These results indicate that: 1) patients with clinical nonsustained ventricular tachycardia and chronic left ventricular dysfunction have a high incidence of inducible sustained ventricular tachycardia or ventricular fibrillation; and 2) electrophysiologic testing may allow further substratification of risk of sudden cardiac death in high risk patients with nonsustained ventricular tachycardia.

Incidence of proarrhythmic effects from quinidine in the outpatient treatment of benign or potentially lethal ventricular arrhythmias

To determine the prevalence and importance of proarrhythmic events secondary to the initiation of quinidine therapy in outpatients with benign or potentially lethal ventricular arrhythmias, the data from 360 patients treated with quinidine as part of 3 outpatient drug trials were retrospectively reviewed. These patients had at least 30 ventricular premature complexes per hour during placebo treatment and had no evidence of unstable clinical states, hypokalemia, digitalis toxicity, atrial fibrillation or a prolonged QT interval (longer than 0.50 second). The quinidine dose varied from 200 to 400 mg 4 times a day for 2 to 4 weeks. Proarrhythmic effect was defined on Holter monitoring as a 400% increase in frequency of ventricular premature complexes, the presence of new ventricular tachycardia not previously identified or a 10-fold increase in the number of beats of ventricular tachycardia. There was no difference in the demography, response to quinidine therapy or side effects on quinidine among the 3 trials. Six of 360 patients (2%) had a proarrhythmic response and none of these patients had hemodynamic symptoms, required hospitalization or died from the proarrhythmic event. Thus, quinidine can be safely initiated to outpatients who meet the inclusion criteria cited herein.

Use of intravenous verapamil for ventricular tachycardia

For more than a decade, intravenous verapamil has been successfully used in the acute management of supraventricular tachyarrhythmiasJ, 2 On the basis of early reports s,4 it was suggested that verapamil would not be a useful agent in the management of ventricular tachycardia (VT). Recently, however, verapamil has been shown to be effective in several types of VT. 5-11 The present report is a review of published data regarding the use of intravenous verapamil for VT. Ventricular tachycardia from coronary heart disease: Heng et al 3 administered 10 mg of verapamil to 4 patients with VT occurring during acute myocardial infarction (MI), and restored sinus rhythm in I patient. Sclarovsky et al7 gave 3 to 5 mg of verapamil to 8 patients with multiform accelerated idioventricular rhythm observed during the first 12 hours of MI. They noted abolition of the arrhythmia in 6 patients, slowing of the ventricular rate in 1 patient and no effect in 1. More recently, Grenadier et alz0 reported successful abolition of polymorphous VT by verapamil treatment during acute MI in 3 of 4 patients. Efficacy of verapamil in these 3 patients contrasted with the failure of lidocaine, various class I antiarr~ythmic agents, overdrive pacing and cardioversion to abolish the arrhythmia. Although confirmatory evidence is needed, these reports suggest that verapamil may be effective in the management of various types of VT that occur during the acute stages of MI. Such an effect of verapamil suggests an involvement of the slow inward current in the genesis of these arrhytlimias. Whether these arrhythmias are due to a reentry mechanism involving slow response action potentials, triggered automaticity or abnormal automaticity is tmknown. Recently, the presence of triggered automaticity has been demonstrated in canine subendocardial Purkinje fibers that have survived I day of MI. 12,13 However, the possibility that efficacy of verapamil during VT in acute MI is, in part, a result of verapamil-induced improvement

Correlation between changes in R wave amplitude and left ventricular volume induced by rapid atrial pacing

To examine the Brody effect in humans, we studied 15 patients by means of coronary sinus pacing. We measured left ventricular (LV) volumes from the cardiac output (measured by the thermodilution technique) and LV ejection fraction (measured by radionuclide ventriculography). Pulmonary blood volume was determined by means of cardiac output and mean pulmonary transit time. In six patients, pacing was performed at two different rates, resulting in 21 pacing measurements. The heart rate increased with pacing from 73 +/- 11 to 119 +/- 19 bpm (mean +/- standard deviation, p less than 0.001). The end-diastolic volume (EDV) and the end-systolic volume (ESV) decreased with pacing (p less than 0.001 each). The R wave amplitude decreased with pacing (1.44 +/- 0.63 mV control vs 1.32 +/- 0.58 mV with pacing; p less than 0.01). R wave amplitude decreased in 19 of the 21 pacing studies (90%); EDV and ESV decreased in all 21 pacing studies, and pulmonary blood volume decreased in 14 of the 15 pacing studies (93%) performed in 11 patients. There was a significant correlation between the percentage of change in R wave amplitude with the percentage of change in EDV (r = 0.54, p less than 0.01) and with the percentage of change in ESV (r = 0.54, p less than 0.01). These results, therefore, validate Brodys hypothesis and indicate that changes in LV volumes affect the R wave amplitude.

Poor R wave progression in the precordial leads: Clinical implications for the diagnosis of myocardial infarction

A definite diagnosis of anterior myocardial infarction is often difficult to make in patients when a pattern of poor R wave progression in the precordial leads is present on the electrocardiogram. The purpose of this study was to determine whether a mathematical model could be devised to identify patients with anterior infarction among 102 consecutive patients with poor R wave progression. Each patient underwent exercise testing with thallium scanning. The diagnosis of anterior infarction was established in 20 (20%) of the 102 patients by the presence of fixed thallium-201 perfusion defects in the anterior wall or septum, or both. With the use of a multivariate stepwise discriminant analysis of clinical and electrocardiographic variables, five variables (sex, ST-T changes, S wave amplitude in leads V2 and V3 and the sum of the R wave amplitude in leads V3 and V4) that were statistically significant by univariate analysis were selected by the model to identify patients with anterior infarction (sensitivity 85%, specificity 71%). The discriminant model was subsequently applied prospectively to an additional 21 patients with poor R wave progression and provided a sensitivity of 85% and a specificity of 88%. Thus, anterior infarction (fixed thallium-201 defects in the anteroseptal segments) was present in 20% of patients with poor R wave progression in the precordial leads; and a mathematical model can be used to identify a subset of patients with anterior infarction in a group of patients with poor R wave progression.

Electrophysiology of esmolol

The electrophysiologic characteristics of esmolol were studied in 14 patients. Ten men and 4 women, mean age 57 years, were electrophysiologically evaluated at baseline, and also at 4 to 8 minutes after the administration of a maintenance infusion of esmolol. Plasma samples for esmolol blood levels were drawn at 10 minutes of the maintenance infusion, at the end of the maintenance infusion and 30 minutes after the maintenance infusion was discontinued. Results of this study showed that esmolol has typical beta-blocker electrophysiologic effects. Its major action was on sinus node function; it prolonged this basic sinus cycle length but had no significant effect on intrinsic automaticity as reflected by the corrected sinus node recovery time and sinoatrial conduction. Direct effects on atrioventricular (AV) nodal function were reflected by effects on AV nodal conduction and refractoriness. There was no direct effect on atrial function and, as expected, no effect on His-Purkinje or ventricular function. The intensity of esmolols electrophysiologic effects on sinus node function, AV nodal conduction and AH interval is comparable to those of other beta blockers.

A review of the uses and limitations of tocainide—a class IB antiarrhythmic agent

In conclusion, it appears that tocainide will be an extremely important new antiarrhythmic agent in the armamentarium of the clinical cardiologist (Table V). Its similarity to lidocaine and the predictability of its efficacy in patients responsive to lidocaine is an important note. Its lack of interaction with beta blockers and digoxin is also a promising feature. While tocainide has proven to be effective in the prophylaxis and treatment of patients with both refractory and chronic ventricular arrhythmias, its efficacy is in the approximate range of other class I agents, such as quinidine, procainamide, and disopyramide. Its side effect profile appears to be similar in percentage to the adverse effects of quinidine, but often these side effects are milder, better tolerated, and respond to dosage alteration. Thus, tocainide will undoubtedly prove to be a useful new antiarrhythmic agent, particularly when compared to the currently available antiarrhythmic agents.

Development of Congestive Heart Failure and Alterations in left Ventricular Function in Patients with Sustained Ventricular Tachyarrhythmias Treated with Amiodarone

The interaction between the efficacy and tolerance of amiodarone and the degree of left ventricular (LV) dysfunction was assessed in 126 patients with sustained ventricular tachyarrhythmias. In all patients radionuclide angiographic LV ejection fraction (EF) was measured before and after 8 to 12 months of amiodarone therapy. At baseline mean EF was 25 +/- 13% and 86 patients had an EF of 30% or less. In patients receiving amiodarone at steady state, there was a small but significant increase in EF (23 to 26%, p less than 0.05). Congestive heart failure (CHF) was present in 43 patients before amiodarone therapy. In 16 patients new (9 patients) or worsened (7 patients) CHF developed during the first year of amiodarone therapy. Development of CHF was not consistently related to a change in EF or heart rate. The clinical efficacy and tolerance of amiodarone were affected by the baseline EF and development of CHF. Efficacy and tolerance was 80% in patients with an EF of more than 30% and 60% in those with an EF of 30% or less. Among the 16 patients in whom new or worsened CHF developed, 6 (38%) died and 9 (56%) had recurrent ventricular tachyarrhythmias. Both baseline EF and development of CHF during amiodarone treatment significantly affect the prognosis in patients with ventricular tachyarrhythmias.