James J. Heger

Clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation

We evaluated the effects of amiodarone in 45 patients with recurrent ventricular tachycardia or ventricular fibrillation. At a mean follow-up time of 12.7 +/- 8.8 months (range, three to 36), amiodarone was successful in nine of 16 patients with recurrent ventricular fibrillation and 21 of 29 with recurrent ventricular tachycardia. During amiodarone therapy, ventricular tachycardia could be induced in 18 of 19 patients in whom it had been induced before therapy, but only six of these 19 had spontaneous recurrence during follow-up. Side effects included corneal microdeposits, hyperthyroidism, blue skin, nausea, and symptomatic bradycardia. Pulmonary fibrosis occurred in three patients. Doses of up to 2000 mg a day did not produce cardiac toxicity, but neurologic side effects precluded long-term therapy at this dose. We conclude that amiodarone is effective for long-term therapy of recurrent ventricular tachyarrhythmias, that induction of arrhythmia during therapy does not always predict efficacy, and that side effects are frequent but do not usually limit therapy.

Cross-sectional echocardiographic analysis of the extent of left ventricular asynergy in acute myocardial infarction

Cross-sectional echocardiography was used to study left ventricular wall motion in 44 patients with myocardial infarction, and the extent of observed asynergy was correlated with left ventricular function. Echocardiographic studies were performed in short and long axes of the ventricle and nine segments were identified for analysis. Wall motion in each segment was classified as normal, hyperkinetic, hypokinetic, akinetic or dyskinetic. Based on this analysis a wall motion index was derived as an overall assessment of left ventricular asynergy. Left ventricular function was measured by clinical and hemodynamic parameters to note the presence of pulmonary congestion or peripheral hypoperfusion or both.Segmental asynergy was detected in all patients with acute myocardial infarction. Patients with uncomplicated infarction had a wall motion index of 3.2 ± 2.4, which was significantly less than that in patients with pulmonary congestion (9.7 ± 3.1, p < 0.001) or with both pulmonary congestion and hypoperfusion (10.6 ± 4.8, p < 0.001).In nine patients with acute ventricular septal defect or acute mitral regurgitation, wall motion index was 6.7 ± 1.9, significantly less than with other complicated infarcts (p < 0.001) but greater than with uncomplicated infarcts (p < 0.005). Wall motion index also discriminated complicated from uncomplicated infarction when death was used as the end point.Cross-sectional echocardiography provides a method of measuring the extent of left ventricular asynergy during acute myocardial infarction that correlates well with hemodynamic parameters of left ventricular function.

Effects of intravenous and chronic oral verapamil administration in patients with supraventricular tachyarrhythmias.

The efficacy of i.v. and oral verapamil was studied in 28 patients with supraventricular tachycardia (SVT). Verapamil (5-10 mg i.v.) terminated SVT in all six patients with atrioventricular nodal (AVN) reentrant tachycardia. In all patients verapamil prolonged antegrade but did not affect retrograde AVN conduction time. Two patients had associated sinus nodal reentrant tachycardia that persisted after the AVN tachycardia terminated. In six patients with SVT using an accessory pathway for retrograde conduction, i.v. verapamil terminated SVT in four and slowed SVT in two patients. Verapamil did not affect the electrophysiologic properties of the accessory pathway and the effect on the SVT, as with AVN reentry, was caused by changes in antegrade AVN function. Verapamil lengthened AVN antegrade conduction time in patients with accessory pathways less than it did in patients with AVN reentry. Verapamil at doses that resulted in AVN Wenckebach block had no effect on the discharge rate of the three patients with automatic atrial tachycardia. In 13 of 14 patients with atrial fibrillation or flutter, i.v. verapamil promptly decreased the ventricular rate. One patient with preexcitation had an increase in ventricular rate after verapamil. The shortest RR intervals before and after verapamil were 260 and 220 msec, respectively, and after verapamil more ventricular beats were preexcited. Oral verapamil was given to 19 of 28 patients. Ten discontinued the drug within 30 days because of side effects or ineffectiveness. Seven patients treated for a mean of 19 months have shown evidence of improvement, judged by decreased frequency and shorter duration of tachycardia when it did recur. Thus, i.v. verapamil is an effective antiarrhythmic drug for most patients with SVT, but oral verapamil is effective in only selected patients.

Regional sympathetic denervation after myocardial infarction in humans detected noninvasively using I-123-metaiodobenzylguanidine.

Transmural myocardial infarction in dogs produces denervation of sympathetic nerves in viable myocardium apical to the infarct that may be arrhythmogenic. It is unknown whether sympathetic denervation occurs in humans. The purpose of this study was to use iodine-123-metaiodobenzylguanidine (MIBG), a radiolabeled guanethidine analog that is actively taken up by sympathetic nerve terminals, to image noninvasively the cardiac sympathetic nerves in patients with and without ventricular arrhythmias after myocardial infarction. Results showed that 10 of 12 patients with spontaneous ventricular tachyarrhythmias after myocardial infarction exhibited regions of thallium-201 uptake indicating viable perfused myocardium, with no MIBG uptake. Such a finding is consistent with sympathetic denervation. One patient had frequent episodes of nonsustained ventricular tachycardia induced at exercise testing that was eliminated by beta-adrenoceptor blockade. Eleven of the 12 patients had ventricular tachycardia induced at electrophysiologic study and metoprolol never prevented induction. Sympathetic denervation was also detected in two of seven postinfarction patients without ventricular arrhythmias. Normal control subjects had no regions lacking MIBG uptake. This study provides evidence that regional sympathetic denervation occurs in humans after myocardial infarction and can be detected noninvasively by comparing MIBG and thallium-201 images. Although the presence of sympathetic denervation may be related to the onset of spontaneous ventricular tachyarrhythmias in some patients, it does not appear to be related to sustained ventricular tachycardia induced at electrophysiologic study.

Cross-sectional echocardiography in acute myocardial infarction: detection and localization of regional left ventricular asynergy.

Left ventricular asynergy associated with acute myocardial infarction was evaluated by crosssectional echocardiography. Patients with acute infarction were studied within 48 hours of admission, and a segmental analysis of left ventricular wall motion was performed using nine segments obtained by short- and long-axis recordings of the left ventricle. By this segmental approach, analysis of wall motion in the entire left ventricle was possible. Complete studies were recorded in 37 of 44 original patients. Segmental wall motion abnormalities were recorded and localized in each of the 37 study patients. Asynergy was detected in 142 segments, and 29 patients had multiple segment involvement. Asynergy was most common in the apical segments of the left ventricle, but the cross-sectional scans permitted detection of asynergy in all segments. Correlation between the ECG and the cross-sectional echocardiogram revealed that 19 of 20 patients with inferior infarction had asynergy in posterior segments, 14 of 14 patients with anterior infarction had asynergy in anterior segments, and three of three patients with anteroinferior infarction had asynergy both anterior and posterior segments. In addition, the location of segmental asynergy followed specific patterns for each ECG subgroup of infarction. In four patients with postmortem examination, 21 of 22 segments that had asynergy by cross-sectional echocardiography also had pathologic evidence of infarction. Therefore, the cross-sectional echocardiogram provides a reliable method for detecting the presence and location of regional asynergy associated with acute myocardial infarction.

Influence of the autonomic nervous system on the Q-T interval in man

Drugs that affect the autonomic nervous system can influence the Q-T interval directly or by changing the heart rate. Bazetts formula to correct for rate may be misleading after certain drug interventions. This hypothesis was tested in 20 patients receiving both propranolol (0.15 mg/kg intravenously) and atropine (0.03 mg/kg intravenously). Six patients received propranolol first, 7 patients received atropine first, and 7 patients received atropine plus propranolol simultaneously. During control and after drug intervention, the Q-T interval was measured directly in sinus rhythm and during a fixed atrial paced rate, and was calculated using Bazetts formula. The ventricular effective refractory period was also determined in 6 patients after administration of atropine plus propranolol. The sinus cycle length (836 ± 156 to 648 ± 84 ms, mean ± standard deviation), measured Q-T interval (367 ± 26 to 329 ± 26 ms), and atrially paced Q-T interval (330 ± 28 to 315 ±27 ms) shortened after atropine plus propranolol (p <0.001), but the corrected Q-T interval with use of Bazetts formula did not change (402 ± 33 to 412 ± 24 ms). The ventricular effective refractory period also shortened from 241 to 20 to 218 ± 21 ms after atropine plus propranolol (p <0.02). The sinus cycle length increased after propranolol (750 ± 97 to 907 ± 108 ms, p <0.001), but no change occurred in the measured Q-T interval or atrial paced Q-T interval although the corrected Q-T interval using Bazetts formula was greatly shortened (428 ± 15 to 391 ±22 ms, p <0.001). The sinus cycle length, measured Q-T interval, and atrially paced Q-T interval decreased after atropine (p <0.01), but the corrected Q-T interval lengthened (375 ± 29 to 418 ± 28 ms, p <0.01). In summary, atropine and atropine plus propranolol shorten the Q-T interval independent of rate, demonstrating a direct vagal effect on the Q-T interval. Bazetts formula inaccurately predicts the Q-T interval after administration of atropine, propranolol, and atropine plus propranolol.

Clinical features of amiodarone-induced pulmonary toxicity.

The incidence and clinical predictors of amiodarone pulmonary toxicity were examined in 573 patients treated with amiodarone for recurrent ventricular (456 patients) or supraventricular (117 patients) tachyarrhythmias. Amiodarone pulmonary toxicity was diagnosed in 33 of the 573 patients (5.8%), based on symptoms and new chest radiographic abnormalities (32 of 33 patients) and supported by abnormal pulmonary biopsy (13 of 14 patients), low pulmonary diffusion capacity (DLCO) (nine of 13 patients), and/or abnormal gallium lung scan (11 of 16 patients). Toxicity occurred between 6 days and 60 months of treatment for a cumulative risk of 9.1%, with the highest incidence occurring during the first 12 months (18 of 33 patients). Older patients developed it more frequently (62.7 +/- 1.7 versus 57.4 +/- 0.5 years, p = 0.018), with no cases diagnosed in patients who started therapy at less than 40 years of age. Gender, underlying heart disease, arrhythmia, and pretreatment chest radiographic, spirometric, or lung volume abnormalities did not predict development of amiodarone pulmonary toxicity, whereas pretreatment DLCO was lower in the group developing it (76.0 +/- 5.5% versus 90.4 +/- 1.4%, p = 0.01). There was a higher mean daily amiodarone maintenance dose in the pulmonary toxicity group (517 +/- 25 versus 409 +/- 6 mg, p less than 0.001) but no difference in loading dose. No patient receiving a mean daily maintenance dose less than 305 mg developed pulmonary toxicity. Patients who developed toxicity had higher plasma desethylamiodarone (2.34 +/- 0.18 versus 1.92 +/- 0.04 micrograms/ml, p = 0.009) but not amiodarone concentrations during maintenance therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone: Electrophysiologic actions, pharmacokinetics and clinical effects

Interest in amiodarone has increased because of its remarkable efficacy as an antiarrhythmic agent. The purpose of this report is to review what is known about the electrophysiologic actions, hemodynamic effects, pharmacokinetics, alterations of thyroid function, response to treatment of supraventricular and ventricular tachyarrhythmias and adverse effects of amiodarone. Understanding the actions of amiodarone and its metabolism will provide more intelligent use of the drug and minimize the development of side effects. The mechanism by which amiodarone suppresses cardiac arrhythmias is not known and may relate to prolongation of refractoriness in all cardiac tissues, suppression of automaticity in some fibers, minimal slowing of conduction in fast channel-dependent tissue, or to interactions with the autonomic nervous system, alterations in thyroid metabolism or other factors. Amiodarone exerts definite but fairly minor negative inotropic effects that may be offset by its vasodilator actions. Amiodarone has a reduced clearance rate, large volume of distribution, low bioavailability and a long half-life that may last 2 months in patients receiving short-term therapy. Therapeutic serum concentrations range between 1.0 and 3.5 micrograms/ml. The drug suppresses recurrences of cardiac tachyarrhythmias in a high percent of patients, in the range of 80% or more for most supraventricular tachycardias and in about 66% of patients with ventricular tachyarrhythmias, sometimes requiring addition of a second antiarrhythmic agent. Side effects, particularly when high doses are used, may limit amiodarones usefulness and include skin, corneal, thyroid, pulmonary, neurologic, gastrointestinal and hepatic dysfunction. Aggravation of cardiac arrhythmias occurs but serious arrhythmias are caused in less than 5% of patients. Amiodarone affects the metabolism of many other drugs and care must be used to reduce doses of agents combined with amiodarone.

Prolongation of the Q-T interval in man during sleep☆

Parasympathetic blockade shortens the duration of the Q-T interval and ventricular effective refractory period independent of heart rate change. Since relative parasympathetic effect increases during sleep, it was determined whether sleep was associated with a change in the Q-T interval. Fifteen patients receiving no drugs underwent 3 to 6 days of continuous electrocardiographic recordings. Tracings were sampled every 30 minutes and recorded at a paper speed of 25 mm/s. This provided 12,000 Q-T and R-R intervals that were measured. Comparison of R-R intervals that had similar durations during sleep and awake states revealed that the duration of the Q-T interval was longer during sleep in all 15 patients (p less than 0.001). Eight patients had sufficient range of overlap of R-R intervals to compare linear regression lines of Q-T intervals recorded while awake with Q-T intervals recorded while asleep. The regression lines during sleep exhibited a mean intercept change of 38 +/- 37 ms and mean slope change of -0.021 +/- 0.040 ms when compared with the regression lines during the awake state. The difference in Q-T interval between awake and sleep states was 19 +/- 7 ms when calculated at a heart rate of 60 beats/min. These statistical comparisons of the relationship of the Q-T interval to R-R interval indicate that the Q-T interval is longer during sleep than during the awake state at the same heart rate. Prolongation of the Q-T interval during sleep may reflect increased vagal tone or sympathetic withdrawal. These changes in repolarization may be related to the diurnal variation of some ventricular arrhythmias.

Role of Electrophysiologic Testing in Managing Patients Who Have Ventricular Tachycardia Unrelated to Coronary Artery Disease

Abstract This study examined the usefulness of programmed electrical stimulation in managing 83 patients who had ventricular tachycardia not due to coronary artery disease. Among 39 patients with a history of sustained ventricular tachycardia, programmed stimulation induced ventricular tachycardia in 14 of 14 patients with mitral valve prolapse or primary electrical disease (arrhythmias without evidence of structural heart disease) and in 13 of 25 with cardiomyopathy (total 27 of 39, 69 percent). Programmed stimulation induced nonsustained ventricular tachycardia in 15 (34 percent) of 44 patients with a history of nonsustained tachycardia (5 of 13 with mitral valve prolapse, 6 of 19 with primary electrical disease and 4 of 12 with cardiomyopathy). Seventy-three of the 83 patients were treated with antiarrhythmic drugs and then followed up for 14.4 ± 11.4 months (mean ± standard deviation). Drug therapy was determined with serial electrophysiologic testing in 31 patients. Twenty-four of these 31 patients had a history of sustained ventricular tachycardia, and drugs prevented induction of ventricular tachycardia in 9 (none of whom manifested symptomatic events) but did not prevent it in 15 (6 of whom had symptomatic events). Among seven patients with a history of nonsustained ventricular tachycardia, drugs prevented induction of ventricular tachycardia in five (none of whom had symptomatic events) and did not prevent it in two (none of whom had symptomatic events). Forty-two patients were treated using the results of noninvasive testing. Drugs suppressed spontaneous ventricular tachycardia in 15 of 15 patients with a history of sustained tachycardia (7 of whom had symptomatic events including one sudden death), and in 26 of 27 with a history of nonsustained tachycardia (6 of whom had symptomatic events including one sudden death). Thus, in patients with ventricular tachycardia unrelated to coronary artery disease: (1) programmed electrical stimulation induced ventricular tachycardia less often than in patients whose tachycardia was due to coronary artery disease; (2) programmed stimulation induced ventricular tachycardia less often in patients with a history of nonsustained versus sustained tachycardia; and (3) suppression of inducible ventricular tachycardia appeared to predict effective drug therapy but drug therapy predicted with noninvasive testing appeared to be unreliable.