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Thrombolytic therapy salvages ischemic myocardium by rapidly reestablishing coronary artery patency in acute myocardial infarction. One of its major limitations is the complication of hemorrhage. A retrospective study of myocardial infarction patients who received thrombolytic therapy was performed to determine risk factors associated with a hemorrhagic event. Three hundred fifty patients were enrolled, and 20 (5.7%) had a bleeding complication, including four patients (1.1%) who had an intracranial hemorrhage. The factors associated with an increased risk for a significant hemorrhagic event were age (>65 years) and female gender. Factors associated with an intracranial hemorrhage were age (>65 years) and a history of hypertension.

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)

Between 1977 and 1986, 589 patients (age, 57 +/- 13 years; 464 men and 125 women) received amiodarone for ventricular fibrillation (VF; 147 patients), sustained (VT-S; 242 patients) or nonsustained (VT-NS; 80 patients) ventricular tachycardia, or supraventricular tachycardia (SVT; 120 patients). Mean left ventricular ejection fraction was 36 +/- 17%, with 23% in New York Heart Association functional class I, 49% in class II, 25% in class III, and 3% in class IV. Sixty-two percent had ischemic heart disease. Follow-up was 32 +/- 27 months (mean +/- SD). Life table analysis revealed that patients with VF, VT-S, and VT-NS had a cumulative incidence of sudden death of 9% at 1 year, increasing by about 3% per year. By years 2 and 5, the cumulative incidence of sudden death, VF, or VT-S recurrence was 26% and 38% and the percent of patients still taking amiodarone was 54% and 32%. For patients with SVT at years 2 and 5, the cumulative incidence of sudden death was 1% and 3%, and of sudden death or SVT recurrence the cumulative incidence was 20% and 29%. The percent of patients still taking amiodarone was 67% and 43%. Of 14 clinical variables assessed, New York Heart Association functional class was the best predictor of sudden death and arrhythmic failure and no other variable added independent predictive power. Older age and lower left ventricular ejection fraction were independent predictors of drug failure (sudden death or arrhythmic failure or need to discontinue amiodarone because of side effects). We conclude that despite its side effect profile, amiodarone is an effective and reasonably well-tolerated antiarrhythmic drug.

The site of ventricular stimulation is an important variable in the initiation of ventricular tachycardia (VT) by programmed ventricular stimulation. Among 169 patients studied consecutively, 17 (10%) had ventricular tachycardia induced by programmed electrical stimulation from the right ventricular outflow tract but not from the apex. Fourteen of these 17 patients had had prior myocardial infarction (12 had inferior, and two had both inferior and anterior myocardial infarction), two had a dilated cardiomyopathy, and one had a localized cardiomyopathy. Fourteen patients had echocardiograms suitable for analysis. Of these, 12 had posterior/inferior ventricular wall motion abnormalities located at the base of the heart. The ventricular effective refractory periods from the right ventricular outflow tract and right ventricular apex were 237 +/- 4 and 244 +/- 5 msec, respectively (p less than 0.05, mean +/- SEM). Induced VT had a cycle length of 229 +/- 4 msec and had the morphology of right bundle branch block in 12 patients, of left bundle branch block in three patients, and had both morphologies in two patients. In 14 patients the axis was superior. VT was initiated with two extrastimuli in 15 patients and with burst right ventricular pacing in two patients. Similar pacing techniques with identical pacing intervals did not induce VT at the right ventricular apex in 14 of these 17 patients. Further, among the 15 patients whose VT was induced at the right ventricular outflow tract with two extrastimuli, neither burst pacing (n = 13) nor two extrastimuli introduced at faster paced rates (n = 12) induced VT at the right ventricular apex.(ABSTRACT TRUNCATED AT 250 WORDS)

We assessed the value of clinical electrophysiologic study using intracardiac recording and programed electrical stimulation in 34 patients who had unexplained syncope and/or presyncope. All patients had normal electrocardiograms, and no abnormality was detected by clinical examination, ambulatory electrocardiographic recording, or treadmill testing. The electrophysiologic results were diagnostic in four patients (11.8 percent) and led to appropriate therapy that totally relieved symptoms. The results were abnormal but not diagnostic in two patients (5.8 percent) and normal in the remaining 28 patients (82.4 percent). The patients were followed for a mean period of 15 months (range two to 44) after electrophysiologic testing. Sixteen patients (47 percent) had no further episodes in the absence of any intervention. In four patients (11.8 percent), a definitive diagnosis was made during follow-up. In seven patients, permanent pacing was instituted empirically with relief of syncope. Two patients continued to have syncopal spells. We conclude that the diagnostic yield of electrophysiologic testing is low in a patient population that has no electrocardiographic abnormality or clinical evidence of cardiac disease. Empirical permanent pacing in patients with symptoms continuing after our study appeared to be beneficial, but this result is difficult to evaluate because of the high incidence of spontaneous remission in this group. Persistent attempts to document electrocardiographic abnormalities during a typical episode of symptoms appears to be the only definitive way to confirm or exclude an arrhythmic cause of the symptoms.

Induction of ventricular tachycardia (VT) at electrophysiologic study in patients taking amiodarone poorly predicts recurrence of VT. Consequently, a discriminant function was developed (using parameters based on retrospective data) that appeared to identify high-risk patients. These parameters included ventricular effective refractory period, corrected QT interval, initiation of a repetitive ventricular response and the mode of VT induction. In the present study these parameters were prospectively evaluated in 60 patients with coronary artery disease and sustained VT or ventricular fibrillation (VF), in whom VT was still induced at electrophysiologic study during amiodarone therapy. Thirteen patients had recurrent events (sudden death in 8 and sustained VT in 5) and 47 patients had no symptomatic arrhythmia recurrence (follow-up for 16 +/- 2 months, mean +/- standard error of the mean). The ventricular effective refractory period, corrected QT interval and presence of a repetitive ventricular response did not discriminate between patients with and without symptomatic arrhythmia recurrence. However, an easier mode of VT induction during amiodarone therapy versus control was highly predictive of arrhythmia recurrence: 9 of 13 (69%) recurrences were in this group. In contrast, only 4 of 44 (9%) patients who had either the same or harder mode of VT induction had a recurrent event. Overall, 9 of 16 (56%) patients with an easier mode of VT induction had a recurrence, including 6 of the 8 patients with subsequent sudden cardiac death. It is concluded that electrophysiologic testing during amiodarone therapy is useful to identify high-risk patients.

The syndrome of enhanced atrioventricular nodal (AVN) conduction has been defined arbitrarily by: AH interval during normal sinus rhythm (AH-NSR) less than or equal to 60 msec; shortest right atrial pacing cycle length (PCL) maintaining 1:1 AVN conduction (shortest PCL 1:1) less than or equal to 300 msec; and at the shortest PCL 1:1, an increase in the AH interval from AH-NSR (delta AH) less than or equal to 100 msec. We examined the relationship between AH-NSR, shortest PCL 1:1, and delta AH in 160 consecutively studied patients who did not have accessory AV pathways or second-degree AV block to determine whether a distinct subgroup of patients with unusually rapid AVN conduction properties could be identified. The frequency distribution of each of the variables was unimodal and continuous. Cluster analysis, combining the three variables, failed to reveal a distinct subgroup at the lower end of the spectrum. Sixty-six patients (41%) had AH-NSR less than or equal to 60 msec, 36 (23%) shortest PCL 1:1 less than or equal to 300 msec, 76 (48%) delta AH less than or equal to 100 msec, and 17 (11%) all three criteria. The shape of the AH vs atrial PCL curve was independent of shortest PCL 1:1. Neither delta AH nor the terminal slope of the curve for AH vs atrial PCL (measured over the 20-40 msec before Wenckebach block) was related to AH-NSR or shortest PCL 1:1. We conclude that a subgroup cannot be identified by AH-NSR, shortest PCL 1:1, and delta AH, and that enhanced AVN conduction as previously defined represents simply one end of the continuous spectrum of normal AVN physiology.

The advantages and disadvantages of pacing and transvenous cardioversion in terminating episodes of tachyarrhythmias are examined.

We followed 11 patients for 5 to 27 months (mean 14.9) after implantation of a permanent transvenous low-energy synchronized cardioverter to evaluate both long-term reproducibility of ventricular tachycardia (VT) induction via noninvasive programmed electrical stimulation with the cardioverter and efficacy of cardioversion. Induction and termination of VT were attempted at implantation and approximately every 3 months thereafter. All patients had coronary artery disease and were receiving antiarrhythmic drug therapy (amiodarone in eight). VT cycle length, morphology, and mode of induction were reproducible on multiple occasions in nine patients; clinical VT was induced inconsistently in two patients. Multiple VT episodes in five patients had one morphology, whereas two morphologies occurred in six patients. Synchronization of the shock within the QRS complex and right ventricular effective refractory periods determined via the cardioverter remained constant over the follow-up period. VT was terminated on every occasion in nine patients and on eight of nine occasions in one patient. Tachycardia was accelerated on three of five occasions in one patient. Consistently effective cardioversion energy (0.2 to 2.0 J) increased modestly in four patients. We conclude that patients with inducible monomorphic VT usually have sustained VT with similar characteristics inducible over a period of time and cardioversion and sensing functions of the cardioverter remain relatively stable over time.

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.

Kent bundle interruption for ventricular preexcitation has been successfully accomplished utilizing several different surgical techniques. The external closed-heart technique of Guiraudon combining surgical dissection and cryoablation has been used to interrupt 52 accessory pathways in 47 consecutive patients since May, 1985. The 35 male and 12 female patients ranged in age from 10 to 67 years (mean, 30 years). There were 25 left free wall, 13 right free wall, 13 posterior septal, and 1 anterior septal accessory pathways. Preoperative and intraoperative electrophysiological studies were performed in all patients to induce the arrhythmia and localize all accessory pathways. The operation consisted of dissection of the atrioventricular fat pad. Following this, the delta wave and retrograde accessory pathway conduction disappeared, thereby indicating successful pathway ablation. In 4 patients with right-sided accessory pathways, interruption of the pathway required cryoablation. Cryolesions (made with cryo-probe at −60°C for two minutes) were created in the region of the accessory pathway insertion. All accessory pathways were successfully ablated without any deaths or heart block. Concomitant surgical procedures were performed in 4 patients. Two patients required a second operation the next day for an accessory pathway not found at the initial operation. Three patients had postpericardiotomy syndrome, and 4 had recurrent atrial fibrillation requiring therapy. The remaining patients have had no arrhythmia recurrence and have remained drug free after a follow-up of 1 month to 22 months (mean, 12.5 months). We conclude that the closed-heart technique of accessory pathway ablation is safe and reproducible, obviates the necessity for aortic cross-clamping and cardioplegic arrest, and allows instantaneous monitoring of conduction over the pathway.

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.

We examined the influence of ventricular tachycardia (VT) cycle length and antiarrhythmic drugs on the frequency of VT termination and acceleration by single and double extrastimuli and right ventricular burst pacing. In 57 patients, 89 episodes of sustained VT (32 control, 57 drug) were induced by programmed electrical stimulation. Overall, 60 of 89 (67%) episodes of ventricular tachycardia were terminated by means of programmed electrical stimulation. In patients with relatively slow ventricular tachycardia (VT cycle length greater than or equal to 350 msec) pacing terminated 37 of 44 (84%) episodes but terminated only 24 of 45 (51%) episodes of more rapid VT (VT cycle length less than or equal to 349 msec, p less than 0.005). Pacing successfully terminated VT in nine of 49 (18%) episodes using a single extrastimulus, 22 of 52 (42%) episodes using double extrastimuli, and 40 of 66 (61%) episodes using burst right ventricular pacing. VT acceleration occurred in none of 49 attempts with a single extrastimulus, in eight of 52 (15%) attempts with double extrastimuli, and in 12 of 66 (18%) attempts using burst right ventricular pacing. During therapy, the frequency of either ventricular tachycardia termination or acceleration did not change regardless of the pacing termination method used. However, by prolonging the mean VT cycle length from 311.1 +/- 82.2 msec to 401.9 +/- 103.5 msec (p less than 0.01), drugs increased the overall frequency of VT termination. We conclude that: (1) pacing terminates VT more frequently if the VT cycle length is long and if right ventricular bursts are used, (2) burst right ventricular pacing increases the risk of VT acceleration, and (3) drugs increase the frequency of ventricular tachycardia termination by prolonging VT cycle length but do not affect frequency of VT acceleration.

Ventricular tachycardia induced by programmed electrical stimulation during amiodarone therapy often does not preclude a good clinical response. The purpose of this study was to determine whether use of discriminant analysis could distinguish patients who remained asymptomatic from those who subsequently developed symptomatic ventricular tachycardia or cardiac arrest. Studies were performed in 37 patients with sustained ventricular tachycardia who still had ventricular tachycardia induced during programmed electrical stimulation during amiodarone therapy. The mean follow-up time was 14.1 ± 1.3 months (± SEM). Twenty-three patients remained asymptomatic, whereas 14 patients had symptomatic recurrence of their ventricular tachycardia.In patients with recurrence of arrhythmia compared with asymptomatic patients, administration of amiodarone caused a longer ventricular effective refractory period (296 ± 8 versus 271 ± 7 ms, p < 0.05) and a greater change in corrected QT [QTc] interval (90 ± 18 versus 44 ± 9 ms, p < 0.02), but no difference in the decrease in premature ventricular complexes after treatment with amiodarone. During amiodarone therapy, nonbundle branch reentrant repetitive ventricular responses were induced by a single ventricular extrastimulus during sinus rhythm in 9 of 14 patients with recurrent arrhythmias compared with 2 of 21 asymptomatic patients (p = 0.001). Also, less aggressive pacing techniques were required to induce ventricular tachycardia in 9 of 14 symptomatic patients compared with 4 of 23 asymptomatic patients (p < 0.02). A discriminant analysis using the presence of nonbundle branch reentrant repetitive ventricular responses, change in method of ventricular tachycardia induction and either the change in QTcinterval or ventricular effective refractory period correctly identified clinical outcome in 90% of the patients, and all patients with recurrent arrhythmias were classified correctly. It is concluded that electrophysiologic testing during amiodarone therapy can provide data that identify patients who appear to be at risk for development of ventricular tachycardia after hospital discharge.

The authors provide an overview of the general features of pharmacokinetics and report the pharmacodynamic and pharmacokinetic interactions of selected antiarrhythmic drugs. Their clinical experience in the use of investigational antiarrhythmic drugs is also presented.

Oral encainide, varying from 75 to 300 mg/day (mean 174 mg/day), was administered to 52 patients with drug-resistant atrioventricular reciprocating tachycardia (AVRT) associated with the Wolff-Parkinson-White syndrome. Electrophysiologic studies were performed before and during drug treatment. Encainide resulted in anterograde accessory pathway block in 15 of 37 (41%) and retrograde accessory pathway block in 11 of 46 (24%) patients. In patients with residual accessory pathway conduction, encainide significantly prolonged the shortest pacing cycle length maintaining anterograde (261 +/- 26 to 404 +/- 85 ms) and retrograde (279 +/- 46 to 436 +/- 87 ms) accessory pathway conduction, as well as the anterograde accessory pathway effective refractory period (271 +/- 32 to 329 +/- 73 ms). AVRT could not be induced during encainide therapy in 20 of 49 patients (41%). In the remaining patients, AVRT cycle length increased (319 +/- 44 to 426 +/- 90 ms, p less than 0.001) due to prolongation of HV and ventriculoatrial intervals. During follow-up (mean 38.5 months), 30 patients continued to take the drug and 7 patients with favorable drug response subsequently elected to undergo surgical accessory pathway ablation (71% overall favorable response). Encainide was ineffective in 11 patients, was discontinued because of drug intolerance in 2 patients and exacerbated ventricular tachycardia in 2 patients. Lack of AVRT inducibility at encainide electrophysiologic study did not always predict recurrence-free follow-up. Encainide is an effective and well-tolerated drug to prevent recurrence of AVRT in patients with Wolff-Parkinson-White syndrome.

Sudden death has occurred in monkeys fed large doses of probucol, a cholesterol-lowering drug, given in combination with an atherogenic diet. These monkeys develop prolonged QT intervals and high serum levels of probucol. We investigated the effect of probucol on QT interval and the incidence of ventricular ectopy during a double-blind placebo-controlled study in 16 patients with less than 600 premature ventricular complexes (PVCs) per day and a corrected QT interval of less than 0.44 second. Seven patients received probucol and nine patients received placebo. Three 24-hour continuous ECG recordings were obtained prior to entry into the study and three additional recordings were obtained after 6 months of drug or placebo therapy. A 15-second ECG tracing was sampled from the continuous ECG recording every 30 minutes and, for the group, 15,000 QT intervals were measured permitting construction of QT versus R-R regression lines for each patient before and during therapy. Comparison of the regression lines revealed that the measured QT interval prolonged 20 +/- 18 msec during the awake state and 24 +/- 20 msec during sleep (mean + standard deviation) at matched heart rates in the seven patients receiving probucol (p less than 0.01). Using Bazett's formula to correct for rate, corrected QT interval prolonged 22 +/- 23 msec in the awake state and 20 +/- 18 msec in the asleep state (p less than 0.01). In probucol treated patients QT interval prolongation was directly related to increasing probucol plasma levels (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Natural history, structural substrate, electrocardiographic and electrophysiologic characteristics and therapy were evaluated in 18 patients who demonstrated repetitive ventricular tachycardia, defined as repeated episodes of ventricular tachycardia that had a uniform QRS configuration and normal sinus-conducted QRS complexes between the episodes of tachycardia. The patients were young (mean age 37 years) and frequently had a long history of arrhythmias before this evaluation; only two patients has a history of syncope and six were completely asymptomatic. Fourteen patients had no evidence of underlying structural heart disease, three had mitral valve prolapse and one had congestive cardiomyopathy. Episodes of ventricular tachycardia tended to occur in clusters over a 24 hour electrocardiographic recording period. Repetitive ventricular tachycardia was induced in two of nine patients by programmed electrical stimulation, and in seven patients incremental atrial and ventricular pacing suppressed spontaneous arrhythmia. In the one patient whose tachycardia was induced by incremental ventricular pacing there was an inverse relation between pacing cycle length and the interval from the last paced complex to the first complex of ventricular tachycardia, indicating there was overdrive suppression. At a follow-up time of 0.5 to 8 years no patient had died or had worsening of symptoms. Encainide completely eliminated episodes of ventricular tachycardia during acute treatment in five of six patients tested. Seven patients received no antiarrhythmic therapy and the arrhythmia appeared to have spontaneously resolved in four of these patients. Repetitive ventricular tachycardia appears to have distinct clinical and electrophysiologic characteristics. In this series the arrhythmia had a good prognosis and often required no treatment. The electrophysiologic features are consistent with a mechanism of automaticity.

Four patients with ventricular preexcitation whose syncope initially was attributed to an arrhythmia utilizing the accessory pathway are presented. At electrophysiologic study, the electrophysiologic characteristics of the accessory pathways were considered unlikely to support a tachycardia of a rate sufficient to result in syncope. Programmed Stimulation of the right ventricle, however, reproducibly induced ventricular tachycardia to which the syncope was subsequently attributed in 3 patients. The importance of identifying ventricular tachycardia as the cause of syncope in these patients is emphasized.

Cibenzoline, a new antiarrhythmic agent, was tested in 26 patients who had symptomatic ventricular tachycardia (24 patients) or premature ventricular complexes (2 patients) unresponsive to conventional drugs. Cibenzoline was given orally every 8 hours to maximal doses of 65 mg in 2 patients, 81.25 mg in 22 patients and 97.5 mg in 2 patients. Cibenzoline abolished spontaneous episodes of ventricular tachycardia in 8 of 16 patients with ventricular tachycardia during a 72 hour control electrocardiographic recording, and 7 of 22 patients had greater than 83% decrease in premature ventricular complexes compared with control. The PR interval increased 14% (p < 0.001), QRS duration increased 17% (p < 0.001), QT interval did not change and mean ejection fraction in 10 patients did not change.Electrophysiologic studies were performed on 10 patients in the control period and during maximal cibenzoline dosage. Cibenzoline did not affect electrophysiologic properties of the atrium or atrioventricular (AV) node. It prolonged the ventricular effective (223 ± 16 to 241 ± 22 ms, p < 0.02) and functional (247 ± 18 to 264 ± 25 ms, p < 0.02) refractory periods. At control electrophysiologic studies, ventricular tachycardia was induced in 9 of 10 patients (mean cycle length 210 ± 31 ms). Cibenzoline therapy prevented ventricular tachycardia induction in two patients, and in the other seven patients the mean ventricular tachycardia cycle length increased from 210 to 260 ms. The one patient with no ventricular arrhythmia induced during the control study still had no arrhythmia induced while receiving cibenzoline. Among six patients receiving cibenzoline during follow-up, one patient died of recurrent myocardial infarction, two patients stopped taking cibenzoline because of recurrent veutricular tachycardia and three patients have continued taking cibenzoline for 10 ± 4 months with control of symptomatic arrhythmias.Thus, cibenzoliue suppressed ventricular tachycardia and premature veutricular complexes in some patients unresponsive to conventional drugs and was well tolerated. Cibenzoline significantly prolonged ventricular effective and functional refractory periods and had minimal negative hemodynamic effects.

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.

Le Symbios 7008 est capable de traiter les bradycardies et les tachycardies. Nous rapportons ici notre experience initiale chez 21 patients chez qui ce boitier a ete implante. Tous presentaient des tachyarythmies supraventriculaires qui ont ete arretees par stimulation auriculaire rapide (19 pts) ou sequentielle. Plus de la moitie des patients presentaient aussi des bradyarythmies necessitant une stimulation et ont done ainsi beneficie des deux fonctions du boitier. En l'etat actuel des choses, l'experience est favorable. The Symbios 7008 pacemaker is capable of treating both bradycardias and tachycardias. In this report, we summarize operation of the pacemaker and the initial experience in 21 patients who have received implants. All patients have supraventricular tachyarrhythmias that have been terminated successfully with automatic atrial burst pacing (19 patients) or AV sequential pacing. More than half of the patients also have bradyarrhythmias requiring pacing and thus benefit from both functions of the device. Experience to date has been favorable.

Antiarrhythmic therapy in 506 consecutive patients undergoing 1,268 antiarrhythmic drug trials for ventricular tachycardia or ventricular fibrillation was reviewed for evidence of arrhythmogenic drug effect defined as the occurrence of a new form of ventricular tachyarrhythmia temporally associated with initiation of drug therapy or dosage increase. Arrhythmogenic effects occurred in 6.9% of patients and 3.4% of drug trials. This ranged from a high of 11.8% caused by encainide to none occurring with procainamide, tocainide or beta-adrenergic blocking drugs. The incidence of arrhythmogenesis was significantly greater in patients whose presenting arrhythmia was sustained ventricular tachycardia than it was in those who presented with nonsustained ventricular tachycardia or ventricular fibrillation (p = 0.02). Decreased systolic function measured echocardiographically at the base of the left ventricle was associated with an increased incidence of arrhythmogenic effects (p = 0.006) whereas global left ventricular ejection fraction was not. Age, gender, cardiac diagnosis, location of prior myocardial infarction and New York Heart Association functional class for heart failure were not related to the occurrence of drug-induced arrhythmias. These findings emphasize the need for in-hospital cardiac monitoring during initiation of antiarrhythmic drug therapy for ventricular tachyarrhythmias.

The development of the transvenous cardioverter, from the initial animal studies, to the clinical studies using temporary leads, to the initial permanent implants is described. Shocks less than or equal to 2.0 joules synchronized to the QRS complex and delivered through a specially designed catheter electrode placed in the apex of the right ventricle successfully terminate most episodes of ventricular tachycardia in patients. The implanted unit which also serves as a demand ventricular pacemaker, can be used to perform programmed electrophysiologic studies. Future devices must be capable of defibrillation and more accurate arrhythmia detection.

Amiodarone and a metabolite, desethylamiodarone, were measured in plasma of 55 patients and in both plasma and red blood cell (RBC) in 28 patients who received chronic amiodarone treatment. The assay for amiodarone and desethylamiodarone was performed by high-pressure liquid chromatography. During chronic treatment, median plasma concentration of amiodarone was 2.80 micrograms/ml and desethylamiodarone was 2.20 micrograms/ml. In matched samples, plasma amiodarone concentration exceeded RBC amiodarone concentration (p less than 0.001) and the RBC-to-plasma concentration ratio averaged 0.31. The plasma desethylamiodarone concentration was not significantly different from its RBC concentration, and the RBC-to-plasma concentration ratio averaged 1.29. There was a linear correlation between plasma concentrations of amiodarone and desethylamiodarone (r = 0.82) and between RBC concentrations of drug and metabolite (r = 0.71). Drug or metabolite concentrations in plasma and RBCs correlated directly with daily dosage of amiodarone. Adverse side effects during chronic amiodarone therapy were related most strongly to RBC drug and metabolite concentrations. The group with adverse side effects had a significantly higher RBC concentration of amiodarone, 150 vs 0.75 micrograms/ml (p less than 0.001), than did patients free of adverse effects. After dosage reduction, side effects abated and plasma and RBC concentrations of drug and metabolite decreased. These data indicate that there is an expected range of amiodarone and desethylamiodarone concentrations during chronic treatment and that adverse side effects correlate best with RBC concentrations of drug and metabolite. Red cell concentrations may reflect the amount of unbound, free amiodarone and desethylamiodarone in plasma.

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.

Programmed ventricular stimulation, electrophysiologic effects of various antiarrhythmic drugs, and the results of serial electrophysiologic testing in patients with ventricular arrhythmias are discussed. The use of discriminant analysis to predict the efficacy of antiarrhythmic drugs is also briefly analyzed.

re-entry andbundle-branch re-entry in47patients withand in50patients without ventricular tachycardia. We alsocompared theprevalence ofrepetitive ventricular responsesusing twotypesofelectrophysiological stimulation: single prematureventricular stimulation during sinus rhythm oratrial pacing, andsingle prematureventricular stimulation during ventricular pacing.Inpatients whohadventricular tachycardia, prematureventricular stimulation during ventricular pacing induced non-bundle-branch re-entry more often thanduring atrial pacing (70-2% versus333%).Bothmethods ofstimulation induced non-bundle-branch re-entry more often inpatients whohadventricular tachycardia thaninthose whodidnot.Inbothgroupsof patients, bundle-branch re-entry was rareduring atrial pacing andmore common butequally prevalent during ventricular pacing. Todetermine ifinduced non-bundle-branch re-entry could identify patients atrisk ofdeveloping future symptomatic ventricular tachycardia or sudden death, 59patients whohada history of documented ventricular tachycardia hadanelectrophysiological study just before discharge andwere followed for anaverageof109months. Non-bundle-branch re-entry induced during ventricular and atrial pacing hadapredictive accuracyof59%and64%,respectively. Thepredictive accuracyof non-bundle-branch re-entry induced during atrial pacing appeared tobegreaterinpatients whoalso hadventricular tachycardia induced during the sameelectrophysiology

Un choc synchronise d'energie inferieure a 2 joules delivrea travers un catheter specialement concu a cet effet peut terminer une tachycardie ventriculaire soutenue chez le chien et l'homme. Une telle fonction est programee dans un boitier de 95 grammes, impiante sous anesthesie locale a la xylocaine, capable par ailleurs de stimulation VVI et d'effectuer des etudes electrophysiologiques. Sept patients ont recu ce boitier et J'experience initiale est rapportee. A synchronized shock of ≤2.0 joules delivered over a specially designed catheter electrode passed to the apex of the right ventricle effectively terminates sustained ventricular tachycardia in dogs and in patients. The capability has been engineered into a 95 gram device implanted using lidocaine anesthesia, which is also capable of VVI pacing and of performing programmed electrophysiologic studies. Seven patients have received the implant and the initial experience is described.

The purpose of these studies is to illustrate that the time of drug administration in experimental animals subjected to coronary artery occlusion is an important influence on the myocardial distribution of the drug as well as its electrophysiologic and arrhythmogenic effects. Also, because several drugs have active metabolites, some studies must be done after oral administration. Finally, electrophysiologic testing to determine drug efficacy may give misieading results with some drugs.

Repetitive ventricular responses thought to be due to bundle branch reentry are induced commonly during programmed ventricular stimulation and are considered to be a physiologic response.’ However, sustained ventricular tachycardia due to bundle branch reentry rarely occurs. We have found only one well-documented case report in the English literature.2 The purpose of this report is to present data from a patient in whom we induced ventricular tachycardia that appeared to be due to bundle branch reentry. A 54-year-old man was referred for further management of recurrent ventricular tachycardia. The diagnosis of congestive cardiomyopathy of unknown origin was first

Patients with ventricular tachycardia run a substantial risk of sudden death; therefore, therapy to prevent such arrhythmias is critical. However, noninvasive tests such as continuous electrocardiographic recordings, exercise testing, or both, often provide data insufficient for determining antiarrhythmic drug efficacy. For example, occurrences of arrhythmia may be separated widely in time, and many patients who are given drugs that seem to be effective at the time of hospital discharge die suddenly or are readmitted because of recurrent arrhythmias and/or syncope. Further, antiarrhythmic drugs are also arrhythmogenic and can result in sudden death although the arrhythmogenicity of the drug may not be apparent for weeks or months (Rinkenberger et al. 1982; Selzer and Wray 1964; Meltzer et al. 1978).

Electrophysiologic and hemodynamic effects of intravenous enoximone were studied in 15 male patients, mean age 62.2 years, with New York Heart Association classes II to IV congestive heart fallure (coronary artery disease in 10 and idlopathic dllated cardiomyopathy in five patients; mean ejection fraction, 0.19). All patients had spontaneous ventricular tachyarrhythmias: eight had sustained ventricular tachycardia (VT), one had ventricular fibrillation, and six had nonsustained VT. Hemodynamic and electrophysiologic parameters including VT induction were determined before and during an intravenous infusion of enoximone. The cardiac index increased (2.49 ± 0.89 to 2.96 ± 0.78), and the pulmonary capillary wedge pressure decreased (22.4 ± 13.2 to 10.0 ± 9.0) after enoximone per predefined protocol endpoints. There was a significant decrease in spontaneous sinus cycle length, corrected sinus nodal recovery time, AH interval during atrial pacing, shortest cycle length at which 1:1 atrioventricular nodal conduction occurred, and refractory periods of the atrium, ventricle, and atrioventricular node. Enoximone did not alter the cycle length of induced VT, and there was no consistent change in the number of extrastimuli required for VT induction. A baseline 24-hour ECG recording was obtained on 14 patients (while recelving a long-term antiarrhythmic drug regimen, if needed) and repeated after 1 week and 1 month of oral enoximone therapy. There was no significant increase in the number of premature ventricular complexes per hour or VT episodes per 24 hours after 1 week or 1 month of therapy with enoximone. However, if four patients who received amiodarone and may not yet have reached steady state were excluded from analysis, there was a significant increase in the frequency of premature ventricular complexes per hour 1 month after initiation of enoximone. We conclude that intravenous enoximone reduces pulmonary capillary wedge pressure and increases cardiac output in most patients. Intravenous enoximone in doses sufficlent to have hemodynamic effects shortens atrial, ventricular, and atrioventricular nodal refractoriness and decreases AV nodal conduction time but has no consistent effect on VT induction or VT cycle length. The frequency of spontaneous ventricular ectopy may increase in some patients after oral enoximone, but its clinical significance is undefined. Enoximone may be administered cautiously to patients with congestive heart fallure and preexisting ventricular tachyarrhythmias.

The pharmacokinetics of oral cibenzoline were studied in 30 arrhythmia patients as part of an ascending multiple-dose efficacy study. The elimination half-life of the drug following repetitive dosing ranged from 7.6 to 22.3 hours, with a harmonic mean of 12.3 hours (n = 24), and increased with age and decreasing renal function. The drug exhibited apparent dose proportional and linear pharmacokinetics over the range of doses studied. Multivariate analysis revealed that the patients' age and serum creatinine concentration accounted for 71% of the variability in the range of beta values (terminal elimination rate constant), and that 69.5% of the intersubject variability in the steady-state trough plasma concentrations could be accounted for by the patients' age, weight and serum creatinine concentration. These data suggest that, although there is some intersubject variability in the elimination and accumulation of cibenzoline, much of the variability can be explained by the patients' age, weight and renal function.

Three patients with drug-resistant atrioventricular (AV) nodal reentrant tachycardia and two patients with reciprocating tachycardia associated with nodoventricular pathways received oral encainide after a control drug-free electrophysiologic study. In one patient with AV nodal reentry, encainide prolonged anterograde AV nodal conduction, produced complete ventriculoatrial (VA) block, and prevented tachycardia induction. Encainide had no effect on AV or VA conduction in the second patient with AV nodal reentry, and tachycardia with similar cycle length was still induced. The third patient was not studied while receiving encainide, but spontaneous AV nodal reentrant tachycardia occurring multiple times daily was abolished. In both patients with nodoventricular pathways, anterograde AV nodal and VA conduction were prolonged by encainide and tachycardia was no longer inducible. Two patients with AV nodal reentry were given long-term encainide therapy and have been free of recurrent arrhythmias for 16 and 30 months. One patient with a nodoventricular pathway has been without arrhythmia recurrence after 73 months of encainide therapy; the other patient required addltion of propranolol to encainide because of recurrent tachycardia. We conclude that encainide can prolong anterograde AV nodal and VA conduction and prevent induced and spontaneous tachycardia in some patients with drug-resistant and highly symptomatic AV nodal or nodoventricular reentry.

Tachyarrhythmias result from disorders of impulse formation, impulse conduction or combinations of both mechanisms. Since cells dependent on the slow inward current possess the properties of impulse formation and conduction [1], it is quite plausible to consider that the slow inward current may serve as an important ionic substrate in fibers responsible for, or at least participating in, the genesis and maintenance of various supraventricular tachyarrhythmias that occur clinically. Such ionic characterization can be made on experimental preparations and ample evidence, reviewed in other chapters of this book, supports the role of the slow inward current in the generation of action potentials from of the slow inward current in the generation of action potentials from normal and abnormal fibers in the atrium. For example, the data strongly indicate that the normal sinus and atrioventricular (AV) nodes are slow-channel dependent. In addition, other atrial fibers, some made abnormal by a variety of methods, may be slow-channel dependent. However, our present diagnostic tools do not permit for most clinically occurring tachyarrhythmias, i.e., reentry or automaticity, and certainly do not allow convincing differentiation into which arrhythmias may be slow-channel dependent. Nevertheless, extrapolating from experimental animal observations, from in vitro studies on human atrial tissues, and from the response of arrhythmias to the clinically available slow-channel blocker, verapamil[2], in this chapter we will consider the evidence supporting the possible participation of the slow inward current in the genesis of supraventricular tachycardia (SVT).

The effects of amiodarone on the pharmacokinetic and electrophysiologic properties of procainamide were examined in eight patients treated for recurrent ventricular arrhythmias who received intravenous procainamide, 6 to 15 mg/kg, at control and after 1 to 2 weeks of oral amiodarone treatment. Compared with control, procainamide plasma clearance decreased from 0.43 +/- 0.12 L/kg-hr to 0.33 +/- 0.12 L/kg-hr (P less than 0.01), plasma elimination half-life increased from 3.77 +/- 0.64 hours to 5.21 +/- 0.42 hours (P less than 0.01), and volume of distribution was unchanged from 2.31 +/- 0.74 L/kg to 2.47 +/- 0.90 L/kg during amiodarone treatment. As single agents, intravenous procainamide and oral amiodarone produced equivalent increases in QRS duration, rate-corrected QT interval, right ventricular effective refractory period, and cycle length of induced ventricular tachycardia. After the addition of intravenous procainamide to amiodarone the QRS duration, rate-corrected QT interval, and, in six of eight patients, ventricular tachycardia cycle length were significantly increased compared with control or either drug alone, suggesting additive electrophysiologic effect. However, acceleration of induced ventricular tachycardia occurred in one patient with combined treatment, suggesting a potential for adverse electrophysiologic interactions. These findings indicate that amiodarone has pharmacokinetic and electrophysiologic interactions with procainamide and suggest that the intravenous dose of procainamide be reduced by 20% to 30% during concurrent drug administration.

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.

Recent investigations have clarified some of the effects of the autonomic nervous system on duration and spatial distribution of the Q-T interval in humans. The use of atrial pacing to fix heart rate or 24-hour continuous electrocardiographic recording to develop a regression formula for individual patients has provided a means to interpret the effects of an intervention that alters both the heart rate and the Q-T interval. Drugs that affect Ihe autonomic nervous system can influence Q-T interval directly or by changing rate. Bazett's formula to correct for rate may be misleading after certain drug interventions. For example, the Q-T interval during sinus rhythm or afrial pacing and the ventricular effective refractory period shorten after atropine plus propranolol, but corrected Q-T interval using Bazetf's formula does not change. No change occurs in the Q-T interval during sinus rhythm or atrial pacing, or in ventricular effective refractory period after administration of propranolol although corrected Q-T interval using Bazett's formula markedly shortens. Q-T interval during sinus rhythm and atrial pacing and ventricular effective refractory period decrease after atropine but correct Q-T interval lengthens. To define further the relationship of the autonomic nervous system on the duration of the Q-T interval we studied the effects of sleep. Fifteen patients receiving no drugs underwent 3–6 days of continuous electrocardiography recordings. The duration of the Q-T interval was longer during sleep in all 15 patients independent of heart rate change. This prolongation of the Q-T interval during sleep may reflect increased parasympathetic tone or decreased sympathetic tone on the ventricle. Further investigation of the relation of the autonomic nervous system to ventricular depolarization and repolarization may delineate some of Ihe trigger mechanisms for the development of lethal ventricular arrhythmias in humans.

A minicomputer-based data management system for the storage, retrieval, and analysis of cardiovascular clinical and basic research data is described and examples given of its potential utility in clinical arrhythmia research. The system links multiple data bases so that subsetting, statistical analyses and a variety of other data manipulations can be accomplished across data bases. Data additions or refinements can be made without restructuring an entire data base and new questions asked without the need for specific program revisions. The system is user-oriented. All aspects from data formulation through analysis can be accomplished by clinical investigators without computer or mathematical backgrounds.

Amiodarone, an investigational drug in the United States, has had considerable use in this country and worldwide in the treatment of cardiac arrhythmias. This article reviews the clinical pharmacology of this potentially useful antiarrhythmic agent.

Twenty-six patients had ventricular tachycardia initiated at control electrophysiologic study and had a repeat study during oral propafenone therapy. Ten patients had had sustained ventricular tachycardia, 6 cardiac arrest and 10 symptomatic, nonsustained ventricular tachycardia. Twenty-two patients had heart disease, 18 of whom had coronary artery disease. During propafenone therapy, ventricular tachycardia could not be initiated during programmed ventricular stimulation in 5 patients, and in 21 patients the cycle length of induced ventricular tachycardia increased from 246 +/- 42 ms at control to 355 +/- 96 ms (p less than 0.001). Seventeen patients were discharged with propafenone therapy and have been followed for a mean of 11 months. No symptomatic ventricular tachycardia recurred in the 5 patients without inducible ventricular tachycardia during drug treatment. Six of 12 patients with inducible ventricular tachycardia during the drug study have remained asymptomatic. In conclusion, propafenone substantially prolongs the cycle length of ventricular tachycardia, and initiation of ventricular tachycardia by programmed ventricular stimulation at drug study does not preclude a favorable clinical outcome.

We have endeavored to relate known electrophysiologic mechanisms of arrhythmia development to clinically occurring arrhythmias, realizing that definitive conclusions can only be surmised at present. Arrhythmias that may be due to disorders of impulse formation include slow atrial, junctional, and ventricular escape rhythms, certain types of atrial tachycardias (such as those produced by digitalis), accelerated junctional (nonparoxysmal junctional tachycardia) and idioventricular rhythms, and parasystole. Arrhythmias that may be due to disorders of impulse conduction include flutter and fibrillation, atrioventricular nodal reentrant tachycardia, reciprocating tachycardias associated with an accessory pathway, sinus nodal reentry, some atrial tachycardias, and many ventricular tachycardias. Understanding the mechanism of the tachycardia, in some instances, helps direct rational therapeutic approaches.

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 amiodarone's 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.

We examined the long-term effects of closed instrumental mitral commissurotomy on mitral valve area (MVA) in 18 patients, followed for as long as 14 years after successful operation. Each patient had preoperative and early postoperative cardiac catheterization; late postoperative determination of MVA was obtained 10-14 years (mean 12.2 years) after commissurotomy. In 17 patients, the MVA was determined by cross-sectional echocardiography and in one patient by repeat cardiac catheterization. Thirteen of 18 patients had no change in MVA between early postoperative study (mean MVA = 2.7 cm2) and late postoperative study (mean MVA = 2.9 CM2). MVA in five patients decreased 0.7-2.2 cm2 (mean 1.4 cm2) during the follow-up period. In these five patients, the mean MVA at early postoperative study was 2.7 cm2 and at late postoperative study was 1.3 cm2 (p less than 0.001). At late postoperative evaluation, cardiac symptoms were associated with severity of mitral stenosis but did not predict restenosis. A successful, closed, instrumental mitral commisurotomy can provide substantial long-term improvement in MVA.