Circadian Modulation of Ventricular Tachycardia Cycle Length Variability in ICD Patients with Dilated Cardiomyopathy

VT is usually characterized by stability of the RR intervals after a few cycles from the onset. The aim of this study was to evaluate the VT cycle length (VTCL) variability in patients with dilated cardiomyopathy (DCM), in whom a third-generation ICD was previously implanted. Eighty-three episodes of VT were analyzed in 10 patients (8 male, 2 female, 65 ± 6 years) with DCM, and NYHA Class II (7 patients) or III (3 patients). As an index of VTCL variability, the coefficient of variance of the last 15 consecutive RR intervals (CVRR) of the detected and stored VT by the device was considered. The mean value of the RR intervals and the mean value of CVRR of the VT episodes recorded during day versus night time were compared. Fifty-five VT episodes were recorded during the day and 28 episodes during the night time. The mean RR intervals of VT episodes during day time was 335 ± 29 ms and during the night time was 350 ± 22 ms (P = NS). The mean CVRR of VT episodes during day time and night time were 2.83 ± 0.52 and 3.36 ± 0.48, respectively (P = 0.017). In conclusion, a circadian modulation of VTCL variability exists in patients with DCM. The VTCL variability is less during day time compared to night time. A possible explanation is a circadian alteration of sympathovagal balance modifying the electrophysiological properties of the arrhythmogenic substrate.     

Efficacy and Safety of Combination Therapy with Amiodarone and Type I Agents for Treatment of Inducible Ventricular Tachycardia

In a prospective study the efficacy of amiodarone in combinalion with the three Class I drugs mexiletine, fiecainide, orencainide was evaluated consecutively in 12 patients with recurrent venlriculav tachycardias (VT) by programmed stimulation. None of the tested drug combinations suppressed induction of sustained VT. The combination of amiodarone with Class IC drugs fJecainide and encainide prolonged the cycle length of VT significantly, whereas the combination with mexiletine did not hove the same degree of slowing on the VT cycle length. Several proarrhythmic effects occurred during the combination therapy with encainide: (1) frequent, spontaneous recurrences of hemodynamically well tolerated VT in four patients; (2) enhanced inducihilily of VT in three patients; (3) impaired termination of VT in three patients. Though a marked increase in QRS and QTc intervals was observed by combined treatment with encainide, no significant correlation could be established between aggravation of arrhythmia and plasma levels of encainide, degree of QRS widening, JT or QTc prolongation. The only predictor for the occurrence of proarrhythmic events was found in left ventricular ejection fraction. These findings suggest that in patients refractory to amiodarone alone or a combination with mexiletine, the combined treatment of amiodarone with other Class IC drugs prolongs the VT cycle length but does not suppress induction of VT during programmed stimulation. Combination therapy of amiodarone with encainide was associated with a high incidence of proarrhythmic effects.     

Electrophysiological, Rate Dependent, and Autonomic Effects of the Class III Antiarrhythmic Almokalant After Myocardial Infarction in the Pig

Ventricular arrhythmias remain a major problem, in particular in patients with left ventricular dysfunction or heart failure. In this group of patients, Class I drugs were shown to be ineffective, and they even increased mortality during chronic treatment. New antiarrhythmic agents should preferably not only have pure antiarrhythmic effects, but should also be free from adverse autonomic properties. In the present study, the electrophysiological, rate dependent and autonomic effects of intravenously administered almokalant, a new Class III antiarrhythmic drug, were investigated in nine pigs surviving a myocardial infarction. The ventricular effective refractory period (VERP) increased after almokalant (loading dose: 0.05 μmoLkg ^?1 .min^?1, continuous infusion: 0.0025 uμmol/kg^?1.min^?1) from 292 ± 25 to 308 ± 13 ms (pacing cycle length [PCL] 500 ms + 1 extrasystole [ES]), from 249 ± 19 to 261 ± 16 ms (PCL 400 ms +1ES), and from 209 ± 18 to 219 ± 18ms (PCL 300 ms +1ES). The VERPs increased most after three ES at PCL 400 ms: from 167 ± 27 to 186 ± 29 ms (P < 0.05) and at PCL 300 ms: from 159 ± 29 to 174 ± 27 ms (P < 0.05). The ventricular monophasic action potential durations (MAPD) were similarly prolonged and the ratio VERP/MAPD did not change. Prolongation of MAPD after almokalant remained present at short pacing cycle lengths. Before almokalant infusion, sustained monomorphic ventricular tachycardia (VT) was inducible in two pigs, and nonsustained VT in a third animal. After almokalant, only one pig remained inducible. Two weeks after myocardial infarction, heart rate variability and baroreflex sensitivity were reduced. Furthermore, subsequent electrophysiological testing transiently reduced these parameters of autonomic activity. During almokalant however, no changes in autonomic functions were observed after programmed stimulation. Heart rate variability decreased after myocardial infarction from 6.3 ± 2.5 ms to 5.4 ± 4,2 ms (P = NS}. After programmed stimulation, it further decreased to 2.8 ± 2.0 ms (P = 0.028). Almokalant infusion prevented autonomic deterioration: 3.3 ± 2.2 ms before stimulation and 3.3 ± 1.3 after stimulation (P = NS). In postinfarct pigs, almokalant prolongs VERP and MAPD at shorter pacing cycle lengths. The results indicate absence of reverse rate dependence and of adverse autonomic changes.     

The Cardiac Vulnerable Period and Reentrant Arrhythmias: Targets of Anti- and Proarrhythmic Processes

Because sudden cardiac death is usually preceded by a reentrant arrhythmia, the precipitating arrhythmia must be multicellular in origin. Therefore clinicians seeking to reduce the incidence of reentrant arrhythmias in their patients with antiarrhythmic drugs that alter propagation may reasonably question the applicability of drug classification schemes (e.g. Sicilian Gambit) that are based on measurements in single cells. This raises a major question: are measures of a drug's anti-and proarrhythmic potential in single cells predictive of its anti- and proarrhythmic properties in tissue? The problem is as follows. From single cell measurements, one expects Class I drugs to reduce excitability, thereby attenuating the occurrence of PVCs. Similarly, one expects Class III drugs to prolong refractoriness and reduce the occurrence of PVCs. We have found in simple models of cardiac tissue that sodium channel blockade (the target of Class I drugs) extends the vulnerable period of a propagating excitation wave, whereas potassium channel blockade (the target of Class III drugs) destabilizes the reentrant path in a manner that amplifies the likelihood of polymorphic tachyarrhythmias. Using analytical, numerical, and experimental studies, we determined that sodium channel blockade was proarrhythmic. In fact, we found that any intervention that slowed conduction was proarrhythmic because slowed conduction increases the vulnerable period and reduces the spatial requirements for sustained reentry. We also found that when obstacles were placed in the path of a propagating wave, reentry occurred when the conduction velocity was less than a critical value. Once reentry was established, we observed that the ECG displayed monomorphic QRS complexes when the reentrant path did not vary from cycle to cycle. Moreover, when the reentiy path did vary from cycle to cycle, the ECG displayed polymorphic QRS complexes. The cycle-to-cycle variation in QRS morphology was caused by the spatial variability of the reentry path. The variability of reentry paths (and hence the degree of polymorphic variation in QRS complexes) was amplified by Class III agents. The results presented here show that multicellular proarrhythmic effects are derived from the same mechanisms that exhibit antiarrhythmic properties in single cells.     

Procainamide Induced Change of the Width of the Zone of Entrainment and its Relation to the Inducibility of Reentrant Ventricular Tachycardia

Procainamide depresses conduction velocity and prolongs refractoriness in myocardium responsible for reentrant VT, but the mechanism by which the induction of VT is suppressed after procainamide administration remains to be determined. In the present study, the relationship between electrophysiological parameters and the noninducibility of VT was assessed during procainamide therapy with a special reference to the change of an excitable gap. Clinically documented monomorphic sustained VT was induced in 30 patients and, utilizing the phenomenon of transient entrainment. the zone of entrainment was measured as the difference between the cycle length of VTand the longest paced cycle length interrupting VT (block cycle length) which was determined as the paced cycle length decreased in steps of 10 ms, and used as an index of the excitable gap. The effective refractory period was measured at the pacing site and the paced QBS duration was used as an index of the global conduction time in the ventricle. The cycle length of VT, the block cycle length, and the width of the zone of entrainment were determined and compared between the responders and nonresponders. In 15 patients, these parameters were determined at the intermediate dose and related to subsequent noninducibility at the final dose. At the final doses of procainamide, VT was suppressed in 8 (26.7%) of 30 patients. However, the cycle length of VT, the block cycle length, and the width of the zone of entrainment were unable to predict the drug efficacy, i.e., noninducibility. The change in the effective refractory period at the pacing site or the width of the paced QRS duration was not different between the responders and nonresponders. Among the variables, only the width of the zone of entrainment showed a significant narrowing in the responders at the intermediate dose of procainamide, and it was smaller than that of the nonresponders. The significant narrowing of the width of the zone of entrainment was associated with the subsequent noninducibility of VT at the final dose. The present study showed that the baseline cycle length of VT, the block cycle length, the drug induced change of the effective refractory period, or the paced QRS duration was not a predictor of the noninducibility after procainamide administration. However, a significant narrowing of the width of the zone of entrainment at the intermediate dose was associated with the noninducibility of VT at the final dose.     

Reduction of Antiarrhythmic Drug Use in Patients Receiving Implantable Cardioverter Defibrillators

Widespread use of implantable cardiovertfir defibrillators (ICDs) for the treatment of ventricular tachycardia (VT) and ventricular fibrillation (VF) occurred in the late 1980s and early 1990s. Additionally, there has been increasing appreciation during this time for both the lack of efficacy and praarrhythmic activity of antiarrhythmic drugs to treat these cardiac arrhythmias. We evaluated the use of antiarrhythmic drugs from 1987 to 1991 (5-year period) at the time of ICD implantation in 25,450 patients. The use of all classes of antiarrhythmic agents decreased from 61% to 24% during this time period (P < 0.05), In addition, there was a significant reduction in antiarrhythmic agent use for each drug class (P < 0.05) with the exception of Class II agents (beta blockers). These changes in drug use occurred independent of any changes in age, sex, ejection fraction, prevalence of coronary artery disease, or type of ventricular arrhythmia (VT vs VF).     

Underdetection of Ventricular Tachycardia Using a 40 ms Stability Criterion: Effect of Antiarrhythmic Therapy

Inappropriate shocks can complicate cardioverter defibrillator therapy. Among solutions proposed to avoid oversensing are algorithms to reduce inappropriate detection of atrial fibrillation (AF) or sinus tachycardia. In patients not on antiarrythmic drugs, an interval stability criterion of 40 ms has been validated with the Medtronic PCD to discriminate ventricular tachycardia (VT) from AF. With this algorithm, VT is considered stable if no interval varies from one of the three preceding in tervals by more than 40 ms. If an interval does not fulfill this criterion, the VT event counter is reset to zero. The aim of this study was to investigate the incidence of underdetection when this criterion is ap plied in patients treated with antiarrhythmic drugs. We studied 132 sustained monomorphic VTs induced in 42 patients during 101 electrophysiological studies (EPS). EPS were performed without treatment (group I. 24 patients, 44 VTs); on Class Ia drug (group II, 17 patients, 24 VTs); Class Ic drug (group III, 22 patients, 39 VTs); or sotalol (group IV, 17 patients, 25 VTs). The endocardial electrogram of all VT episodes was digitized and the stability algorithm was applied. The reset arrhythmias were distributed among no delay, small, moderate (<10 s) and important (>15 s) delay in VT detection. The relation be tween drug use and reset was analyzed. Beset was found in 86 (65%) of induced VTs. No difference in heart rate or induction mode was shown between reset and nonreset VTs. There was a significative asso ciation between drag use and reset probability (Chi² significantly different, P < 0.05). In patients treated with Class Ic drugs, the probability of finding an important delay in VT detection was 12.5% versus 0% in nontreated patients or in patients treated with sotalol. We conclude that a stability criterion of 40 ms is probably safe in nontreated patients but should be used with caution in patients treated with antiarrhythmics, especially in the presence of Class Ic drags.     

Long-term reproducibility of ventricular tachycardia induction with electrophysiological testing in patients with coronary heart disease and depressed left ventricular ejection fraction

The Multicenter Automatic Defibrillator Implantation Trial (MADIT) has recently confirmed the role of programmed ventricular stimulation (PVS) to identify the high risk patients of sudden death after myocardial infarction and to prevent this risk. The purpose of this study was to evaluate the long-term reproducibility of PVS in these patients. Thirty patients with coronary heart disease without spontaneous documented sustained ventricular tachycardia (VT) underwent two programmed stimulations in the absence of antiarrhythmic drug treatment between 2 and 6 years (mean 4 years). No patient had a myocardial infarction or intervening cardiac surgery during this period. The protocol of study was similar using up to three extrastimuli in two sites of the right ventricle, delivered in sinus rhythm and driven rhythm (600 ms, 400 ms, respectively). On the first PVS, 17 patients had inducible sustained VT (group I). Thirteen patients did not have inducible VT (group II). On the second PVS all group I patients but one had inducible VT, but the cycle length was significantly modified in 11. In group II, five patients had inducible VT and in the other patients the PVS remained negative. In conclusion, in patients with coronary heart disease, but without documented VT, the long-term reproducibility of PVS was excellent in those with inducible VT (94%); the patients remain at risk of VT and a prophylactic implantable cardioverter defibrillator could be considered. In patients with initially negative study, reproducibility of PVS was lower (61.5%), probably because of the progressive remodeling after myocardial infarction. Therefore, the occurrence of new symptoms in patients with previously negative study requires a second programmed ventricular stimulation.     

Programmable External Automatic Antitachycardia Pacing as a Bridge to Definitive Therapy in Patients with Recurrent Sustained Ventricular Tachycardia

The efficacy and safety of external programmable automatic antitachycardia pacemakers (ATPs) used in the critical care setting for recurrent sustained monomorphic ventricular tachycardia (VT) was evaluated. Ten patients who had failed a mean of 4.0 +/- 1.4 antiarrhythmic medications (range 2-7) and who had previously required electrical cardioversion for VT were enrolled. Prior to ATP use, successful overdrive pacing termination of VT was demonstrated in all patients. Intertach (Intermedics, Inc.; n = 9) and Orthocor II (Cordis, Inc.; n = 1) ATPs were attached to temporary bipolar transvenous or epicardial pacing leads. Mean patient age was 66.4 +/- 11.5 years, and mean left ventricular ejection fraction was 22 +/- 7.5%. At the time of initial ATP use, mean VT cycle length was 347 +/- 88 msec (range 280-550 msec). A burst scanning antitachycardia pacing algorithm was used in each patient; one patient was also treated with a fixed rate burst adapted to VT cycle length. The duration of ATP use ranged from 2-25 days (median 5), successfully terminating greater than 3,369 VT episodes (median 3, range 0 to greater than 3,103 episodes per-patient). Two episodes of ATP induced rate acceleration occurred, each successfully terminated by the ATP. Only two patients required external cardioversion during ATP use, one for primary ventricular fibrillation and one for rapid polymorphic VT associated with antiarrhythmic drug withdrawal. ATPs also provided antibradycardia pacing and allowed for serial programmed ventricular stimulation. No complications were associated with transvenous catheter or ATP use.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Role of Combination Therapy with Mexiletine and Procainamide in Patients with Inducible Sustained Ventricular Tachycardia Refractory to Intravenous Procainamide

This study evaluated the role of serial electropharmacological testing on combination therapy with mexiletine and procainamide in 20 patients with inducible sustained ventricular tachycardia (VT) refractory to intravenous procainamide. The clinical arrhythmias were cardiac arrest in five patients, sustained VT in 11 patients, and recurrent syncope of presumably arrhythmic origin in four patients. The mean left ventricular ejection fraction (LVEF) was 0.40 +/- 0.12 (mean +/- SD). All patients had inducible sustained VT at baseline and after administration of intravenous procainamide. All 20 patients underwent electropharmacological testing on combination therapy with mexiletine and procainamide. The mean cycle length of inducible sustained VT was 251 +/- 48 ms at baseline, 324 +/- 81 ms on intravenous procainamide (P less than 0.014 vs baseline), and 365 +/- 82 ms on combination therapy (P less than 0.0001 vs baseline, P = NS vs intravenous procainamide). Combination therapy did not suppress VT inducibility, nor did it make VT more difficult to induce in 19 of 20 patients. The remaining one patient had a partial response (runs of nonsustained VT, longest 10 seconds). Furthermore, combination therapy did not significantly prolong the VT cycle length over and above that observed during testing with intravenous procainamide. Therefore, in patients with inducible sustained VT refractory to procainamide during initial electropharmacological testing, mexiletine in combination with procainamide appears to be of little or no value and serial electropharmacological testing on these drugs is of limited usefulness. Early initiation of alternative therapy may be the preferred clinical option.     

Efficacy and Safety of Low Doses of Beta-Blocker Agents Combined with Amiodarone in Refractory Ventricular Tachycardia

Twenty patients aged 55 ± 16 years with 40 chronic ventricular tachycardias (VT) refractory to 4.6 ± 1.9 antiarrhythmic drugs, used alone or in combination, were managed by low doses of beta-blocker agents combined with oral amiodarone (Am), either after loading (1.2 g for 7 days, n: 5) or reloading (1.2 g for 4 days, n: 15) of Am. All patients proved refractory to Am alone. Seven VT were also refractory to endocardial catheter fulguration in six patients. Thirteen patients had coronary artery disease, three had arrhythmogenic right ventricular dysplasia, two had dilated cardiomyopathy, one had valvular disease, and one had no structural heart disease. Ten patients had an EF <30%. Ten patients were in NYHA functional class three. VT was permanent in three patients, daily in three, weekly in seven, paroxysmal in seven. In 11 patients, VT occurred both at day and night. In 11 patients, decrease of the sinus cycle preceeded VT. Oral administration of a daily low dose of a beta blocker agent (acebutolol 100 mg, betaxolol 5–10 mg, metoprolol 50 mg, nadolol 20–40 mg, pindolol 2.5 mg, propanolol 30 mg, sotalol 80–160 mg, terta-tolol 2.5 mg) combined with 400 mg/day of Am suppressed VT episodes in all patients. None presented heart failure or collapse. The mean reduction of the heart rate was 15% (65 to 55/min). At discharge, exercise ECG (n: 14) induced non sustained VT in two patients. At programmed electrical stimulation (PES) (n: 15), VT was no longer inducible in 4 patients, was slower, well-tolerated in nine patients, and remained inducible at the same rate in only two patients. Chronic treatment prevents recurrence of VT in 19 patients during a follow-up of 14 ± 9 months (range 2 to 33). Conclusions: (1) beta blockers agents and Am have strong synergistic effects; (2) antiarrhythmic treatment with low doses of beta blockers could be managed by PES; (3) at the doses used in (his study, all beta blockers presented the same safety; (4) combination of low doses of beta blockers agents with chronic Am therapy inhibit VT.     

Value of Serial Electropharmacological Testing in Managing Patients Resuscitated from Cardiac Arrest

Electrophysiologic studies were performed in 11 patients (9 men, 2 women; mean age: 59.9 yrs) who had survived an episode of cardiac arrest due to ventricular tachycardia (VT) or ventricular fibrillation. The purpose of the studies was to evaluate the usefulness of serial acute drug testing in selecting an effective chronic antiarrhythmic regimen. Ten of the patients were suffering from chronic ischemic heart disease with one or more previous myocardial infarctions while one had no evidence of structural heart disease. A ventricular aneurysm was present in four of them. During control electrophysiologic study, a sustained VT was induced by ventricular stimulation (single and double extrastimuli at various paced ventricular cycle lengths plus bursts of rapid ventricular pacing) in nine of the ten patients (90%) who were studied while not receiving antiarrhythmic drugs; a non-sustained VT was induced in one of them (10%). In three patients (30%) VT could be initiated only by right ventricular stimulation at a side different from the apex (outflow tract). No arrhythmia was observed in the only patient who was studied while taking amiodarone orally (400 mg/day for more than three months). During serial acute drug testing a totally effective drug regimen (successful in preventing the induction of any ventricular arrhythmia) was found in seven of the ten patients (70%) who underwent this procedure and a partially effective drug regimen (a sustained VT was no longer inducible; it was easier to interrupt and it was considerably slower) was found in two patients (20%). None of the nine patients who received chronic antiarrhythmic therapy based on the results of serial acute drug testing died suddenly during a mean follow-up of 14 months (range: 3-28) and only one had a recurrence of cardiac arrest. The latter, however, was taking antiarrhythmic drugs at a dosage less than that proved to be effective during electropharmacological testing. The only patient who refused serial acute drug testing and received an empiric antiarrhythmic therapy died suddenly at the 21st month of follow-up. These results indicate that serial electropharmacological testing is useful in selecting an effective long-term drug regimen in survivors of cardiac arrest.     

The Effects of Type I Antiarrhythmic Drugs on the Signal-Averaged Electrocardiogram in Patients with Malignant Ventricular Arrhythmias

The effects of type I antiarrhythmic drugs on the signal-averaged electrocardiogram (SAECG) were analyzed in 58 patients with inducible sustained monomorphic ventricular tachycardia. SAECGs were acquired before and after drug therapy. A total of 99 drug trials were analyzed (mean 1.7 per patient). Analysis of temporal domain parameters included the duration of the QRS complex (QHSD), the high frequency total duration of the filtered QRS complex (HFTD), the duration of the signal under 40 μV (D40), initial QRS (HFTD minus D40), and the root mean square amplitude (RMSA)of the terminal 40 msec of the QRS signal. Changes in temporal parameters failed to predict drug efficacy. There were, however, type-specific drug effects on the SAECG. With the exception of type IB drugs, all drugs increased the QRSD, HFTD, and D40. Type IC drugs caused more prolongation of the QRSD and HFTD than type IA, IB, and the combination of IA + IB drugs. Prolongation of the HFTD was related to prolongation of the late potential and the initial portion of the QRS complex. A preferential effect of these drugs on the late potential was not observed. Type IC drugs also caused more prolongation of ventricular tachycardia cycle length than type IA or IB drugs. However, the increase in ventricular tachycardia cycle length did not correlate with a change in the SAECG. In summary, type I antiarrhythmic drugs cause a global slowing of ventricular activation. Although analysis of the SAECG following drug therapy was not useful for predicting drug efficacy, drug induced changes in the SAECG may be helpful for categorizing antiarrhythmic agents.     

Ventricular refractory periods in relation to rate and test-site VT intervals in anesthetized and conscious dogs: a canine model for conscious state measurements

The functional relationship of ventricular effective refractory period (ERP) with basic cycle length (BCL) of stimulated ventricular depolarization and VT intervals of test-site unipolar ventricular electrograms were studied in five conscious and eight anesthetized (sodium pentobarbital, 30 mg/kg) open-chested dogs. The range of BCLs studied was 300 to 1000 ms, achieved through ventricular stimulation following chemically-induced complete AV block. In the conscious animal model developed for this study, two-to-four ventricular electrode leads were exteriorized and the ventricular rate was maintained by an implanted programmable VVI pacemaker. In all animals studied, the BCL-ERP relation was closely represented by the empirical equation ERP = A-B.Exp(-k.BCL), and the VT-ERP relation over the same range of BCLs was linear: ERP = C + D.VT. The correlation coefficients were in the range of 0.991 to 0.999. The mean values of the parameters in the above equations determined by the appropriate non-linear or linear regression analysis showed significant differences between the two groups of animals studied. In three conscious animals a strong linear correlation between the test-site VT intervals and simultaneously measured QT intervals measured from the lead II surface electrogram was demonstrated (r = 0.993 to 0.998). For a fixed site of stimulation, the morphology of ventricular depolarization complexes as well as the corresponding T-waves remained essentially unaltered with BCL for both myocardial and surface electrograms. The possible applications of developed canine model and the results of the present study include: (1) the study of the rate-dependent effects of cardioactive drugs on ventricular electrophysiology and, (2) the improved design of electronic refractory periods of rate programmable pacemakers.     

Cardioversion, Defibrillation, and Overdrive Pacing of Ventricular Arrhythmias: The Effect of Moricizine in Dogs with Sustained Monomorphic Ventricular Tachycardia

The purpose of this investigation is to define whether the antiarrhythmic drug moricizine has beneficial or adverse effects on currently used antitachycardia and antifibrillatory devices. These studies were performed in a dog model of sustained monomorphic ventricular tachycardia (VT). In 11 dogs, the left anterior descending artery and all surrounding epicardial collateral feeder vessels were ligated. Defibrillator patches were implanted and the dogs were allowed to recover. After a 7-day recovery period, effective refractory period (ERP), end diastolic threshold (EDT), VT induction, and VT and ventricular fibrillation (VF) termination data were collected before and after moricizine infusion (2 mg/kg). In this experimental model, moricizine caused the folIowing electrophysiological changes: a prolongation of the ERP from 173 ± 14 to 182 ± 15 fP < 0.02) with no significant effect on the EDT for pacing; a prolongation of the VT cycle length from 175 ± 18 to 201 ± 23 msec (P < 0.003); an increased cycle length required for overdrive pacing from 136 ± 20 to 157 ± 22 msec (P < 0.01); no effect on the energy required to cardiovert VT; an increase in the defibrillation threshold from 7.5 ±4 to 9.4 ± 4 joules (P < 0.006) and; in 5 of the 8 dogs with VT, theVT could be initiated with somewhat less aggressive stimulation. Significant beneficial electrophysiological effects were noted on theVT cycle length, including a proportionately prolonged overdrive pacing cycle length for VT termination. These changes were contrasted by the significant increase in the VF conversion energy required and the ease with which the VT could be induced postmoricizine. These findings suggest a possible proarrhythmic effect of moricizine.     

Initiating Sequences in Exercise Induced Idiopathic Ventricular Tachycardia of Left Bundle Branch-Like Morphology

Initiating Sequences in Exercise Induced Idiopathic Ventricular Tachycardia of Left Bundle Branch-Like Morphology. Initiating sequences for VT may infer the underlying arrhythmogenic mechanisms. This study examines the initiating sequences of exercise induced idiopathic VT of left bundle branch block-like (LBBB-like) morphology and makes an attempt to relate these to clinical aspects and the mechanisms of arrhythmia. Thirty-two patients (mean age 33.4 ± 13.2 years; 18 men) with exercise induced VT in the absence of structural cardiac abnormality on history, clinical examination, and noninvasive and invasive investigations were divided into two groups on the basis of the initiating sequence of VT on exercise. Group I consisted of patients with long-short sequence of RR intervals prior to the onset of VT (initiating/preinitiating cycle length ratio < 0.78). Group II consisted of patients without changes in cycle length prior to VT. Group I mechanism would suggest delayed afterdepolarizations (DADs) or reentry whereas group II mechanism triggered activity due to early afterdepolarizations. Fourteen patients (group I) had long-short sequence and 18 patients (group II) were without cycle length changes prior to VT initiated during exercise. VT axis was inferior in all 18 patients in group II but only in 9 patients in group I (P = 0.02). In these predefined patient groups, sustained monomorphic VT could not be initiated by programmed stimulation in any patient in group I, whereas four patients in group II had inducible VT. Patients in group II also had higher incidence of sustained VT on ambulatory monitoring (P < 0.05). The two groups did not differ in other respects. This study demonstrates the existence of at least two possible mechanisms of initiation of exercise induced idiopathic VT of LBBB-like morphology. VT initiated without cycle length changes is more common, more likely to have an inferior axis suggesting an outflow tract origin, and is probably related to triggered activity secondary to DADs. VT initiated with a long-short sequence is more often nonsustained and may have a superior axis suggesting an origin from the body or septal region of the ventricle. The two groups, therefore, exhibit differences in electrophysiological characteristics that may aid classification and therapy of this arrhythmia.     

Ventricular Refractory Periods in Relation to Rate and Test-Site VT Intervals in Anesthetized and Conscious Dogs: A Canine Model for Conscious State Measurements

The functional relationship of ventricular effective refractory period (ERP) with basic cycle length (BCL) of stimulated ventricular depolarization and VT intervals of test-site unipolar ventricular eJectrograms were studied in five conscious and eight anesthetized (sodium pentobarbital, 30 mg/kg) open-chested dogs. The range of BCLs studied was 300 to 1000 ms, achieved through ventricular stimulation following chemically-induced complete A V block. In the conscious animal model developed for this study, two-to-four ventricular electrode Jeads were exteriorized and the ventricular rate was maintained by an implanted programmeble VVI pacemaker. In all animals studied, the BCL-ERP relation was closely represented by the empirical equation ERP = A-B.Exp(-k.BCL), and the VT-ERP relation over the same range of BCLs was linear: ERP = C+D. VT. The correlation coefficients were in the range of 0.991 to 0.999. The mean values of the parameters in the above equations determined by the appropriate non-linear or linear regression analysis showed significant differences between the two groups of animals studied. In three conscious animals a strong linear correlation between the test-site VT intervals and simultaneously measured QT intervals measured from the lead II surface electrogram was demonstrated (r = 0.993 to 0.998). For a fixed site of stimulation, the morphology of ventricular depolarization complexes as well as the corresponding T-waves remained essentially unaltered with BCL for both myocardial and surface eJectrograms. The possible applications of developed canine model and the results of the present study include: (1) the study of the rate-dependent effects of cardioactive drugs on ventricular electrophysiology and, (2) the improved design of electronic refractory periods of rate programmable pacemakers.     

Mechanisms of antiarrhythmic drug action on termination of atrial flutter

Atrial flutter is an important arrhythmia in clinical practice. Although the reentrant circuit of human typical atrial flutter is well characterized, the action of antiarrhythmic drugs on this tachycardia is less understood. Based on the recent clinical trials, pure Class III drugs like ibutilide or dofetilide are more effective in acute termination of human atrial flutter than Class I drugs like procainamide or flecainide. The mechanisms of drug induced termination of atrial flutter include refractory block due to cycle length oscillation, fixed block due to a reduced safety factor for conduction, or a collision of opposing wavefronts due to loss of the lateral boundaries or return reexcitation. Because ventricular proarrhythmia is a major concern with ibutilide or dofetilide therapy, development of new drugs with more specific target profiles is a future direction for treatment of human atrial flutter.     

Therapy Assessment for Sustained Ventricular Tachyarrhythmias: How Many Electropharmacological Tests are Appropriate?

Surgery, implantable devices or catheter ablations offer therapeutic choices for the treatment of malignant ventricular tachyarrhythmias (VT) resistant to antiarrhythmic drugs. The number of electropharmacological (EP) tests that should precede consideration of a nonpharmacological therapy has not been defined. We performed serial EP tests in 94 patients with inducible sustained VT until an effective drug was identified or all available drugs had failed to suppress VT induction. With up to 11 tests in individual patients, suppression of VT inducibility was finally achieved in 66 patients (70%). In 47 of these 66 patients (70%), only one or two tests were necessary to identify an effective regimen. However, in 40%, 28%, 18%, and 9% of the patients still inducible after 2, 3, 4, and 5 drug tests, respectively, an effective agent could be identified during subsequent tests. No critical number of unsuccessful EP tests clearly separated responders and nonresponders to medical therapy. During follow-up (34 +/- 11 months), 14 patients placed on antiarrhythmic drugs predicted to be effective had symptomatic VT recurrence. VT recurrence was unrelated to the type or the number of unsuccessful EP tests preceding identification of the prescribed drug. Extensive EP testing with all available agents might therefore be worthwhile in selected patients. An "appropriate" number of EP studies has to be determined individually for each patient, based on the chance of finding an effective drug during subsequent studies and the risk and benefit of the therapeutic choices.     

Classification and mechanism of action of antiarrhythmic drugs*

Summary— The present paper reviews classification and mode of action of agents that suppress extrasystoles and tachyarrhythmias. These are classified according to their electrophysiological effects observed in isolated cardiac tissues in vitro (Vaughan Williams, 1989). Fast sodium channel blockers (class I) which reduce the upstroke velocity of the action potential are usually subclassified into three groups, class I A-C, according to their effect on the action potential duration. Beta-adrenergic antagonists (class II) exert their effects by antagonizing the electrophysiological effects of beta-adrenergic catecholamines. Class III antiarrhythmic agents (eg amiodarone) prolong the action potential and slow calcium channel blockers (class IV) suppress the calcium inward current and calcium-dependent action potentials. The classification of antiarrhythmic drugs is still under debate. This particularly applies to agents of class I and III. The effect of class I agents is frequency-dependent because the binding affinity of these drugs to the sodium channel is modulated by the state of the channel (modulated receptor hypothesis). Class I agents bind to the channel in the activated and inactivated state and dissociate from the channel in the rested state. This occurs at a drug-specific rate so that class I agents can be subclassified into only two groups, namely in those of the slow- and fast-recovery type respectively (time constant of reactivation greater or smaller than 1 s). Slow-recovery class I agents affect regular action potentials at normal heart rates which can more easily lead to a lengthening of the QRS duration in the ECG, to conduction disturbances and hence to pro-arrhythmic effects. Class I antiarrhythmic agents have also been subclassified according to the saturation behaviour of frequency-dependent sodium channel blockade (Weirich and Antoni, 1990), but the relevance of this subclassification remains to be elucidated. This applies also to a recent attempt (Hondeghem) to subclassify class III agents according to the frequency dependency of their antiarrhythmic actions.