Author + information
- Received January 31, 1996
- Revision received July 24, 1996
- Accepted September 17, 1996
- Published online January 1, 1997.
- ↵*Dr. Paul Dorian, Division of Cardiology, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8.
Objectives. We sought to determine the electrophysiologic mechanisms explaining the efficacy of combination therapy with dl-sotalol and a type Ia drug in the treatment of ventricular tachycardia (VT).
Background. Combination antiarrhythmic drug therapy with low dose dl-sotalol plus a type Ia antiarrhythmic agent has been shown to prevent spontaneous and induced VT. The mechanisms underlying the efficacy of this drug combination have not been fully elucidated.
Methods. We studied 32 patients with spontaneous sustained VT by using programmed electrical stimulation in the drug-free condition and after treatment with dl-sotalol (average dose [mean ± SE] 151 ± 8 mg/day) and a class Ia agent (quinidine, 1,337 ± 59 mg/day, or procainamide, 2,083 ± 327 mg/day). Sustained VT was induced in all patients at baseline study, and induction was reattempted during drug therapy. Monophasic action potential duration at 90% repolarization (APD90) and ventricular effective refractory period (ERP) were recorded with use of a contact electrode.
Results. Ventricular ERP increased from 258 ± 4 ms at baseline to 310 ± 6 ms at a 600-ms drive cycle length (DCL600) with treatment (p < 0.001). APD90increased from 288 ± 6 ms by +10.1% at DCL600 and from 267 ± 7 ms by +13.3% at a 400-ms drive cycle length (DCL400) (p < 0.001). Paced QRS duration increased from 141 ± 3 to 158 ± 6 ms at DCL400 (p < 0.05).
At baseline, the shortest achieved coupling interval between successive propagated extrastimuli decreased progressively with respect to the first extrastimulus, following double and triple extrastimuli, at both DCL600 (−14.0% and −20.0%, respectively) and at DCL400 (−16.4% and −22.4%, respectively). This “peeling back” of refractoriness was attenuated on therapy with sotalol plus a class Ia antiarrhythmic agent to −6.7% and −10.5% (DCL600, p < 0.05), and −8.1%, −9.5% (DCL400, p < 0.05), for double and triple extrastimuli, respectively. The absolute prolongation of functional refractory periods by the drug combination increased with successive extrastimuli, from 55 ± 6 ms for the V1V2interval to 75 ± 6 ms for V2V3and 67 ± 6 ms for V3V4at DCL600, and from 51 ± 5 ms for V1V2to 69 ± 6 ms for V2V3and 74 ± 7 ms for V3V4at DCL400 (p < 0.001).
Conclusions. The combination of low dose sotalol and a class Ia agent greatly prolongs refractoriness. The magnitude of the effect increases at shorter coupling intervals.
(J Am Coll Cardiol 1997;29:100–5)>
Electropharmacologic studies of ventricular tachycardia have demonstrated the importance of lengthening of repolarization and prolongation of refractoriness in predicting a favorable response to drug therapy ([1, 2]). Drugs that prolong cardiac refractoriness such as sotalol or amiodarone appear to be superior to sodium channel blocking agents, which primarily slow cardiac conduction, in preventing recurrent ventricular tachycardia (VT) or sudden death ([3, 4]). However, prolongation of action potential duration (class III effect) is often characterized by a progressive loss of effect at higher stimulation rates, otherwise known as “reverse use dependence” ().
A drug or combination of drugs that prolong ventricular refractoriness, and whose effects are preserved at high cardiac frequencies, would be expected to be clinically useful in preventing induced and spontaneous VT (). Amiodarone may have some of these properties (), which may be the result of combined sodium channel blocking and action potential prolongation (). Combination antiarrhythmic therapy with low dose dl-sotalol and a type Ia antiarrhythmic agent is highly effective in preventing or modifying inducible VT at electrophysiologic study and in preventing recurrences of spontaneous VT (). The aim of the present study was to elucidate the electrophysiologic mechanisms underlying the efficacy of this drug combination.
We hypothesized that moderate doses of these antiarrhythmic agents would minimize the incidence of adverse effects while maintaining a beneficial effect on ventricular refractoriness. Furthermore, we postulated that the drug combination would attenuate the reverse use dependent effect on refractoriness after successive extrastimuli expected with “pure” class III activity. This study examines the effect of dl-sotalol and quinidine or procainamide on simultaneous measures of ventricular refractoriness and monophasic action potential (MAP) duration in response to extrastimuli in patients undergoing electrophysiologic study.
1.1 Study patients.
Patients were referred to the cardiac electrophysiology service for evaluation and treatment of documented or suspected sustained VT or ventricular fibrillation (VF). Thirty-two patients underwent baseline electrophysiologic study in the absence of antiarrhythmic medications (discontinuation of all antiarrhythmic drugs for ≥5 half-lives) and were found to have inducible sustained monomorphic VT at baseline study. No patient had received amiodarone in the previous 6 months. All patients had been treated with at least one antiarrhythmic drug that failed to suppress inducible sustained VT.
1.2 Electrophysiologic testing.
Programmed electrical stimulation was performed with the patient in the fasting sedated state with use of a constant current stimulator (Medtronic Inc.) applying rectangular pulses of 2-ms duration at twice diastolic threshold. Induction of VT was attempted with single, double and triple ventricular extrastimuli delivered to the right ventricular apex and decrementing in 10-ms steps to ventricular refractoriness or 200 ms. Coupling intervals were not decremented beyond 200 ms to avoid inducing polymorphic VT or VF. Further extrastimulation was not attempted if VT or VF was induced with single or double extrastimuli. Decremental extrastimuli were delivered after eight-beat trains of ventricular pacing with 3-s intertrain pauses.
The ventricular effective refractory period (ERP) was measured by the decremental extrastimulus technique at cycle lengths of 600 and 400 ms (DCL600 and DCL400, respectively) in the drug-free condition and during treatment with S + Ia. The ventricular ERP was the longest S1S2interval at which S2failed to capture. Monophasic action potentials were measured by a quadripolar contact monophasic action potential recording electrode (EPT Technologies Inc.), allowing for recording of action potential signals that are determined from the same population of myocardial cells for which refractory period measurements were made ([8, 9]). Action potential duration (APD) at 90% repolarization (APD90) was measured as previously reported (). To determine the shortest coupling intervals for triple extrastimulation, stimulus to stimulus intervals were decremented in 10-ms steps for the first, second and third extrastimuli until noncapture resulted for each. The shortest coupling intervals for each of S2, S3, and S4achieving ventricular capture were designated the “shortest coupling interval.”
1.3 Combination drug therapy.
Sotalol and either quinidine or procainamide were administered orally, and repeat electrophysiologic study was conducted ≥72 h after the initiation of combination drug therapy. Patients were treated with 80 or 160 mg of sotalol twice daily with the dose adjusted downward if dose-related adverse effects appeared before repeat electrophysiologic study. Quinidine (as quinidine bisulfate) was administered in doses of 500 mg two or three times daily. Procainamide (slow release formulation) was given as 500 to 1,500 mg every 6 h.
We used the following definitions: Spontaneous or induced sustained VT was monoform VT lasting >30 s or causing syncope or hemodynamic deterioration requiring immediate termination of the arrhythmia. Inducible VT was ≥15 repetitive ventricular responses after programmed stimulation. Modified VT inducibility was induced VT meeting all of the following prospectively defined criteria as previously defined (): 1) induced VT cycle length ≥50 ms longer than the baseline induced VT cycle length; 2) pacing termination of induced VT was possible; and 3) the induced VT was well tolerated with mild or no symptoms and no presyncope or loss of consciousness. Although intraarterial blood pressure was measured for all patients, no specific blood pressure cutoff point was included in the definition. Patients whose VT was rendered noninducible (≤15 repetitive ventricular responses) by the combination drug therapy or whose inducible VT was modified were eligible for long-term treatment on this regimen. Patients whose arrhythmia did not meet either of these criteria (unmodified VT) were treated with other regimens.
S1, S2, S3and S4represent stimulus artifacts of the last beat of the ventricular drive train and of the first, second and third extrastimulus, respectively. Corresponding ventricular electrograms resulting from these stimuli are designated V1, V2, V3and V4. Ventricular functional refractory period (FRP) was measured as the shortest interval from onset of the upstroke of the MAP to onset of the immediately following MAP upstroke, where both stimuli in the sequence resulted in ventricular depolarization. Shortest intervals between successive MAP upstrokes for S1S2, S2S3and S3S4are designated as FRP, FRP3and FRP4, respectively. The QRS duration of the last complex of the eight-beat ventricular drive train at cycle lengths of 600 and 400 ms was measured from surface lead V1at 100-mm/s paper speed and was used as a measure of ventricular conduction.
1.5 Statistical analysis.
Continuous variables were compared using the Student ttest or two-way analysis of variance for repeated measures where appropriate; p values < 0.05 were considered significant. The Duncan multiple range test was used for multiple comparisons. All data are expressed as mean value ± SE unless otherwise indicated.
2.1 Study patients.
There were 28 men and 4 women with a mean age ± SD of 63 ± 11 years. Most patients (97%) had coronary artery disease, and one patient had idiopathic VT, with a mean ± SD ejection fraction of 29 ± 11%. The largest group of patients (47%) presented with sustained VT without syncope; the others had VF (25%) or sustained VT with syncope (28%). All patients had inducible sustained VT at baseline study. There were no documented instances of torsade de pointes in the study group over ≥2 years of follow-up. Of the 32 patients, 26 were studied while taking sotalol plus quinidine and 6 while taking sotalol plus procainamide. The average drug dosages were as follows: sotalol, 151 ± 8 mg/day; quinidine, 1,337 ± 59 mg/day; and procainamide 2,083 ± 327 mg/day.
2.2 Ventricular ERP.
Baseline ventricular ERP was 258 ± 4 ms and increased significantly to 310 ± 6 ms (+20.2%) during therapy at DCL600 (p < 0.001). At DCL400, ventricular ERP also increased significantly from 242 ± 4 to 292 ± 5 ms (+20.7%) (p < 0.001). With successive extrastimulus delivery, there was a significant progressive decline in the shortest coupling intervals (i.e., S3S4vs. S2S3; S2S3vs. S1S2) (p < 0.01, p < 0.05 for DCL400 and DCL600, respectively) (Table 1). The study was discontinued without progressing further to double or triple extrastimuli if sustained VT was induced with single or double extrastimuli, respectively. Thus, fewer patients received triple extrastimuli: nine patients at DCL600 (control) and eight patients at DCL400. With therapy, it became more difficult to induce VT, and more patients received triple extrastimuli: 17 patients at DCL600 and 14 patients at DCL400.
2.3 Ventricular FRP.
Ventricular FRP during treatment with sotalol plus a type Ia antiarrhythmic agent was significantly prolonged at both DCL600 and DCL400, from 291 ± 3 ms (control) to 334 ± 6 ms at DCL600 (+14.9% vs. control, p < 0.001) and from 273 ± 3 ms (control) to 315 ± 4 ms at DCL400 (+15.7% vs. control, p < 0.001) (Fig. 1). There was a significant progressive decline in shortest MAP upstroke to subsequent MAP upstroke interval with successive extrastimuli (i.e., FRP4<FRP3<ventricular FRP) in the control state (representing “peeling back” of refractoriness) at both DCL600 and DCL400 (p < 0.0001). Compared with the shortest V1V2interval during single extrastimulus delivery (i.e., ventricular FRP), the shortest V2V3interval (FRP3) and shortest V3V4interval (FRP4) in the control state decreased by −14.0% and −20.0%, respectively, at DCL600. Similarly, at DCL400, the shortest MAP to MAP interval decreased with successive extrastimuli by −16.4% (FRP3) and −22.4% (FRP4) (Fig. 1).
During drug therapy with sotalol and a type Ia agent, this shortening of refractoriness was attenuated significantly (p < 0.0001 for drug effect). The percent decline relative to ventricular FRP was significantly reduced for the shortest V2V3interval (or FRP3) and the shortest V3V4interval (or FRP4) at both DCL600 and DCL400 (p < 0.01). There was a significant drug by number of extrastimuli interaction (p < 0.002); that is, the slope of FRP versus the number of extrastimuli was significantly less steep after drug therapy than at baseline (Fig. 1). FRP3and FRP4shortened only by −6.6% (334 ± 6 to 312 ± 9) and −10.5% (334 ± 6 to 299 ± 8), respectively, at DCL600 and by −8.0% (315 ± 4 to 290 ± 6) and −9.5% (315 ± 4 to 285 ± 8) respectively at DCL400.
The absolute prolongation of refractoriness with respect to baseline control, representing drug effect, increased with successive extrastimuli (Fig. 2). Increasing number of extrastimuli resulted in more absolute prolongation of FRP, with an increase in drug effect from 55 ± 6 ms at V1V2, to 75 ± 6 ms at V2V3(p < 0.001 vs. V1V2) and to 67 ± 6 ms at V3V4(p < 0.001 vs. V1V2), respectively, at DCL600. At DCL400, the corresponding values were 51 ± 5 ms (V1V2), 69 ± 6 ms (V2V3; p < 0.001 vs. V1V2) and 74 ± 7 ms (V3V4; p < 0.001 vs. V1V2).
2.4 APD and ERP/APD90ratio.
APD90prolonged significantly during therapy with sotalol and a type Ia agent as compared with control values at both cycle lengths. APD90increased from 288 ± 6 to 318 ± 4 ms at DCL600 ms (+10.1% vs. control, p < 0.001). At DCL400, APD90increased from 267 ± 7 to 303 ± 5 ms (+13.3% vs. control, p < 0.001). Control APD90decreased by −7.5% from DCL600 to DCL400. The drug combination attenuated this decrease in APD90to −4.8% (p < 0.05).
The ERP/APD90ratio in the control state at DCL600 was 0.89 ± 0.01. This increased to 0.98 ± 0.02 during therapy with sotalol plus a type Ia agent at DCL600 (p < 0.05). The ERP/APD90ratio at DCL400 also increased, from 0.91 ± 0.01 to 0.97 ± 0.01 (p < 0.05). The VERP/APD ratios for patients receiving therapy did not change with repetitive extrastimuli. Thus, with the combination therapy, ERP/APD ratios for S2S3and S3S4were 0.90 ± 0.02 and 0.90 ± 0.02 (at DCL600) and 0.98 ± 0.03 and 0.98 ± 0.03 (at DCL400), respectively. ERP/APD ratios for control patients were not analyzed because of the small numbers of patient studies available for comparison.
2.5 QRS duration.
QRS duration at DCL600 at baseline was 134 ± 5 ms. There was no significant increase in QRS duration at DCL400, which was 141 ± 3 ms (p = NS vs. DCL600). During therapy with sotalol and either procainamide or quinidine, there was a slight conduction delay: QRS duration increased from 134 ± 5 to 151 ± 5 ms at DCL600, representing an increase of +12.7% (p < 0.05). At DCL400, QRS duration increased by +11.9%, from 141 ± 3 to 158 ± 6 ms (p < 0.05).
2.6 Clinical outcome.
Among 32 patients who underwent a trial of sotalol plus a type Ia agent, VT was rendered noninducible in 15 and was modified in 12; these 27 patients were discharged receiving sotalol plus a type Ia agent. The remaining five patients received other drug therapy. Fourteen of the 27 patients continued to receive the drug without interruption throughout the follow-up period (2 years). The other 13 discontinued therapy because of side effects (9 patients) or recurrence of arrhythmia (4 patients) and underwent other treatment: implantable cardioverter-defibrillator implantation (6 patients), VT surgery (1 patient) or another drug regimen (6 patients). One patient, with recurrent arrhythmia, was resuscitated from cardiac arrest during therapy with sotalol and quinidine; he underwent VT surgery and subsequently died suddenly while being treated with amiodarone.
The main findings of this study are that combination therapy with dl-sotalol and a type Ia drug prolongs the ERP and APD and that the magnitude of this effect increases with repetitive extrastimulation. The ERP/APD ratio was prolonged and unaffected by repetitive extrastimuli. We () have previously shown that this drug combination prevents recurrence of arrhythmia in patients with modified or noninducible tachycardia and thus has clinical benefit.
Prolongation of ventricular refractoriness is beneficial in suppression of VT, with an increase in right ventricular ERP being correlated with antiarrhythmic efficacy (). Multicenter randomized trials ([3, 11]) have shown sotalol to be more effective than type I agents alone in suppressing VT and this may be a result of refractoriness prolongation without conduction delay. Furukawa et al. () demonstrated that more prolongation of refractoriness and relatively less slowing of intraventricular conduction was useful in preventing VT. Subsequent studies ([13, 14]) have confirmed that ventricular ERP prolongation with either quinidine or procainamide is a predictor of drug efficacy. Our study confirms in vitro findings () that the drug combination results in additive prolongation of repolarization and refractoriness with minimal slowing of conduction.
Prolongation of refractoriness results from prolongation of the APD and postrepolarization refractoriness. Sotalol increases refractoriness without affecting conduction (). Low doses (160 to 320 mg/day) of sotalol prolong repolarization (), but the effect of sotalol alone on ERP at the doses used in this study is modest (). The beta-blocking actions of dl-sotalol probably contribute to its clinical efficacy because d-sotalol, which is devoid of beta-blocking action, increases mortality in patients with left ventricular dysfunction after myocardial infarction ().
Agents with class Ia action also prolong refractoriness, in part by a direct effect on prolongation of APD by the parent drug or its metabolites and in part by causing postrepolarization refractoriness. Quinidine and procainamide exhibit a class III effect by inhibiting Ik(delayed outward rectifier potassium current) in a time- and voltage-dependent manner thus prolonging APD ([20, 21]). Quinidine also blocks multiple potassium currents other than Ikin vitro, including Itoand Ik1(). These class III effects are more marked at long cycle lengths whereas sodium channel blockade (depression of maximal rate of increase of action potential upstroke [Vmax]) occurs to a greater degree at shorter cycle lengths ([23, 24]). Furthermore, class Ia drugs cause postrepolarization refractoriness by a relatively greater increase in refractoriness relative to repolarization (). Drug combinations of class I agents with beta-blockers prolong refractoriness to a greater degree than would be expected from the class I agent alone (), and this may be due to adrenergic effects on potassium currents (). Adrenergic stimulation can shorten the APD by increasing the magnitude of Ikcurrents () and thus attenuate the effect of class III drugs (). Newman et al. () found that drug-mediated APD and refractoriness prolongation are attenuated by isoproterenol, independently of rate (). Thus, refractoriness prolongation by both lengthening APD and postrepolarization refractoriness, which has been demonstrated with the drugs on an individual basis, can be augmented when the drugs are used in combination.
3.1 Reverse use dependence.
A potentially important finding is the effect on “reverse use dependence.” Certain “pure” class III agents, such as sotalol, exhibit less relative APD or ERP prolongation as cycle length decreases, with almost complete loss of effect at short cycle lengths ([29, 30]). The term “reverse use dependence” has been proposed by Hondeghem and Snyders () to represent this effect, implying that there is less antiarrhythmic effectiveness at shorter cycle lengths. It has been speculated that some of this rate-related shortening of APD and loss of drug-related APD prolongation may be due to a relatively greater contribution of Iks, a slowly activating outward potassium current (), at faster rates. We hypothesized that the combination of class I and class III agents and beta-blockade may eliminate reverse use dependence. If one defines drug effect as the relative difference in electrophysiologic measures from control values, the relatively greater effect on refractory periods for subsequent extrastimuli versus the first extrastimulus represents positive rate dependence of drug effect. This effect occurs on the background of shortening of APD and refractoriness normally seen with successive extrastimuli, accounting for the overall shorter FRP for the third versus the second and first extrastimulus. The absolute difference in FRP between treated and untreated groups is greater for the third versus the first extrastimulus, suggesting that there is greater drug effect at faster rates (Fig. 2).
3.2 ERP/APD relation.
Koller et al. () demonstrated the “peeling back” of functional refractoriness with successive extrastimuli in the control state. Repetitive extrastimulation shortened both APD and the ERP/APD ratio, and capture occurred at progressively less complete repolarization levels resulting in a higher incidence of VT induction (). This progressive encroachment of the preceding repolarization phase is eliminated by sotalol plus a type Ia agent, resulting in an increased and unchanging ERP/APD ratio with repetitive extrastimulus delivery. Our results support the hypothesis that the changing ERP/APD relation with repetitive, closely coupled extrastimuli is conducive to VT induction (). Procainamide has been shown to exhibit a cycle length–dependent increase in ERP relative to APD, which may reflect use-dependent sodium channel blockade (), and thus the addition of a class Ia agent may be responsible for the postrepolarization refractoriness which is evident even at close coupling intervals and at faster drive rates. However, this cycle length–dependent increase of ERP for type Ia drugs alone occurs at the cost of increasing conduction slowing and is more modest than the marked ERP and FRP increases seen with the sotalol-type Ia combination.
In our baseline studies, we stopped continued extrastimulation at a coupling interval of 200 ms (S3S4), even if VT was not induced, and thus we may have overestimated the FRP, particularly at V3V4(FRP4). During treatment with sotalol and a type Ia drug, no patient had an FRP <230 ms. The net result was that the true increase in V3V4(FRP4) may be even greater than we have observed, and the divergence between treatment and control groups shown in Fig. 1may be larger than illustrated.
Despite marked prolongation of refractoriness, no patient had documented torsade de pointes. Refractoriness was increased markedly with a moderate increase in APD, probably secondary to the relatively low drug doses employed. There was a minimal but significant increase in ventricular conduction slowing with sotalol plus a type Ia agent. Thus, the combined effects of these two drugs had a positive effect on increasing refractoriness and in maintaining this effect at faster rates while potentially minimizing the potentially harmful electrophysiologic effects of high drug dosages, including torsade de pointes and markedly prolonged conduction delay.
3.3 Study limitations.
Electrophysiologic studies were discontinued when sustained VT was induced; thus, some patients did not undergo testing with double or triple extrastimuli at faster rates. Data on FRP4intervals may therefore be available only for the subgroups whose arrhythmia was difficult to induce or noninducible, and they may represent a subset of the patients with greater drug effect. However, higher drug dose or concentration was not responsible for the observed clinical efficacy or longer ERP in these subgroups ().
Patients in this study had simultaneous recordings of MAPs and surface electrocardiograms (ECGs), although eight had only ECG recordings. In these cases, RR intervals were used in FRP analysis since the effect of the drug combination on conduction was small, the difference in the local MAP to surface QRS onset interval was likely to be very small.
Use dependence of drug action is usually assessed at steady state pacing, after ≥60 s. We assessed rate (use) dependence after successive extrastimuli, or “step” increases in rate. However, much of rate-related APD shortening is evident after the first few beats at a faster rate (), and all comparisons are made with respect to the same methods before and after drug therapy. In addition, an 8-beat drive train might not have been long enough to attain a steady state of effect on refractoriness, but steady state is almost achieved () and is clinically relevant for VT induction. Finally, we were not able to study patients given monotherapy with sotalol or a class Ia drug, but the ERP prolongation in this study is greater than has been seen with either drug as monotherapy and probably reflects the combined effect of both drugs.
We thank Kim Brown for secretarial assistance in the preparation of the manuscript and Jan Mitchell, RN for technical assistance.
☆ This study was supported in part by the Heart and Stroke Foundation of Ontario, Toronto.
- action potential duration
- action potential duration at 90% repolarization
- drive cycle length at 400 ms
- drive cycle length at 600 ms
- effective refractory period
- functional refractory period
- monophasic action potential
- ventricular fibrillation
- ventricular tachycardia
- Received January 31, 1996.
- Revision received July 24, 1996.
- Accepted September 17, 1996.
- The American College of Cardiology
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