Increases In Ventricular Refractoriness Research Articles

Dofetilide, a new class III antiarrhythmic agent.

Dofetilide is a new antiarrhythmic agent recently approved for conversion and maintenance of sinus rhythm in patients with atrial fibrillation (AF) and atrial flutter (AFl). It is a class III antiarrhythmic that works by selectively blocking the rapid component of the delayed rectifier outward potassium current. Dofetilide prolongs the effective refractory period in accessory pathways, both anterograde and retrograde. This can be seen on the electrocardiogram through a dose-dependent prolongation of the QT and QTc intervals, with parallel increases in ventricular refractoriness. Approximately 80% of drug is excreted in urine, so dosing must be based on creatinine clearance. The elimination half-life is approximately 10 hours. In clinical trials dofetilide was superior to flecainide in converting patients with AFl to normal sinus rhythm (NSR; 70% vs 9%, p<0.01). It also was more effective than sotalol in converting patients with both AF and AFl to NSR (29% vs 6%, p<0.05) and maintaining them in NSR for up to 1 year. Most patients converted within 24-36 hours. Dofetilide has a favorable risk:benefit profile. Torsades de pointes is the most serious side effect; it occurs in 0.3-10.5% of patients and is dose related. To minimize the risk of induced arrhythmia, patients who start or restart the drug should be hospitalized a minimum of 3 days for creatinine clearance measurements, continuous electrocardiographic monitoring, and cardiac resuscitation, if necessary.

Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter.

Dofetilide is a new antiarrhythmic agent recently approved for the conversion of and maintenance of sinus rhythm in patients with atrial fibrillation (AF) and atrial flutter (AFl). Dofetilide is a selective class III antiarrhythmic drug which works by selectively blocking the rapid component of the delayed rectifier outward potassium current (I(kr)). Dofetilide has been shown to prolong the effective refractory period which is accompanied by a dose-dependent prolongation of the QT and QTc intervals, with parallel increases in ventricular refractoriness. Approximately 80% of dofetilide is excreted in the urine which requires dose adjustments in renal insufficiency. The elimination half-life is approximately 10 h in patients with normal renal function. The therapeutic blood level range of dofetilide is presently unknown and monitoring of dofetilide blood levels is not available at this time. Clinical trials have shown dofetilide to be superior to flecainide in converting AFl patients to normal sinus rhythm (NSR) (70% vs. 9%; p<0.01). It also was more effective than sotalol in converting AF and AFl patients to NSR (29% vs. 6%; p<0.05) and maintaining these patients in NSR for up to 1 year (p<0.05). Most patients convert to NSR within 24-36 h. Torsade de pointes is the most serious side effect occurring in 0.3-10.5% of patients and is dose related. Other common side effects include headache, chest pain and dizziness. To minimize the risk of induced arrhythmia, patients initiated or reinitiated on dofetilide should be hospitalized for a minimum of 3 days where continuous electrocardiographic monitoring, evaluation of renal function and serum electrolytes and cardiac resuscitation can be provided.

Electrophysiologic effects and predictors of success of combination therapy with class Ia and Ib antiarrhythmic drugs for sustained ventricular arrhythmias

Antiarrhythmic drugs remain the first line of therapy in patients with sustained ventricular arrhythmias. Although success with class la antiarrhythmic medications has been limited, there is evidence that the addition of a class Ib agent may improve results. A total of 110 consecutive patients referred for electrophysiologic evaluation who had inducible sustained ventricular arrhythmias resistant to a class la agent underwent repeat electrophysiologic study after the addition of a class Ib drug. Patients with ejection fraction >40% and ventricular fibrillation inducible in the baseline study had an 80% response rate, whereas those with inducible ventricular tachycardia and ejection fraction ≤40% responded 11% of the time. Responders demonstrated marked prolongation of ventricular refractoriness and slight shortening of the QRS, whereas nonresponders had QRS prolongation and a more modest increase in ventricular refractoriness. Thus, the efficacy of class Ia/Ib combination therapy in patients with inducible sustained ventricular arrhythmias refractory to a class la drugs alone can be predicted by baseline variables. Marked prolongation of ventricular refractoriness in the absence of QRS prolongation appears to be a key factor in the success of this combination.

Effect of flecainide on atrial and ventricular refractoriness and conduction in patients with normal left ventricle. Implications for possible antiarrhythmic and proarrhythmic mechanisms.

We studied the effects of intravenous flecainide (2 mg.kg-1) on atrial and ventricular refractoriness and conduction during sinus rhythm, induced atrial fibrillation and atrial pacing at rates of 100, 120 and 150 ppm, in 14 patients with normal left ventricle. Flecainide caused a significant increase in QRS duration during sinus rhythm (mean +/- SD: 87.2 +/- 8.4 ms vs 102.8 +/- 9.1 ms, P < 0.001), atrial fibrillation (87.8 +/- 10.0 ms vs 108.8 +/- 13.7 ms, P < 0.001) and at all paced rates. The duration of the atrial electrogram was significantly increased during sinus rhythm (54.9 +/- 13.2 ms vs 64.8 +/- 16.6 ms, P = 0.003) and at all pacing rates. The PA interval was also significantly prolonged, as was the pacing stimulus-to-atrial-electrogram interval at all pacing rates. There was increased QRS duration and atrial electrogram prolongation at higher pacing rates. Atrial refractoriness was prolonged during sinus rhythm (216.4 +/- 28.2 vs 228.6 +/- 36.1, P = 0.02), but not during atrial pacing at any rate. The QT interval, but not the JT interval or ventricular refractoriness, was significantly prolonged during sinus rhythm and at all pacing rates. Flecainide slows atrial conduction in a use dependent manner and increases atrial refractoriness during sinus rhythm but not during faster atrial pacing, thus not displaying a use-dependent effect. QRS duration is prolonged in a use-dependent manner without a commensurate increase in ventricular refractoriness. In the presence of rapidly conducted atrial fibrillation, which was not found to be slowed by flecainide, this effect may constitute a proarrhythmic mechanism even in patients with no apparent myocardial abnormality.

1026-86 The Influence of Sodium Channel Blockade on the Defibrillation Threshold of Biphasic versus Monophasic Defibrillation Waveforms

Several Class I antiarrhythmic drugs are known to increase the defibrillation threshold (DFT) of monophasic shock waveforms delivered by implantable defibrillators (ICD). The influence of sodium channel blockade on biphasic shocks is unknown. The purpose of this study was to determine the effects of lidocaine (LIDO) on the DFT with biphasic versus monophasic shock waveforms in an anesthetized canine model of transvenous defibrillation (n = 101. The DFT was determined by the iterative increment-decrement protocol. Monophasic and biphasic shock OFT's were tested in random order at baseline and during LIDO infusion (8 mg/kg load; 400 microgm/kg/min) and presented below. Monophasic DFT (Joules) Biphasic DFT (Joules) P Value * Baseline 160 ± 56 11.1 ±2.7 0.006 LIDO 264 ± 109 16.9 ± 9.0 0.018 P Value ** 0.009 0.054 * p value of monophasic vs biphasic ** p value of baseline vs LIDO In 2 dogs, the DFT during LIDO was &gt; 50 joules with monophasic shock and 27.9 ± 5.6 joules with biphasic shocks. LIDO caused a 13.1 ± 9.8% increase in ventricular refractoriness (p &lt; 0.037) and a 29.8 ± 22.7% increase in GAS duration (p &lt; 0.01). neither of which were predictive of DFT response. Sodium channel blockade does increase the DFT of biphasic shocks but to a lesser extent than observed with monophasic shock DFT's. These results may have favorable implications for the use of Class I antiarrhythmics in patients with newer generation lCD's.

Effects of artilide on spontaneous and induced ventricular arrhythmias in 24‐hour canine myocardial infarction

AbstractThe electrophysiologic and antiarrhythmic effects of artilide were evaluated in dogs 24 h after myocardial infarction. Artilide (0.1 to 3.0 mg/kg or 0.2 to 7.0 μuM/kg iv) prevented programmed stimulation induced ventricular arrhythmias in 9 out of 9 dogs that had demonstrated inducibe ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Lower doses of artilide tended to reduce the incidence of spontaneous ventricular arrhythmias but these effects were not significant. These results are consistent with the concept that spontaneous and pacing induced ventricular arrhythmias result from different mechanisms, and that class III anti‐arrhythmic agents are more effective in suppressing induced ventricular tachycardia due to reentry than spontaneous arrhythmias which result from nonreentrant mechanisms. © 1993 wiley‐Liss, Inc.

Cardiac Electrophysiologic and Inotropic Actions of New and Potent Methanesulfonanilide Class III Antiarrhythmic Agents in Anesthetized Dogs

The effects of cumulative intravenous (i.v.) administration of potent and selective methanesulfonanilide class III antiarrhythmic agents on cardiac electrophysiologic and hemodynamic parameters were compared with those of D-sotalol in chloralose-anesthetized dogs. The new class III agents tested were E-4031 [1-(2-(6-methyl-2-pyridyl)ethyl)-(4-methanesulfonamidobenzoyl)pipe ridine]; UK-66,914 [N-(4-(1-hydroxy-2-(4-(4-pyridinyl)-1-piperazinyl)ethyl)phenyl) methanesulfonamide], and UK-68,798 [1-(4-methanesulfonamidophenoxy)-2-(N- (4-methanesulfonamidophenethyl)-N-methylamino)ethane]. The class III agents produced significant and dose-dependent increases in ventricular refractoriness, with effective doses required to increase ventricular relative refractory period 20 ms above baseline (ED20, micrograms/kg i.v., with 95% confidence limits) of 5.2 (4.2-6.6) for UK-68,798, 17 (13-23) for E-4031, 75 (58-99) for UK-66,914, and 3,700 (2,600-5,800) for D-sotalol. Significant increases in the electrocardiographic QT and QTc intervals paralleled the increases in ventricular refractoriness for the four class III agents. Significant increases in left ventricular (LV) + dP/dt also paralleled increases in ventricular refractoriness and QT intervals for E-4031 (10-1,000 micrograms/kg i.v.), UK-66,914 (100-1,000 micrograms/kg i.v.), and UK-68,798 (30-1,000 micrograms/kg i.v.), but not for D-sotalol. No concomitant alterations in LV-dP/dt were observed for the new and potent methanesulfonanilide class III agents, resulting in significant increases in the ratio of LV + dP/dt/-dP/dt for E-4031, UK-66,914, and UK-68,798. Potent and selective methanesulfonanilide class III agents therefore may augment cardiac contractility in addition to prolonging ventricular refractoriness.

The effect of beta-adrenergic blockade on vulnerability to ventricular fibrillation and inducibility of ventricular arrhythmia in short- and long-term feline infarction models

Previous investigation, predominantly in the short-term canine model, has documented a potent antifibrillatory effect of beta-adrenergic blockade. To determine whether the protection afforded by beta blockade is species- and model-specific, we studied 23 chloralose-anesthetized cats. Eight animals were studied over a short term and underwent serial determinations of the ventricular fibrillation (VF) threshold prior to and 1 minute after occlusion of the left anterior descending coronary artery (LAD) and immediately following reperfusion of a 10-minute occlusion. Beta-blocking doses of intravenous propranolol (P) (0.5 mg/kg) attenuated the fall in VF threshold during acute ischemia. Increasing the dose of P to 1 mg/kg did not provide further protection, nor did P protect against reperfusion VF. The other 15 animals underwent a preliminary surgical procedure during which the LAD was completely and irreversibly occluded (nine animals) or in which a sham procedure was performed (six animals). Two weeks later, we measured ventricular refractoriness at several left ventricular sites, ventricular inducibility using programmed electrical stimulation, and VF thresholds both before and after administration of intravenous P (1 mg/kg). Ventricular refractory periods in the infarcted zones were significantly increased compared with normal sites and with values obtained in sham-operated animals. In addition, VF thresholds in the infarcted animals were lower than those obtained in the sham-operated group. Before treatment, a reproducible sustained ventricular tachyarrhythmia was induced by means of programmed stimulation in seven of the nine chronically infarcted animals but in none of the sham-operated animals ( p < 0.02). P increased refractory periods in the normal and infarcted zones proportionately and significantly. After P, sustained ventricular arrhythmia was induced in only one cat in the infarcted group ( p < 0.03). This attenuated inducibility was coincident with a significant increase in VF threshold after P ( p < 0.02). Beta blockade exerts a significant electrophysiologic effect in the feline ventricle. Protection against VF induced in both short-term and long-term infarction is coincident with an increase in ventricular refractoriness and with prevention of inducibility by programmed stimulation.

Reduction in digitalis-associated postinfarction mortality with nadolol in conscious dogs

Previously, we have demonstrated an increased incidence of lethal ischemic arrhythmias in postinfarction dogs with clinically observable serum digoxin concentrations, and a significant reduction in digitalis-related lethal ischemic arrhythmias after subacute left stellectomy. In the present study, the protective actions of acute beta-adrenoceptor blockade with nadolol, 1.0 mg/kg administered intravenously immediately preceding the induction of posterolateral myocardial ischemia, were assessed in conscious dogs with recent, small anterior myocardial infarctions pretreated with digoxin, 0.0125 mg/kg/day intravenously, for 5 to 7 consecutive days (total n = 11). A cohort of postinfarction dogs pretreated with digoxin alone served as a control group (total n = 26). Pre vs postdigoxin electrophysiologic testing indicated reductions in myocardial refractoriness in ventricular noninfarct and infarct in both treatment groups, whereas the administration of nadolol tended to reverse the reductions in ventricular refractoriness. Arrhythmia-related deaths in response to posterolateral myocardial ischemia were reduced from 12 of 20 (60%) in the digoxin control group to 2 of 10 (20%) in the digoxin + nadolol group ( p = 0.039). Serum digoxin concentrations (1.29 ± 0.14 ng/ml vs 1.39 ± 0.24 ng/ml), underlying anterior myocardial infarct size (6.9 ± 1.5% vs 4.6 ± 0.9% of left ventricle), and developing posterolateral myocardial infarct size (22.8 ± 2.5% vs 17.5 ± 3.6% of left ventricle) did not differ significantly between the digoxin and digoxin + nadolol groups. Acute beta-adrenoceptor blockade with nadolol appears to reduce digitalis-mediated ischemic postinfarction mortality, possibly because of a salutary increase in ventricular refractoriness.

Pharmacodynamics of intravenous procainamide as used during acute electropharmacologic testing

No previous studies have determined the pharmacodynamics of intravenous procainamide when administered in a dose of 15 mg/kg and at a rate of 50 mg/min, as is common practice during etectropharmacologic testing. In this study, 30 patients received procainamide in this fashion; the right ventricular effective refractory period and the QRS duration at a ventricular pacing rate of 120/minute were then determined every minute for 20 minutes. Ten patients received no maintenance infusion of procainamide (group A), 10 received a 4 μg/min maintenance infusion (group B) and 10 received an 8 mg/min maintenance infusion (group C). Ten additional patients received no procainamide and served as control subjects (group D). The plasma procainamide concentration was measured at 1, 5, 10,15 and 20 minutes after the loading dose was administered. A stable plasma procainamide concentration was not present in group A, B, or C until 15 minutes after infusion of the loading dose. The effective refractory period and QRS duration increased compared with baseline at 1 minute, decreased between 1 and 10 minutes and then remained essentially unchanged between 10 and 20 minutes in all 3 treatment groups. Concentration-effect relation was linear in each treatment group. The plasma procainamide concentrations in group C were significantly greater than in group A; however, the effects on refractoriness and QRS duration were similar in both groups. These findings indicate that with a procainamide dosing method commonly used during electropharmacologic testing, the plasma procainamide concentration decreases significantly during the first 15 minutes after the loading dose is administered; the effects of procainamide on ventricular refractoriness and conduction parallel the changes in the plasma procainamide concentration; and an 8 mg/min maintenance infusion of procainamide results in higher plasma procainamide concentrations without an associated increase in ventricular refractoriness or slowing of conduction.

THE ELECTROPHYSIOLOGIC EFFECTS OF SOTALOL IN THE IMMATURE MAMMALIAN HEART

Sotalol (So), a new antiarrhythmic agent, is a beta-blocker that also has been shown to have some class III electrophysiologic (EP) effects. To evaluate the EP effects of So on the immature heart and to assess the relative importance of its class III actions, two groups of neonatal canines, ages 4-15 days, were studied and compared. Group I consisted of 6 puppies in whom EP studies were performed in the control state (C) and following 1.5, 2.5 and 4.0 mg/kg I.V. So. Group II consisted of 6 puppies in whom EP studies were performed prior to and following beta-blockade with 0.6 mg/kg I.V. propranolol (P). So caused a dose dependent decrease in heart rate (181 ± 27 to 125 ± 21 bpm, p< 0.001) while P caused no significant change (169 ± 9 to 159 ± 14, ns). So significantly prolonged atrial refractoriness (AERP: 67 ± 14 C, 117 ± 28 So; AFRP: 102 ± 9 C, 152 ± 31 So, p < 0.001) while P only slightly increased the AFRP (114 ± 12 C, 120 ± 10 P, p < 0.03). While the AV node FRP was prolonged by P (183 ± 9 C, 193 ± 19 P, p< 0.05) So caused a greater increase (171 ± 29 C, 244 ± 57 So, p< 0.01). Similarly, while P slightly increased the VERP (158 ± 12 C to 168 ± 13, p <0.05) So caused a far greater increase in ventricular refractoriness (VERP: 152 ± 26 C, 227 ± 41 So; VFRP: 173 ± 23 C, 253 ± 34 So, p < 0.001). Because the EP changes with beta-blockade in the immature heart are modest, the large changes in myocardial refractoriness induced by So must be largely due to a significant class III antiarrhythmic effect.

Electrophysiologic effects of disopyramide phosphate on reentrant ventricular arrhythmia in conscious dogs after myocardial infarction

The electrophysiologic actions of disopyramide phosphate on reentrant ventricular tachycardia induced by premature ventricular stimuli were evaluated in conscious dogs 2 to 4 days after myocardial infarction. Disopyramide was administered as a series of intravenous infusions to obtain successive steady state plasma disopyramide concentrations of 1.02 ± 0.02, 2.05 ± 0.08, 3.94 ± 0.09 and 7.69 ± 0.18 μg/ ml (mean values ± standard error of the mean). Disopyramide plasma concentrations of 1.02 ± 0.02 μg/ ml produced an increase in the rate and duration of ventricular tachycardia as well as in the interval during which premature ventricular stimuli produced ventricular tachycardia. The effective refractory period of normal myocardium was decreased and conduction (activation time) was improved in ischemic myocardium. Increasing steady state plasma disopyramide concentrations slowed the rate of ventricular tachycardia without decreasing its duration. Slowing of the rate of tachycardia occurred simultaneously with a depression of conduction in normal and ischemic myocardium and an increase in ventricular refractoriness. Induction of ventricular tachycardia was prevented only at steady state plasma disopyramide concentrations of 7.69 ± 0.18 μg/ ml. The results of this study suggest that subtherapeutic plasma concentrations of disopyramide may facilitate the development of reentrant ventricular arrhythmia in the electrically unstable heart. Ventricular tachycardia or fibrillation, or both, may be prevented only by plasma disopyramide concentrations that are in excess of the normal therapeutic range of 2 to 4 μg/ml.