Increase In Effective Refractory Period Research Articles

Losartan inhibits hyposmotic-induced increase of IKs current and shortening of action potential duration in guinea pig atrial myocytes

Objective:The present study aims to investigate the effect of losartan, an selective angiotensin II type 1 receptor (AT1R) blocker, on both the increase of IKs current and shortening of action potential duration (APD) induced by stretch of atrial myocytes, and to uncover the mechanism underlying the treatment of fibrillation (AF) by AT1R blockers.Methods:Hyposmotic solution (Hypo-S) was applied in the guinea pig atrial myocytes to simulate cell stretch, then patch-clamp technique was applied to record the IKs and APD in atrial myocytes.Results:Hypo-S increased the IKs by 105.6%, while Hypo-S+1-20 µM of losartan only increased the IKs by 70.3-75.5% (p<0.05 vs. Hypo-S). Meanwhile, Hypo-S shortened APD90 by 20.2%, while Hypo-S+1-20 µM of losartan shortened APD90 by 13.03-14.56% (p<0.05 vs. Hypo-S).Conclusion:The above data indicate that the effect of losartan on the electrophysiological changes induced by stretch of atrial myocytes is associated with blocking of AT1 receptor, and is beneficial for the treatment of AF that is often accompanied by the expansion of atrial myocytes and the increase of effective refractory period.

Permanent and Transient Electrophysiological Effects During Cardiac Cryoablation Documented by Optical Activation Mapping and Thermal Imaging.

Cardiac catheter cryoablation is a safer alternative to radiofrequency ablation for arrhythmia treatment, but electrophysiological (EP) effects during and after freezing are not adequately characterized. The goal of this study was to determine transient and permanent temperature induced EP effects, during and after localized tissue freezing. Conduction in right (RV) and left ventricles (LV) was studied by optical activation mapping during and after cryoablation in paced, isolated Langendorff-perfused porcine hearts. Cryoablation was performed endocardially (n=4) or epicardially (n=4) by a cryoprobe cooled to -120 °C for 8 minutes. Epicardial surface temperature was imaged with an infrared camera. Viability staining was performed after ablation. Motion compensation and co-registration was performed between optical mapping data, temperature image data, and lesion images. Cryoablation produced lesions 14.9 +/- 3.1 mm in diameter and 5.8 +/- 1.7 mm deep. A permanent lesion was formed in tissue cooled below -5 +/- 4 °C. Transient EP changes observed at temperatures between 17 and 37 °C during cryoablation surrounding the frozen tissue region directly correlated with local temperature, and include action potential (AP) duration prolongation, decrease in AP magnitude, and slowing in conduction velocity (Q10=2.0). Transient conduction block was observed when epicardial temperature reached <17 °C, but completely resolved upon tissue rewarming, within 5 minutes. Transient EP changes were observed surrounding the permanent cryo lesion (<-5 °C), including conduction block (-5 to 17 °C), and reduced conduction velocity (>17 °C). The observed changes explain effects observed during clinical cryoablation, including transient increases in effective refractory period, transient conduction block, and transient slowing of conduction. The presented quantitative data on temperature dependence of EP effects may enable the prediction of the effects of clinical cryoablation devices.

Electrophysiological profile of vernakalant in an experimental whole-heart model: the absence of proarrhythmia despite significant effect on myocardial repolarization

The most recent European Society of Cardiology (ESC) update on atrial fibrillation has introduced vernakalant (VER) for pharmacological cardioversion of atrial fibrillation. The aim of the present study was to investigate the safety profile of VER in a sensitive model of proarrhythmia. In 36 Langendorff-perfused rabbit hearts, VER (10, 30 µM, n = 12); ranolazine (RAN, 10, 30 µM, n = 12), or sotalol (SOT, 50; 100 µM, n = 12) were infused after obtaining baseline data. Monophasic action potentials and a 12-lead electrocardiogram showed a significant QT prolongation after application of VER as compared with baseline (10 µM: +25 ms, 30 µM: +50 ms, P < 0.05) accompanied by an increase of action potential duration (APD). The increase in APD90 was accompanied by a more marked increase in effective refractory period (ERP) leading to a significant increase in post-repolarization refractoriness (PRR, 10 µM: +30 ms, 30 µM: +36 ms, P < 0.05). Vernakalant did not affect the dispersion of repolarization. Lowered potassium concentration in bradycardic hearts did not provoke early afterdepolarizations (EADs) or polymorphic ventricular tachycardia (pVT). Comparable results were obtained with RAN. Hundred micromolars of SOT led to an increase in QT interval (+49 ms) and APD90 combined with an increased ERP and PRR (+23 ms). In contrast to VER, 100 µM SOT led to a significant increase in dispersion of repolarization and to the occurrence of EAD in 10 of 12 and pVT in 8 of 12 hearts. In the present study, application of VER and SOT led to a comparable prolongation of myocardial repolarization. Both drugs increased the PRR. However, VER neither affect the dispersion of repolarization nor induce EAD and therefore did not cause proarrhythmia.

Electrophysiological effect of rotigaptide in rabbits with heart failure.

IntroductionRotigaptide is a new anti-arrhythmic peptide, which has recently been found to increase junctional conductance and prevent ischemia-induced ventricular tachycardia. In this study, we attempted to investigate the effects and mechanisms of rotigaptide on the vulnerability to ventricular arrhythmias in rabbits with heart failure (HF).Material and methodsChronic volume-pressure overload was used to induce HF. After rotigaptide infusion, an electrophysiological study was performed to record monophasic action potential (MAP), determine the effective refractory period (ERP) and ventricular fibrillation threshold (VFT), and assess the susceptibility to ventricular arrhythmia. Finally, real-time PCR was used to detect the changes of connexin 43 (Cx43) mRNA expression.ResultsHF rabbits exhibited significant down-regulation of Cx43 mRNA, increase of effective refractory period (ERP) and decrease of VFT (p < 0.05, respectively). These changes resulted in an increase of vulnerability to ventricular tachyarrhythmias (VT/VF). Rotigaptide administration shortened ERP (113.3 ±8.6 ms vs. 131.7 ±12.5 ms, p < 0.05), restored VFT (15.0 ±2.0 V vs. 6.3 ±1.4 V, p < 0.05), and decreased the vulnerability to VT/VF. However, short-term rotigaptide treatment had no significant effect on MAP duration (MAP duration at 90% repolarization: 169.3 ±6.0 ms vs. 172.7 ±6.2 ms, p > 0.05) or connexin 43 mRNA expression (p > 0.05).ConclusionsRotigaptide decreases the ERP, elevates VFT, and reduces the vulnerability to ventricular arrhythmias without changing Cx43 expression in rabbits with HF. It may be a promising antiarrhythmic drug for preventing ventricular arrhythmia in HF.

New class III antiarrhythmic drugs.

Several new antiarrhythmic compounds with pure class III activity are currently under development and seem to possess considerable antiarrhythmic potential. The primary electrophysiological action of class III agents is selective prolongation of repolarization without conduction slowing. This effect is usually mediated by block of one or more potassium currents which results in prolongation of the action-potential duration and refractoriness in both atrial and ventricular myocardium. The magnitude of increases in effective refractory period decreases as the heart rate is increased, i.e. these drugs display 'reverse use-dependence'. Initial animal and clinical studies have shown that class III agents are effective against re-entrant supraventricular and ventricular arrhythmias without having any important negative inotropic effect in the compromised ventricle. Animal studies have also suggested that these drugs may be useful in suppressing postinfarction arrhythmias and preventing arrhythmic sudden death. However, concerns have been raised by reports of substantial proarrhythmic tendency associated with these drugs, mainly in the form of torsade de pointes. Careful clinical evaluation is required to establish the clinical benefits of these potentially promising new compounds.

Effect of high-current stimulation in patients with sustained ventricular tachycardia rendered noninducible by antiarrhythmic drugs

Successful antiarrhythmic drug therapy for sustained ventricular tachycardia (VT) is presumed to be related to effects on myocardium within the reentrant circuit. To test the hypothesis that prevention of VT induction may be related to effects on myocardium other than that directly involved in the tachycardia circuit, high-current stimulation was used to achieve shorter coupling intervals in 22 patients with sustained uniform VT that was rendered noninducible by antiarrhythmic agents during stimulation at twice threshold. Sustained uniform VT was induced in 10 patients in response to high-current stimulation (group 1), including 4 tachycardias with the same morphology observed in the baseline study. There were no inducible arrhythmias in 12 patients (group 2). Patients were receiving several different antiarrhythmic regimens, but there was no particular drug associated with the induction of VT using high-current stimulation. There was no statistically significant difference between groups 1 and 2 in baseline VT cycle length (247 ± 41 vs 253 ± 44 ms), drug-induced increase in effective refractory period (20 ± 15 vs 16 ± 7%), QRS duration (25 ± 10 vs 20 ± 17%) or maximal current strength delivered (10.9 ± 5.3 vs 9.3 ± 4.0 mA). There was no significant difference in local activation with high-current stimulation between groups 1 and 2. In conclusion, sustained uniform VT was induced in 45% (10 of 22) of patients whose arrhythmias were rendered noninducible by antiarrhythmic agents during programmed stimulation at twice threshold. This suggests that prolongation of refractoriness at the site of stimulation or slowing in conduction time of extrastimuli to the presumed reentrant circuit, or both, may be one mechanism by which antiarrhythmic drugs prevent induction of VT during programmed stimulation.

Proarrhythmic and Antiarrhythmic Effects of Flecainide on Nonsustained Reentry Around the Canine Atrial Tricuspid Ring In Vitro

The effect of flecainide, 0.3 mg/L and 1.0 mg/L, on inducible nonsustained reentry was studied, in vitro, in the canine tricuspid ring. Nonsustained reentry was engineered by cutting the ring and reconnecting it with an adjustable electronic delay. Delays were used that produced reentry lasting 1-3 beats (group A), 4-10 beats (group B), and 11-25 beats (group C). Reentry was initiated multiple times at each selected delay. A proarrhythmic effect, defined as a significant increase in the duration of reentry, was observed in all 14 trials at the low dose and in two of 15 trials at the high dose in seven experiments. In four more trials a transient proarrhythmic response was seen initially during exposure to the high dose. In five of seven experiments, reentry became sustained after at least one dose of flecainide. Proarrhythmic responses resulted when flecainide increased the tachycardia cycle length more than the effective refractory period and there was less cycle length oscillation after initiation. Antiarrhythmic responses resulted either from a marked increase in effective refractory period at the site of block or production of fixed block.

Selective Class III Antiarrhythmic Properties of a Novel Agent, UK‐66,914, During Chronic Myocardial Infarction

Antiarrhythmic Properties of UK‐ 66,914. UK‐66,914 is a potent Class III antiarrhythmic agent that has no effect on conduction velocity in normal tissue in vitro. The present study was performed to evaluate the influence of UK‐66,914 on conduction velocity in vivo in canine hearts with a previous myocardial infarction. Detailed three‐dimensional mapping of the heart in vivo was obtained using simultaneous recordings from 232 transmural sites. In dogs with a chronic anterior myocardial infarction, UK‐66,914 (50 μg/kg) did not alter conduction velocity in regions exhibiting normal conduction (gt; 50 cm/sec) or regions with slowed conduction (&lt; 50 cm/sec) despite an 11%‐15% increase in the ventricular effective refractory period. UK‐66,914 prevented the induction of ventricular tachycardias by programmed electrical stimulation due to lengthening of the effective refractory period with no direct or indirect effects on conduction velocity in dogs with chronic infarcts of 1‐year duration. Because the endocardial border zone surrounding the infarct was critical to the development of the reentrant pathway in vivo, studies were performed in tissue from this region in vitro utilizing a high‐resolution, 224 bipolar grid recording array. The effects of UK‐66,914, d‐sotalol, and procainamide on conduction velocity were compared in this region at concentrations that elicited a comparable increase in the effective refractory period of 40 msec. UK‐66,914 and d‐sotalol did not alter conduction velocity in regions with conduction velocities &gt; 30 cm/sec, 15‐30 cm/sec, or &lt; 15 cm/sec, whereas procainamide significantly decreased conduction velocity at all three levels. Evaluation of the hemodynamic profile of UK‐66,914 revealed no negative ionotropic effects in conscious dogs even at doses twentyfold those required to elicit increases in the effective refractory period. Therefore, UK‐66,914 is a potent and specific Class III antiarrhythmic agent, which does not alter conduction velocity in hearts with a previous myocardial infarction and exerts no negative inotropic effects.

Electrophysiologic Properties of UK-66,914, a Novel Class III Antiarrhythmic Agent

A class III antiarrhythmic agent that preferentially increases the effective refractory period without altering conduction velocity holds considerable promise for the treatment of life-threatening cardiac arrhythmias dependent on a reentrant mechanism. In the present study, the cellular electrophysiologic effects of a novel class III antiarrhythmic agent, UK-66,914, were evaluated. UK-66,914 prolonged action potential duration and extended the effective refractory period in isolated canine ventricular muscle and Purkinje fibers in a concentration-dependent manner, beginning at a threshold concentration of 0.1 microM. Analogous effects were found in isolated rabbit atrium beginning at a threshold concentration of 2 microM. At concentrations of UK-66,914 up to 20 microM there was no effect on the maximum rate of phase 0 depolarization (Vmax) or the amplitude of the action potential. In guinea pig papillary muscles. UK-66,914 at concentrations from 0.1 to 20 microM increased the effective refractory period at stimulation frequencies of 1 or 5 Hz, but did not slow conduction velocity. Therefore, UK-66,914 exhibits high selectivity for a class III antiarrhythmic effect in normal tissue. To elucidate the mechanisms responsible for the increase in effective refractory period, voltage clamp procedures were used in guinea pig ventricular myocytes. UK-66,914 reduced the amplitude of outward tail currents following depolarizing clamp steps with little effect either on the background K+ current or calcium currents, indicating that UK-66,914 selectively blocked the time-dependent potassium current. In anesthetized dogs, UK-66,914 (10 micrograms/kg to 1 mg/kg i.v.) prolonged both atrial and ventricular effective refractory periods, but in contrast to the studies performed in vitro, the minimum effective doses required to increase the effective refractory period in atria and ventricle were the same. Therefore, UK-66,914 is a potent selective class III antiarrhythmic agent, which owes its electrophysiologic profile to blockade of the time-dependent potassium current.

Direct electrophysiological actions of pentobarbital at concentrations achieved during general anesthesia

Pentobarbital and alpha-chloralose are widely used for experimental anesthesia, but their direct electrophysiological actions at anesthetic concentrations are unknown. Trough and peak concentrations measured by high-performance liquid chromatography averaged 27 +/- 3 and 45 +/- 13 mg/l (means +/- SD) for pentobarbital and 41 +/- 15 and 103 +/- 13 mg/l for alpha-chloralose in dogs receiving them for general anesthesia. The direct effects of each agent on papillary muscle action potentials obtained from guinea pigs killed by decapitation were studied in vitro. Pentobarbital increased action potential duration to 95% by 24 +/- 6 and 33 +/- 4% at 25 and 50 mg/l (P less than 0.001 for each), respectively, and caused corresponding increases in effective refractory period. Furthermore, pentobarbital reduced maximum rate of voltage change (Vmax) of phase 0 in a voltage-, rate-, and concentration-dependent fashion, suggesting use-dependent sodium channel blocking actions. The voltage dependence of Vmax was shifted by 3.7 +/- 1.7 (P less than 0.01) and 6.5 +/- 1.8 mV (P less than 0.001) by 25 and 50 mg/l pentobarbital, respectively. In canine ventricular muscle, pentobarbital caused rate- and concentration-dependent decreases in Vmax and increases in action potential duration and refractory period over a concentration range of 5-100 mg/l. alpha-Chloralose was devoid of direct electrophysiological effects in both species. We conclude that pentobarbital has potentially important electrophysiological actions on ventricular tissues at concentrations required for general anesthesia and may confound the results of in vivo studies.

Effects of N-Acetylprocainamide and Recainam in the Pharmacologic Conversion and Suppression of Experimental Canine Atrial Flutter

The electrophysiologic determinants of the pharmacologic conversion and the prevention of atrial flutter are poorly defined. This study investigated the effects of pharmacologically induced changes in atrial conduction velocity and refractoriness, in the conversion and suppression of atrial flutter induced in the open-chest anesthetized dog by intercaval crush and rapid atrial pacing. The effects of an intravenous infusion of the new class III antiarrhythmic drug N-acetylprocainamide (30 mg/kg over 15 min) and the class Ic antiarrhythmic drug recainam (10 mg/kg over 20 min followed by 10 mg/kg/h) were evaluated. N-acetylprocainamide restored sinus rhythm in 10 of 15 (66%) dogs, while recainam converted only 2 of 10 (20%). N-acetylprocainamide prevented reinduction in 3 (20%), while recainam was effective in none. In the atria, N-acetylprocainamide induced significant increases in effective refractory period (+27%, p less than 0.01), functional refractory period (+22%, p less than 0.01), and in atrial flutter cycle length (+13%, p less than 0.01). Recainam increased effective refractory period (+28%, p less than 0.01), functional refractory period (+20%, p less than 0.01), conduction time at atrial paced cycle length of 150 msec (+70%, p less than 0.01) and atrial flutter cycle length (+56%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of sotalol, aprindine and their combination on maximum upstroke velocity of action potential in guinea-pig papillary muscle

Microelectrode experiments were performed on papillary muscle of 11 guinea-pigs at driven heart rates of 60 and 120 b.p.m. to study the effect of sotalol 10 −4M, aprindine 10 −6 M and the combination of both on V̇ max, action potential duration and effective refractory period. Only sotalol exerted tonic V̇ max block. Aprindine, sotalol and their combination produced an increase in phasic, combined tonic and phasic, and in steady state V̇ max block: the effect of the combination on these parameters being larger than the effect of the single agents alone. Action potential duration was lengthened by both drugss and their combination. A statistically significant increase in effective refractory period was observed for sotalol and the combination sotalol-aprindine but not for aprindine. It can be concluded that simulataneous application of sotalol and aprindine enhances phasic, combined tonic and phasic, and steady state V̇ max block with an unchanged effect of sotalol on repolarization. The effect of combinations can be explained on the basis of competition for the same receptor in the Na + channel.

Pharmacologic conversion and suppression of experimental canine atrial flutter: differing effects of d-sotalol, quinidine, and lidocaine and significance of changes in refractoriness and conduction.

The electrophysiologic determinants of conversion and the prevention of atrial flutter are poorly defined. This issue was therefore investigated by evaluating the effects of the new class III antiarrhythmic drug d-sotalol and the class I antiarrhythmic drugs quinidine and lidocaine. Atrial flutter was reproducibly induced in the open-chest anesthetized dog with intercaval crush and rapid atrial pacing. In this preparation, intravenous d-sotalol restored sinus rhythm in 14 of 15 (93%) dogs, whereas quinidine converted nine of 15 (60%) and lidocaine two of 10 (20%). d-Sotalol prevented reinduction in eight (53%), whereas quinidine was effective in four (27%) and lidocaine in none (0%). In the atria, d-sotalol induced significant increases in effective refractory period (+32%; p less than .01), functional refractory period (+30%; p less than .01), conduction time at an atrial paced cycle length of 150 msec (+9%; p less than .05), and atrial flutter cycle length (+8%; p less than .01). Quinidine increased effective refractory period (+40%; p less than .01), functional refractory period (+27%; p less than .01), conduction time at sinus cycle length (+13%; p less than .01), conduction time at an atrial paced cycle length of 150 msec (+18%; p less than .01), and atrial flutter cycle length (+31%; p less than .01). Lidocaine decreased functional refractory period (-6%; p less than .05) while lengthening the atrial flutter cycle length (+13%; p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Subthreshold conditioning stimuli prolong human ventricular refractoriness

This study tested whether a subthreshold stimulus (S c) inserted before a premature stimulus prolonged the right ventricular effective refractory period in humans, and whether the degree of effective refractory period lengthening was influenced by heart rate, S c current intensity or S c pulse duration. S c at current intensity 10 mA and pulse width 2 ms prolonged mean effective refractory period from 255 ms to 277 ms (p < 0.001, n = 20). The increase in effective refractory period was similar in 6 patients studied at pacing cycle lengths 600 (259 to 289 ms) and 400 ms (236 to 258 ms). When S c current intensities were varied at 2, 5 or 10 mA at a constant pulse duration of 100 ms the effective refractory period progressively prolonged by 6, 40 and 81 ms respectively (p < 0.02, n = 6). The pulse duration of S c at a constant current of 10 mA significantly influenced effective refractory period prolongation. With S c pulse durations of 2, 10, and 100 ms the effective refractory period prolonged by 16, 33 and 66 ms respectively (p < 0.01, n = 7). Thus, subthreshold impulses prolong the effective refractory period in human right ventricular myocardium. The prolongation of effective refractory period depended on S c current intensity and pulse duration but was independent of heart rate at the cycle lengths tested. The use of subthreshold stimuli as antiarrhythmic therapy may be feasible in some patients.

Abolition and modification of reentry within the His-Purkinje system by procainamide in man.

The effects of intravenous procainamide infusion of 10--14 mg/kg body weight (i.e., 750 mg) of procainamide (PA) on reentry within the His-Purkinje system (HPS) were studied in 13 patients using His bundle electrograms and ventricular extrastimulus method. PA abolished reentry in eight patients (group 1) and decreased the width of reentry zone in the remaining five (group 2). At comparable S1S2 intervals, the S2H2 intervals after PA were longer than control in all patients. In group 1 patients, after PA, reentry did not occur even at S2H2 intervals that were significantly longer than control critical S2H2 intervals. In two of eight patients in group 1, PA abolished reentry by converting unidirectional block into bidirectional block in the antegrade limb (right bundle) of the reentry circuit. In the remaining six patients reentry was abolished because of consistent retrograde block of S2 impulse at some point between the site of stimulation and the His bundle recording site. In group 2, reentry was initiated after PA at approximately the same S1S2 intervals as in control, but required significantly longer S2H2 intervals; in these patients the zone of reentry was shortened due to increase in effective refractory period of the ventricular muscle. PA significantly increased the functional refractory period of HPS and the effective refractory period of ventricular muscle. The results of this study differ from the previously reported effects of lower concentrations of PA which facilitated reentry within the same circuit. We conclude that the effects of PA on reentry are dose-related and can both facilitate and suppress reentry, depending on critical changes in conduction and refractoriness of the HPS.

Beta-receptor blocking and cardiodepressant actions of 2-nitrilophenoxypropanolamines

The β-adrenoreceptor blocking and cardiodepressant activities of a series of 1-alkylamino-3-(2-nitrilophenoxy)-2-propanols have been studied in isolated rabbit atria. Increasing the amine substituent through the series -H, -CH 3, -C 2H 5, -CH(CH 3) 2, and -C(CH 3) 3 increases both the β-receptor blocking and the cardiodepressant activity of the compounds. In the above series p A 2 values against isoprenaline ranged from 5.83 to 8.65. Cardiodepressant activity, as judged by negative inotropic and chronotropic actions and by increases in effective refractory period, occurred at much higher concentrations than those required for β-receptor blockade. The potency ratio of the -C(CH 3) 3 to the -H derivative was 661 for β-receptor blockade, and ranged from 7 to 14 for the cardiodepressant actions. Despite the same rank order of potency of the compounds in producing cardiodepressant actions and β-receptor blockade, no correlation exists between the two effects.