Peter Milberg

Inhibition of the Na+/Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3.

BACKGROUND Long QT syndrome (LQTS) is associated with sudden cardiac death resulting from torsades de pointes (TdP), which are triggered by early afterdepolarizations (EADs). The cardiac Na(+)/Ca(2+) exchanger (NCX) has been suggested to work as a trigger for EADs. OBJECTIVE The purpose of this study was to test the hypothesis that inhibition of NCX with a newly developed selective NCX inhibitor (SEA0400) reduces TdP. METHODS AND RESULTS In 34 Langendorff-perfused rabbit hearts, the I(Kr)-blocker sotalol (100 microM; n = 18) as well as veratridine (0.5 microM; n = 16), an inhibitor of sodium channel inactivation, led to a significant increase in monophasic action potential (MAP) duration thereby mimicking LQTS2 and LQTS3. In bradycardic hearts, recordings of eight MAPs demonstrated an increased dispersion of repolarization (sotalol: 67%; veratridine: 89%; P <.05). After lowering of potassium concentration, sotalol (56%) and veratridine (63%) induced TdP. Perfusion with SEA0400 (1 microM) suppressed EADs in 15 of 16 sotalol hearts and in seven of 13 veratridine hearts. SEA0400 significantly shortened MAP duration and reduced dispersion of repolarization in both groups (P <.05). This reduced TdP incidence in the sotalol group (100%) and in the veratridine group (77%). To investigate the effects of NCX inhibition on the cellular level, we used a computer model of the rabbit ventricular myocyte. I(Na) and I(Kr) were modified to mimic the effects of veratridine and sotalol, respectively. Consistent with our in vitro experiments, reduction of NCX activity accelerated repolarization of the cellular action potential and prevented EADs. CONCLUSION In an intact rabbit heart model of LQT2 and LQT3 as well as in a computer model of the rabbit cardiac myocyte, inhibition of NCX is effective in preventing TdP due to a suppression of EADs, a reversion of action potential prolongation, and a reduction of dispersion of repolarization. Our observations suggest a therapeutic benefit of selective NCX inhibition in LQTS.

Reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short QT syndrome.

Background: Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS.

Prolonged action potential durations, increased dispersion of repolarization, and polymorphic ventricular tachycardia in a mouse model of proarrhythmia.

Introduction: In the congenital long QT syndrome, inhomogeneously prolonged action potentials, bradycardia, and hypokalemia can cause afterdepolarizations and torsade de pointes. Other genetic factors may contribute to similar forms of ventricular tachycardias in hypertrophied or failing hearts, especially if the outward current IKr is blocked pharmacologically. We sought to develop a mouse heart model for such arrhythmias in order to identify the proarrhythmic potential in transgenic animals. Methods and results: Hearts of adult wild-type (CD1) mice were isolated and the aorta was retrogradely perfused. Three monophasic action potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10-5M and 2 × 10-5M) prolonged action potential duration (APD) in a concentration-dependent and reverse frequency-dependent fashion (from 34 ± 1 to 48 ± 2 ms at 100 ms basic cycle length (BCL), from 38 ± 2 to 54 ± 3 ms at 180 ms BCL for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular bradycardia and doubled dispersion of APD (APD70max-min: 11 ± 1 vs. 4 ± 1 ms, APD90max-min: 12 ± 1 vs. 5 ± 1 ms, p < 0.05). If combined with hypokalemia, afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8 hearts at K+ =3.0 mM and in 10 of 12 hearts at K+ = 2.0 mM. Prior to polymorphic ventricular tachycardia, dispersion of APD further increased (APD70max-min: 17 ± 3 ms; APD90max-min: 25 ± 3 ms; p < 0.05). Conclusions: This isolated beating mouse heart model can be used to study drug-induced action potential prolongation and repolarization-related ventricular arrhythmias provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic predisposition to ventricular arrhythmias that may only become apparent under such proarrhythmic conditions.

Comparison of the in vitro electrophysiologic and proarrhythmic effects of amiodarone and sotalol in a rabbit model of acute atrioventricular block

The mechanisms for the different proarrhythmic potential of antiarrhythmic drugs in the presence of comparable QT prolongation are not completely understood. The reasons for the lower proarrhythmic potential of amiodarone as compared with other class-III antiarrhythmic drugs such as sotalol, a fact that has been well established for years, is insufficiently known. Therefore, the aim of our study was to assess the different electrophysiologic effects of amiodarone and sotalol in a previously developed experimental model of proarrhythmia. In eight male rabbits, amiodarone (280–340 mg/d) was fed over a period of six weeks. Hearts were excised and retrogradely perfused. Up to eight simultaneous epi- and endocardial monophasic action potentials (MAP) were recorded. Results were compared with sotalol-treated (10-50-100 μM) hearts (n = 13). Amiodarone and sotalol (50 μM and 100 μM) led to a significant increase in QT interval (mean increase: amiodarone: 31 ± 6 ms; sotalol: 41 ± 4 ms and 61 ± 9 ms) and MAP-duration (mean increase-MAP90: amiodarone: 20 ± 5 ms; sotalol: 17 ± 5 ms and 25 ± 8 ms) (P < 0.01). In bradycardic (AV-blocked) hearts, MAP-recordings demonstrated reverse-use dependence and a significant increase in dispersion of repolarization (MAP90) in the presence of sotalol (P < 0.01), but not in amiodarone-treated hearts (10%; p = ns). Sotalol led to early afterdepolarizations (EAD) and torsade de pointes (TdP) after lowering of potassium concentration (6 of 13 hearts). In amiodarone-treated, hypokalemic hearts, no EAD or TdP occurred. Sotalol changed the MAP configuration to a triangular pattern (ratio-MAP90/50: 1.52 as compared with 1.36 at baseline) whereas amiodarone caused a rectangular pattern of MAP prolongation (ratio-MAP90/50: 1.36). In conclusion, these results show no direct correlation between the occurrence of TdP and the degree of QT prolongation. Several factors including reverse-use dependence, dispersion of repolarization, and the propensity to induce early afterdepolarizations but also differences in the action potential configuration may help to understand proarrhythmic side effects of drugs.

Randomized study comparing duty-cycled bipolar and unipolar radiofrequency with point-by-point ablation in pulmonary vein isolation

BACKGROUND Pulmonary vein (PV) electrical isolation is a therapeutic option in atrial fibrillation (AF). New technologies may reduce the complexity of the procedure. OBJECTIVE The aim of the present study was to compare immediate results and short-term efficacy of a new circular ablation catheter (PVAC) with a conventional point-by-point ablation. METHODS The prospective study enrolled 80 consecutive patients with paroxysmal AF or persistent AF, refractory to antiarrhythmic drugs, who were randomized to radiofrequency ablation using duty-cycled bipolar and unipolar radiofrequency by a decapolar circular catheter (PVAC group) or to point-by-point ablation supported by a 3-dimensional mapping system (3D group). RESULTS Forty patients per group were included. Mean age was 58 ± 10 years, 64% were male; 55% had paroxysmal AF, 45% had persistent AF. There were no significant differences between groups. Complete electrical isolation was reached in all but 1 PV, which was not isolated in the PVAC group because of phrenic nerve capture. Procedure and fluoroscopy times were lower in the PVAC group: 171 ± 40 minutes vs. 224 ± 27 minutes, P < .001; 26 ± 8 minutes vs. 35 ± 9 minutes, P < .001; respectively. There were no major complications. During a mean follow-up of 254 ± 99 days, 72% in the PVAC group and 68% in the 3D group were free of AF recurrences irrespective of the initial AF type (P = NS). CONCLUSION PVAC represents a safe alternative for PV isolation. It reduces both procedure and fluoroscopy time. The short- and middle-term efficacy is comparable to a conventional point-by-point antral ablation technique.

Damage to the esophagus after atrial fibrillation ablation: Just the tip of the iceberg? High prevalence of mediastinal changes diagnosed by endosonography.

Background—Radiofrequency catheter ablation is increasingly used in the treatment of atrial fibrillation. Esophageal wall changes varying from erythema to ulcers have been described by endoscopy in up to 47% of patients following pulmonary vein isolation (PVI). Although esophageal changes are frequently reported, the development of a left atrial (LA)-esophageal fistula is fortunately rare. Nevertheless, mucosal changes may just represent “the tip of the iceberg.” The aim of this study was, therefore, to investigate the more subtle changes of and injuries to the posterior wall of the LA, the periesophageal and mediastinal connective tissue, and the whole wall of the esophagus, including mucosal changes by esophagogastroduodenoscopy (EGD) combined with radial endosonography (EUS). Methods and Results—Twenty-nine patients (7 females; mean age, 57.7±10.5 years [range, 23–75 years]) underwent EGD and EUS before and after PVI within 48 hours. PVI was performed as a circumferential antral isolation of the septal and lateral pulmonary veins guided by a decapolar circular mapping catheter using a 3-dimensional mapping system with the integration of a preprocedurally acquired computed tomography scan of the left atrium. The maximum power applied was 30 W, with an open-irrigated catheter using a maximum flow rate of 30 mL/min. In all patients, the esophagus was reconstructed using the same computed tomography scan and displayed during the ablation procedure. In case of newly detected periesophageal changes, EGD and EUS were repeated 1 week after the PVI. In all patients, a regular contact area between the LA and the esophagus could be demonstrated before PVI. The mean vertical contact length was 4.4±1.5 cm (range, 2–10 cm); and the mean distance between the anterior wall of the esophagus and the endocardium was 2.6±0.8 mm (range, 1.4–4.0 mm). After PVI, morphological changes of the periesophageal connective tissue and the posterior wall of the LA were diagnosed by endosonography in 8 patients (27%; 95% confidence interval, 12.73–47.24). No mucosal changes of the esophagus in terms of erythema or ulcers were found. In all but one patient (who refused the control), all periesophageal and atrial changes had resolved within 1 week. No atrioesophageal fistula occurred during follow-up (mean follow-up, 294±110 days [range, 36–431 days]). Conclusions—Mucosal changes of the esophagus after PVI-like ulcers or erythema could not be demonstrated, yet structural changes of the mediastinum, which were only visible by endosonography, occurred in 27% of patients in the present study. This may indicate a higher than expected periesophageal injury because of PV ablation. Endosonography might prove to be a sensitive and reliable tool in the follow-up after PVI.Background— Radiofrequency catheter ablation is increasingly used in the treatment of atrial fibrillation. Esophageal wall changes varying from erythema to ulcers have been described by endoscopy in up to 47% of patients following pulmonary vein isolation (PVI). Although esophageal changes are frequently reported, the development of a left atrial (LA)-esophageal fistula is fortunately rare. Nevertheless, mucosal changes may just represent “the tip of the iceberg.” The aim of this study was, therefore, to investigate the more subtle changes of and injuries to the posterior wall of the LA, the periesophageal and mediastinal connective tissue, and the whole wall of the esophagus, including mucosal changes by esophagogastroduodenoscopy (EGD) combined with radial endosonography (EUS). Methods and Results— Twenty-nine patients (7 females; mean age, 57.7±10.5 years [range, 23–75 years]) underwent EGD and EUS before and after PVI within 48 hours. PVI was performed as a circumferential antral isolation of the septal and lateral pulmonary veins guided by a decapolar circular mapping catheter using a 3-dimensional mapping system with the integration of a preprocedurally acquired computed tomography scan of the left atrium. The maximum power applied was 30 W, with an open-irrigated catheter using a maximum flow rate of 30 mL/min. In all patients, the esophagus was reconstructed using the same computed tomography scan and displayed during the ablation procedure. In case of newly detected periesophageal changes, EGD and EUS were repeated 1 week after the PVI. In all patients, a regular contact area between the LA and the esophagus could be demonstrated before PVI. The mean vertical contact length was 4.4±1.5 cm (range, 2–10 cm); and the mean distance between the anterior wall of the esophagus and the endocardium was 2.6±0.8 mm (range, 1.4–4.0 mm). After PVI, morphological changes of the periesophageal connective tissue and the posterior wall of the LA were diagnosed by endosonography in 8 patients (27%; 95% confidence interval, 12.73–47.24). No mucosal changes of the esophagus in terms of erythema or ulcers were found. In all but one patient (who refused the control), all periesophageal and atrial changes had resolved within 1 week. No atrioesophageal fistula occurred during follow-up (mean follow-up, 294±110 days [range, 36–431 days]). Conclusions— Mucosal changes of the esophagus after PVI-like ulcers or erythema could not be demonstrated, yet structural changes of the mediastinum, which were only visible by endosonography, occurred in 27% of patients in the present study. This may indicate a higher than expected periesophageal injury because of PV ablation. Endosonography might prove to be a sensitive and reliable tool in the follow-up after PVI. Received October 19, 2009; accepted February 16, 2010. # CLINICAL PERSPECTIVE {#article-title-2}

Proarrhythmia as a Class Effect of Quinolones: Increased Dispersion of Repolarization and Triangulation of Action Potential Predict Torsades de Pointes

Background: Numerous noncardiovascular drugs prolong repolarization and thereby increase the risk for patients to develop life‐threatening tachyarrhythmias of the torsade de pointes (TdP) type. The development of TdP is an individual, patient‐specific response to a repolarization‐prolonging drug, depending on the repolarization reserve. The aim of the present study was to analyze the underlying mechanisms that discriminate hearts that will develop TdP from hearts that will not develop TdP. We therefore investigated the group of quinolone antibiotics that reduce repolarization reserve via IKr blockade in an intact heart model of proarrhythmia.

A new mechanism preventing proarrhythmia in chronic heart failure: rapid phase-III repolarization explains the low proarrhythmic potential of amiodarone in contrast to sotalol in a model of pacing-induced heart failure.

Life‐threatening arrhythmias are a major problem in chronic heart failure (CHF). The aim of the present study was to investigate the mechanism underlying the low proarrhythmic potential of amiodarone in a model of pacing‐induced heart failure.

Verapamil prevents torsade de pointes by reduction of transmural dispersion of repolarization and suppression of early afterdepolarizations in an intact heart model of LQT3

AbstractBackgroundIn long QT syndrome (LQTS), prolongation of the QT–interval is associated with sudden cardiac death resulting from potentially life–threatening polymorphic tachycardia of the torsade de pointes (TdP) type. Experimental as well as clinical reports support the hypothesis that calcium channel blockers such as verapamil may be an appropriate therapeutic approach in LQTS. We investigated the electrophysiologic mechanism by which verapamil suppresses TdP, in a recently developed intact heart model of LQT3.Methods and results In 8 Langendorff–perfused rabbit hearts, veratridine (0.1 µM), an inhibitor of sodium channel inactivation, led to a marked increase in QT–interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p < 0.05) thereby mimicking LQT3. In bradycardic (AV–blocked) hearts, simultaneous recording of up to eight epi– and endocardial MAPs demonstrated a significant increase in total dispersion of repolarization (56%, p < 0.05) and reverse frequency–dependence. After lowering potassium concentration, veratridine reproducibly led to early afterdepolarizations (EADs) and TdP in 6 of 8 (75%) hearts. Additional infusion of verapamil (0.75 µM) suppressed EADs and consecutively TdP in all hearts. Verapamil significantly shortened endocardial but not epicardial MAPs which resulted in significant reduction of ventricular transmural dispersion of repolarization.ConclusionsVerapamil is highly effective in preventing TdP via shortening of endocardial MAPs, reduction of left ventricular transmural dispersion of repolarization and suppression of EADs in an intact heart model of LQT3. These data suggest a possible therapeutic role of verapamil in the treatment of LQT3 patients.

Further insights into the underlying electrophysiological mechanisms for reduction of atrial fibrillation by ranolazine in an experimental model of chronic heart failure

Ranolazine (RAN) was reported to be effective and safe in converting atrial fibrillation (AF) to sinus rhythm by administration of a single dose (‘pill in the pocket’) to patients with structural heart disease. This study examines the underlying mechanisms for the antiarrhythmic benefit of RAN application in chronic heart failure (CHF).