Gerrit Frommeyer

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.

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.

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).

Antiarrhythmic effects of free polyunsaturated fatty acids in an experimental model of LQT2 and LQT3 due to suppression of early afterdepolarizations and reduction of spatial and temporal dispersion of repolarization

BACKGROUND Torsades de pointes (TdP) are induced by early afterdepolarizations (EADs) in the presence of an increased dispersion of repolarization. Free polyunsaturated fatty acids (PUFAs) have been suggested to influence cardiac repolarization. OBJECTIVE The purpose of this experimental study was to investigate the electrophysiologic effects of PUFAs in a model of LQT2 and LQT3. METHODS We investigated the acute antiarrhythmic potential of α-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) in a whole-heart model of long QT2 (LQT2) and long QT3 (LQT3) syndrome. RESULTS In 123 Langendorff-perfused rabbit hearts, the I(Kr)-blocking drug erythromycin (E; 300 μM) or veratridine (V; 0.5 μM), an inhibitor of sodium channel inactivation, significantly increased monophasic ventricular action potentials (MAPs), thereby mimicking LQT2 and LQT3 syndrome. In atrioventricular-blocked hearts, 8 epicardial and endocardial MAPs demonstrated a significant increase in spatial and temporal dispersion. After lowering potassium concentration, E led to EADs and TdP in 44 and 41 of 53 hearts, respectively. Pretreatment with V led to EAD (TdP) in 39 (32) of 43 hearts. Additional treatment with ALA, DHA, or EPA (10 to 20 μM) in the LQT2 model, randomly assigned to 3 groups, suppressed EAD in 72% of ALA-treated hearts and in all hearts that were treated with EPA or DHA. This led to a reduction of TdP of 67% (ALA) and to complete abolishment of TdP in all hearts that were treated with EPA or DHA. A comparable finding was seen in V-pretreated hearts. In addition, DHA and EPA significantly shortened MAP duration and reduced spatial and temporal dispersion of repolarization (P <.01). CONCLUSION The present study showed for the first time that PUFAs are effective in preventing TdP in an experimental model of LQT2 and LQT3 syndrome due to a reversion of AP prolongation, a reduction of spatial and temporal dispersion of repolarization and a suppression of EAD. The PUFA effect is stronger in LQT2 than in LQT3 syndrome, and the antitorsadogenic effect is more remarkable with DHA and EPA as compared with ALA.

Supraventricular Premature Beats and Short Atrial Runs Predict Atrial Fibrillation in Continuously Monitored Patients With Cryptogenic Stroke

Background and Purpose— Supraventricular premature beats (SPBs) may help to assess the risk of atrial fibrillation (AF) in patients with cryptogenic stroke and therefore guide therapy. Methods— An internal loop recorder was implanted in consecutive patients with acute cryptogenic stroke. The occurrence and quantity of SPBs and short supraventricular runs (SVRs) in 24-hour ECG in patients with and without future AF were analyzed. We evaluated the relative risk of the upper quartile of SPB and SVR patients against the remainder and used binary logistic regression to evaluate a possible independent influence of SPBs and SVRs on AF occurrence. Results— Twelve of 70 included patients (mean age, 59±13 years) experienced development of AF during a mean monitoring duration of 536±212 days. Patients with AF had a median of 22.8 SPBs/h versus 1.2 SPBs/h (P<0.0001) in patients without AF and a median of 0.7 SVRs/h (AF) versus 0 SVR/h (non-AF). Patients in the upper quartile of SPBs (>14.1/h) and SVRs (>0.2/h) demonstrated a relative risk of 4.0 (95% confidence interval, 1.1–14.6; P=0.04) and 6.9 (95% confidence interval, 1.8–26.7; P=0.005) for future AF, respectively. In binary logistic regression, SPBs (P=0.02) and SVRs (P=0.05) remained significant independent predictors for occurrence of AF. Conclusions— Numerous SPBs and SVRs demonstrated a high risk for future AF in patients with cryptogenic stroke.

Effect of ranolazine on ventricular repolarization in class III antiarrhythmic drug-treated rabbits

BACKGROUND Ranolazine exhibits a synergistic effect in combination with class III drugs to suppress atrial fibrillation. OBJECTIVE To investigate whether a combination therapy affects repolarization and provokes ventricular tachyarrhythmias (VT) in a sensitive model of proarrhythmia. METHODS Thirty-seven rabbits were assigned to 3 groups and fed with amiodarone (50 mg/kg/d; n = 10) or dronedarone (50 mg/kg/d; n = 10) over a period of 6 weeks. A third group was used as control (n = 17). After obtaining baseline data in Langendorff-perfused control hearts, sotalol (100 μM) was administered in this group. Thereafter, ranolazine (10 μM) was additionally infused on top of amiodarone, dronedarone, or sotalol. RESULTS Chronic treatment with amiodarone or dronedarone as well as sotalol significantly increased action potential duration at 90% repolarization (APD(90)). Additional treatment with ranolazine further increased APD(90) in amiodarone- and dronedarone-pretreated hearts but not in sotalol-treated hearts. Ranolazine increased postrepolarization refractoriness as compared with amiodarone or dronedarone alone owing to a marked effect on the refractory period. In contrast to amiodarone and dronedarone, acute application of sotalol increased dispersion of repolarization (P < .05). Additional treatment with ranolazine did not further increase spatial or temporal dispersion. After lowering extracellular [K(+)] in bradycardic hearts, no proarrhythmia occurred in amiodarone- or dronedarone-treated hearts whereas 11 of 17 sotalol-treated hearts showed early afterdepolarizations and subsequent polymorphic VT. Additional treatment with ranolazine reduced the number of VT episodes in sotalol-treated hearts and did not cause proarrhythmia in combination with amiodarone or dronedarone. CONCLUSIONS Application of ranolazine on top of class III drugs does not cause proarrhythmia despite a marked effect on ventricular repolarization. The effect of ranolazine on the repolarization reserve is associated with the lack of effect on early afterdepolarizations and dispersion of repolarization.

Acute inhibition of the Na/Ca 2 exchanger reduces proarrhythmia in an experimental model of chronic heart failure

BACKGROUND Molecular remodeling in heart failure includes slowing of repolarization, leading to proarrhythmia. OBJECTIVE To evaluate the effects of Na(+)/Ca(2+) exchanger (NCX) inhibition on repolarization as a novel antiarrhythmic concept in chronic heart failure (CHF). METHODS AND RESULTS CHF was induced by rapid ventricular pacing in rabbits. Left ventricular function was assessed by echocardiography. Monophasic action potentials (MAPs) showed a prolongation of repolarization in CHF after atrioventricular block and stimulation at different cycle lengths. Sotalol (100 μM, n = 13) or veratridine (0.5 μM; n = 15) resulted in a further significant increase in the MAP duration. CHF was associated with an increased dispersion of repolarization, as compared with sotalol-treated (+22 ± 7 ms; P < .05) and veratridine-treated (+20 ± 6 ms; P < .05) sham hearts. In the presence of a low potassium concentration, sotalol and veratridine reproducibly induced early afterdepolarizations (EADs) and polymorphic ventricular tachyarrhythmias (VTs). SEA0400 (1 μM), a pharmacological inhibitor of NCX, significantly shortened the MAP duration (P < .01) and reduced dispersion (P < .05). It suppressed EAD in 6 of 13 sotalol-treated failing hearts and in 9 of 10 veratridine-treated failing hearts, leading to a reduction in VT (60% in sotalol-treated failing hearts and 83% in veratridine-treated failing hearts). Simulations using a mathematical model showed a reduction in the action potential duration and the number of EADs by the NCX block in all subgroups. CONCLUSIONS In an experimental model of CHF, the acute inhibition of NCX (1) reduces the MAP duration, (2) decreases dispersion of repolarization, and (3) suppresses EAD and VT. Our observations indicate for the first time that pharmacological NCX inhibition increases repolarization reserve and protects against VTs in heart failure.

Sodium channel block by ranolazine in an experimental model of stretch-related atrial fibrillation: prolongation of interatrial conduction time and increase in post-repolarization refractoriness

AIMS In several clinical and pre-clinical studies, application of ranolazine (RAN) led to suppression of atrial fibrillation (AF). The aim of the present study was to investigate whether RAN can suppress AF in an experimental rabbit whole heart model, in which acute haemodynamic changes trigger AF. Ranolazine was compared with flecainide and sotalol as established antiarrhythmic agents. METHODS AND RESULTS In 60 Langendorff-perfused, isolated rabbit hearts, AF episodes were evoked by burst pacing with a fixed number of stimuli at baseline and following acute atrial stretch. Data were obtained in the absence and presence of acute dilatation of the left atrium (20 mmHg) at baseline and after drug application (RAN 10 µM, n = 10; flecainide 2 µM, n = 10; sotalol 50 µM, n = 10). Application of sotalol, but not RAN or flecainide increased the atrial action potential duration at 90% repolarization (aAPD90); however, both RAN (+8 ms) and flecainide (+13 ms) increased interatrial conduction time. All three drugs caused a significant increase in atrial effective refractory period (aERP) and, thus, an increase in atrial post-repolarization refractoriness (aPRR: +11 ms each, P < 0.05). Acute dilatation of the left atrium reduced aAPD90 and aERP. The described drug effects were preserved in the setting of acute atrial dilatation. Acute atrial dilatation significantly increased the incidence of AF. Ranolazine and flecainide, but not sotalol, decreased the number of responses. CONCLUSION Ranolazine-related sodium channel block is preserved upon acute atrial stretch. Ranolazine suppresses stretch-induced AF by increasing interatrial conduction time and aPRR. These results shed further evidence on the potential role of RAN in the prevention of AF. This might also apply to clinical conditions that are associated with haemodynamic or mechanical disorders, leading to acute dilatation of the atria.

Electrophysiologic profile of dronedarone on the ventricular level: beneficial effect on postrepolarization refractoriness in the presence of rapid phase 3 repolarization.

Background Dronedarone (D) is developed to maintain sinus rhythm in patients suffering from atrial fibrillation. The aim of the present study was to investigate, whether dronedarone also has an antiarrhythmic potential in the ventricle and to elucidate the mechanisms for its low proarrhythmic potential in an experimental whole heart model. Methods and Results Thirty-five rabbits underwent chronic treatment with D (n = 15; 50 mg·kg−1·d−1) and amiodarone (A; n = 20; 50 mg·kg−1·d−1). Hearts were perfused on a Langendorff apparatus. Results were compared with hearts acutely treated with sotalol (S; 50–100 &mgr;M; n = 14). A 12-lead electrocardiogram and up to 8 ventricular epi- and endocardial monophasic action potentials showed a significant prolongation of QT interval (D: +24 milliseconds, A: +28 milliseconds, S: +35 milliseconds (50 &mgr;M), +56 milliseconds (100 &mgr;M); P < 0.02) compared with baseline. In contrast to D and A, S led to a significant increase in dispersion of repolarization and exhibited reverse use dependence. D, A, and S increased refractory period, resulting in a significant increase in postrepolarization refractoriness (effective refractory period minus action potential duration; D = +12 milliseconds; A = +14 milliseconds; S = +25 milliseconds; P < 0.05). S led to a triangular action potential configuration, whereas D and A caused a fast phase 3 prolongation. After lowering of potassium concentration, 50% of S-treated hearts showed torsade de pointes, in contrast to an absence of torsade de pointes in D and A. Conclusions Prolongation of myocardial repolarization and postrepolarization refractoriness by D may act antiarrhythmic. A fast phase 3 repolarization in the absence of both increased dispersion of repolarization and reverse use dependence prevents proarrhythmia.

Intraoperative Defibrillation Testing of Subcutaneous Implantable Cardioverter‐Defibrillator Systems—A Simple Issue?

Background The results of the recently published randomized SIMPLE trial question the role of routine intraoperative defibrillation testing. However, testing is still recommended during implantation of the entirely subcutaneous implantable cardioverter‐defibrillator (S‐ICD) system. To address the question of whether defibrillation testing in S‐ICD systems is still necessary, we analyzed the data of a large, standard‐of‐care prospective single‐center S‐ICD registry. Methods and Results In the present study, 102 consecutive patients received an S‐ICD for primary (n=50) or secondary prevention (n=52). Defibrillation testing was performed in all except 4 patients. In 74 (75%; 95% CI 0.66–0.83) of 98 patients, ventricular fibrillation was effectively terminated by the first programmed internal shock. In 24 (25%; 95% CI 0.22–0.44) of 98 patients, the first internal shock was ineffective and further internal or external shock deliveries were required. In these patients, programming to reversed shock polarity (n=14) or repositioning of the sensing lead (n=1) or the pulse generator (n=5) led to successful defibrillation. In 4 patients, a safety margin of <10 J was not attained. Nevertheless, in these 4 patients, ventricular arrhythmias were effectively terminated with an internal 80‐J shock. Conclusions Although it has been shown that defibrillation testing is not necessary in transvenous ICD systems, it seems particular important for S‐ICD systems, because in nearly 25% of the cases the primary intraoperative test was not successful. In most cases, a successful defibrillation could be achieved by changing shock polarity or by optimizing the shock vector caused by the pulse generator or lead repositioning.