Nils Bögeholz

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na+/Ca2+ Exchanger in a Murine Model.

Background—The Na+/Ca2+ exchanger (NCX) has been implied to cause arrhythmias. To date, information on the role of NCX in arrhythmogenesis derived from models with increased NCX expression, hypertrophy, and heart failure. Furthermore, the exact mechanism by which NCX exerts its potentially proarrhythmic effect, ie, by promoting early afterdepolarization (EAD) or delayed afterdepolarization (DAD) or both, is unknown. Methods and Results—We investigated isolated cardiomyocytes from a murine model with heterozygous knockout of NCX (hetKO) using the patch clamp and Ca2+ imaging techniques. Action potential duration was shorter in hetKO with IKtot not being increased. The rate of spontaneous Ca2+ release events and the rate of DADs were unaltered; however, DADs had lower amplitude in hetKO. A DAD triggered a spontaneous action potential significantly less often in hetKO when compared with wild-type. The occurrence of EADs was also drastically reduced in hetKO. ICa activity was reduced in hetKO, an effect that was abolished in the presence of the Ca2+ buffer BAPTA. Conclusions—Genetic suppression of NCX reduces both EADs and DADs. The following molecular mechanisms apply: (1) Although the absolute number of DADs is unaffected, an impaired translation of DADs into spontaneous action potentials results from a reduced DAD amplitude. (2) EADs are reduced in absolute number of occurrence, which is presumably a consequence of shortened action potential duration because of reduced NCX activity but also reduced ICa the latter possibly being caused by a direct modulation of Ca2+-dependent ICa inhibition by reduced NCX activity. This is the first study to demonstrate that genetic inhibition of NCX protects against afterdepolarizations and to investigate the underlying mechanisms.

Effective suppression of atrial fibrillation by ivabradine: Novel target for an established drug?

BACKGROUND Ivabradine is an inhibitor of mixed Na+-K+-currents and routinely administered in chronic heart failure. Clinical studies reported divergent trends regarding proarrhythmic and antiarrhythmic effects in atrial fibrillation (AF). METHODS AND RESULTS In 12 isolated rabbit hearts AF was induced in 7 of 12 hearts (13 episodes) under baseline conditions by a standardized protocol employing atrial burst pacing. Thereafter, a combination of acetylcholine and isoproterenol was employed to enhance AF occurrence. Monophasic action potential recordings showed a decrease of atrial action potential duration (aAPD,-37ms, p<0.05) and atrial effective refractory period (aERP;-39ms, p<0.05) after infusion of both acetycholine (1μM) and isoproterenol (1μM) as compared with baseline. This led to induction of AF in 11 of 12 hearts (124 episodes). Simultaneous infusion of ivabradine (3μM) led to a significant reduction of AF (6 of 11 hearts, 63 episodes). Ivabradine induced an increase of aAPD (+9ms) and aERP (+30ms, p<0.05) leading to a marked increase of atrial post-repolarization refractoriness (aPRR), defined as the difference of aERP and aAPD (+21ms, p<0.05). Results were compared to 10 rabbits treated with flecainide. Flecainide treatment also induced a significant increase of aPRR and resulted in induction of AF in 6 of 10 hearts (58 episodes) while 9 of 10 hearts were inducible during sole treatment with acetylcholine and isoproterenol (129 episodes). CONCLUSION In the present experimental study, administration of ivabradine reduced inducibility of AF and therefore may represent a supplemental therapeutic option in AF. Of note, its antiarrhythmic efficacy was comparable to the established agent flecainide.

The physiology of cardiac calcium handling.

ZusammenfassungDer myokardiale Kalziumstoffwechsel ist für eine physiologische Herzfunktion von essentieller Bedeutung. Diese Übersichtsarbeit beschreibt die Rolle von Ca2+ Ionen während des kontraktilen Zyklus und der myokardialen Erregung sowie den modulierenden Einfluss β-adrenerger Stimulation.SummaryCardiac calcium (Ca2+) handling subsumes the mechanisms maintaining the myocardial Ca2+ homeostasis that contribute essentially to cardiac performance. This review addresses the interaction of transplasmalemmal and transsarcoplasmic Ca2+ flux, its potential modifications due to β-adrenergic stimulation and its implications on cardiac action potential.

Direct comparison of the novel automated screening tool (AST) versus the manual screening tool (MST) in patients with already implanted subcutaneous ICD

BACKGROUND The subcutaneous implantable cardioverter-defibrillator (S-ICD) has evolved as a valuable alternative to the transvenous ICD, especially in young patients. Unfortunately, some of these patients are ineligible for S-ICD implantation due to specific electrocardiographic features. So far, these patients were identified by mandatory pre-implantation screening using the manual screening tool (MST), which lacks objective value. Therefore, a novel automated screening tool (AST) has been introduced recently for objective screening, which has not been evaluated yet. METHODS/RESULTS We here first investigate the novel AST, in direct comparison to MST, in 33 consecutive patients with already implanted S-ICD system to compare predicted eligibility by screening tools with true sensing of the S-ICD system. Both screening tools reliably predicted true ineligible single vectors, but also suggested overall ineligibility in a similar fraction of patients (MST: 3.0%; AST: 6.1%), albeit the implanted S-ICD worked flawlessly in these patients. AST did not predict the finally selected sensing vector better than MST. There was a surprising mismatch between AST and MST for the predicted eligibility of single vectors; only in 49% of patients did both screening tools predict eligibility for the same vectors. CONCLUSIONS The novel AST predicted overall eligibility approximately similar to MST. Both tools predicted ineligibility in a few patients, who were actually eligible. There was a striking mismatch between both screening tools when eligibility of single vectors was predicted. Thus, the AST seems to be a valuable advance, due to its standardized and objective process, but it still lacks specificity.

Slow pathway modification in patients presenting with only two consecutive AV nodal echo beats

BACKGROUND Slow pathway modification (SPM) is the therapy of choice for AV-nodal reentry tachycardia (AVNRT). When AVNRT is not inducible, empirical ablation can be considered, however, the outcome in patients with two AV nodal echo beats (AVNEBs) is unknown. METHODS Out of a population of 3003 patients who underwent slow pathway modification at our institution between 1993 and 2013, we retrospectively included 32 patients with a history of symptomatic tachycardia, lack of paroxysmal supraventricular tachycardia (pSVT) inducibility but occurrence of two AVNEBs. RESULTS pSVT documentation by electrocardiography (ECG) was present in 20 patients. The procedural endpoint was inducibility of less than two AVNEBs. This was reached in 31 (97%) patients. Long-term success was assessed by a telephone questionnaire (follow-up time 63±9 months). A total 94% of the patients benefited from the procedure (59% freedom from symptoms; 34% improvement in symptoms). Among those patients in whom ECG documentation was not present, 100% benefited (58% freedom from symptoms, 42% improvement). CONCLUSION This is the first collective analysis of a group of patients presenting with symptoms of pSVT and inducibility of only two AVNEBs. Procedural success and clinical long-term follow-up were in the range of the reported success rates of slow pathway modification of inducible AVNRT, independent of whether ECG documentation was present. Thus, SPM is a safe and effective therapy in patients with two AVNEBs.

The Effects of SEA0400 on Ca2+ Transient Amplitude and Proarrhythmia Depend on the Na+/Ca2+ Exchanger Expression Level in Murine Models

Background/Objective: The cardiac Na+/Ca2+ exchanger (NCX) has been identified as a promising target to counter arrhythmia in previous studies investigating the benefit of NCX inhibition. However, the consequences of NCX inhibition have not been investigated in the setting of altered NCX expression and function, which is essential, since major cardiac diseases (heart failure/atrial fibrillation) exhibit NCX upregulation. Thus, we here investigated the effects of the NCX inhibitor SEA0400 on the Ca2+ transient amplitude and on proarrhythmia in homozygous NCX overexpressor (OE) and heterozygous NCX knockout (hetKO) mice compared to corresponding wild-types (WTOE/WThetKO). Methods/Results: Ca2+ transients of field-stimulated isolated ventricular cardiomyocytes were recorded with fluo-4-AM or indo-1-AM. SEA0400 (1 μM) significantly reduced NCX forward mode function in all mouse lines. SEA0400 (1 μM) significantly increased the amplitude of field-stimulated Ca2+ transients in WTOE, WThetKO, and hetKO, but not in OE (% of basal; OE = 98.7 ± 5.0; WTOE = 137.8 ± 5.2*; WThetKO = 126.3 ± 6.0*; hetKO = 140.6 ± 12.8*; *p < 0.05 vs. basal). SEA0400 (1 μM) significantly reduced the number of proarrhythmic spontaneous Ca2+ transients (sCR) in OE, but increased it in WTOE, WThetKO and hetKO (sCR per cell; basal/+SEA0400; OE = 12.5/3.7; WTOE = 0.2/2.4; WThetKO = 1.3/8.8; hetKO = 0.2/5.5) and induced Ca2+ overload with subsequent cell death in hetKO. Conclusion: The effects of SEA0400 on Ca2+ transient amplitude and the occurrence of spontaneous Ca2+ transients as a proxy measure for inotropy and cellular proarrhythmia depend on the NCX expression level. The antiarrhythmic effect of SEA0400 in conditions of increased NCX expression promotes the therapeutic concept of NCX inhibition in heart failure/atrial fibrillation. Conversely, in conditions of reduced NCX expression, SEA0400 suppressed the NCX function below a critical level leading to adverse Ca2+ accumulation as reflected by an increase in Ca2+ transient amplitude, proarrhythmia and cell death. Thus, the remaining NCX function under inhibition may be a critical factor determining the inotropic and antiarrhythmic efficacy of SEA0400.

Change of sensing vector in the subcutaneous ICD during follow-up and after device replacement: BETTIN et al.

The subcutaneous implantable cardioverter defibrillator (S‐ICD) has been established as a valuable alternative to transvenous ICD for prevention of sudden cardiac death. The system automatically chooses the optimal sensing vector. However, during follow‐up and especially after device replacement we observed a change of the suggested sensing vector in automatic setup. Therefore, we analyzed frequency and reasons of vector change and its impact on inappropriate shocks (IAS).

Increased sodium/calcium exchanger activity enhances beta-adrenergic–mediated increase in heart rate: Whole-heart study in a homozygous sodium/calcium exchanger overexpressor mouse model

BACKGROUND The cardiac sodium/calcium (Na+/Ca2+) exchanger (NCX) contributes to diastolic depolarization in cardiac pacemaker cells. Increased NCX activity has been found in heart failure and atrial fibrillation. The influence of increased NCX activity on resting heart rate, beta-adrenergic-mediated increase in heart rate, and cardiac conduction properties is unknown. OBJECTIVE The purpose of this study was to investigate the influence of NCX overexpression in a homozygous transgenic whole-heart mouse model (NCX-OE) on sinus and AV nodal function. METHODS Langendorff-perfused, beating whole hearts of NCX-OE and the corresponding wild-type (WT) were studied ± isoproterenol (ISO; 0.2 μM). Epicardial ECG, AV nodal Wenckebach cycle length (AVN-WCL), and retrograde AVN-WCL were obtained. RESULTS At baseline, basal heart rate was unaltered between NCX-OE and WT (WT: cycle length [CL] 177.6 ± 40.0 ms, no. of hearts [n] = 20; NCX-OE: CL 185.9 ± 30.5 ms, n = 18; P = .21). In the presence of ISO, NCX-OE exhibited a significantly higher heart rate compared to WT (WT: CL 133.4 ± 13.4 ms, n = 20; NCX-OE: CL 117.7 ± 14.2 ms, n = 18; P <.001). ISO led to a significant shortening of the anterograde and retrograde AVN-WCL without differences between NCX-OE and WT. CONCLUSION This study is the first to demonstrate that increased NCX activity enhances beta-adrenergic increase of heart rate. Mechanistically, increased NCX inward mode activity may promote acceleration of diastolic depolarization in sinus nodal pacemaker cells, thus enhancing chronotropy in NCX-OE. These findings suggest a novel potential therapeutic target for heart rate control in the presence of increased NCX activity, such as heart failure.

Ivabradine Reduces Digitalis‐induced Ventricular Arrhythmias

The I(f) channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of this study was to examine the electrophysiological effects of ivabradine on digitalis‐induced ventricular arrhythmias.

Ryanodine‐receptor inhibition by dantrolene effectively suppresses ventricular arrhythmias in an ex vivo model of long‐QT syndrome

A significant antiarrhythmic potential of ryanodine receptor inhibition was reported in experimental studies. The aim of the present study was to assess potential antiarrhythmic effects of dantrolene in an experimental whole‐heart model of drug‐induced long‐QT syndrome (LQTS).