Contact force sensing manual catheter versus remote magnetic navigation ablation of atrial fibrillation: a single-center comparison.

BACKGROUND: Data comparing remote magnetic catheter navigation (RMN) with manual catheter navigation in combination with contact force sensing (MCN-CF) ablation of atrial fibrillation (AF) is lacking. The primary aim of the present retrospective comparative study was to compare the outcome of RMN versus (vs.) MCN-CF ablation of AF with regards to AF recurrence. Secondary aim was to analyze periprocedural risk, ablation characteristics and repeat procedures. METHODS: We retrospectively analyzed 452 patients undergoing a total of 605 ablations of AF: 180 patients were ablated using RMN, 272 using MCN-CF. RESULTS: Except body mass index there was no significant difference between groups at baseline. After a mean 1.6 ± 1.6 years of follow-up and 1.3 ± 0.4 procedures, 81% of the patients in the MCN-CF group remained free of AF recurrence compared to 53% in the RMN group (P < 0.001). After analysis of 153 repeat ablations (83 MCN-RF vs. 70 RMN; P = 0.18), there was a significantly higher reconnection rate of pulmonary veins after RMN ablation (P < 0.001). In multivariable Cox-regression analysis, RMN ablation (P < 0.001) and left atrial diameter (P = 0.013) was an independent risk factor for AF recurrence. Procedure time, radiofrequency application time and total fluoroscopy time and fluoroscopy dose were higher in the RMN group without difference in total number of ablation points. Complication rates did not differ significantly between groups (P = 0.722). CONCLUSIONS: In our retrospective comparative study, the AF recurrence rate and pulmonary vein reconnection rate is significantly lower with more favorable procedural characteristics and similar complication rate utilizing MCN-CF compared to RMN.

Remote magnetic navigation versus manual catheter ablation of atrial fibrillation: A single center long-term comparison.

BACKGROUND: Data comparing remote magnetic catheter navigation (RMN) with manual catheter navigation (MCN) ablation of atrial fibrillation (AF) is lacking. The aim of the present prospective observational study was to compare the outcome of RMN versus (vs.) MCN ablation of AF with regards to AF recurrence. METHODS: The study comprised 667 consecutive patients with a total of 939 procedures: 287 patients were ablated using RMN, 380 using MCN. RESULTS: There was no significant difference between the groups at baseline. After 2.3 ± 2.3 years of follow-up, 23% of the patients in the MCN group remained free of AF recurrence compared to 13% in the RMN group (p < .001). After analysis of 299 repeat ablations (133 MCN, 166 RMN) there was a significantly higher reconnection rate of pulmonary veins after RMN ablation p < .001). In multivariable Cox-regression analysis, RMN ablation was an independent risk factor for AF recurrence besides age, persistent AF, number of isolated pulmonary veins, and left atrial diameter. Procedure time, radiofrequency application time and total number of ablation points were higher in the RMN group. Total fluoroscopy time and total fluoroscopy dose were significantly lower for RMN. Complication rates did not differ between groups (p = .842), although the incidence of significant pericardial effusion was higher in the MCN group (seven cases vs. three in RMN group). CONCLUSIONS: In our study the AF recurrence rate and pulmonary vein reconnection rate is higher after RMN ablation with a similar complication rate but reduced probability of pericardial effusion when compared to MCN.

Heart Failure Results in Inspiratory Muscle Dysfunction Irrespective of Left Ventricular Ejection Fraction.

BACKGROUND: Exercise intolerance in heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) results from both cardiac dysfunction and skeletal muscle weakness. Respiratory muscle dysfunction with restrictive ventilation disorder may be present irrespective of left ventricular ejection fraction and might be mediated by circulating pro-inflammatory cytokines. OBJECTIVE: To determine lung and respiratory muscle function in patients with HFrEF/HFpEF and to determine its associations with exercise intolerance and markers of systemic inflammation. METHODS: Adult patients with HFrEF (n = 22, 19 male, 61 ± 14 years) and HFpEF (n = 8, 7 male, 68 ± 8 years) and 19 matched healthy control subjects underwent spirometry, measurement of maximum mouth occlusion pressures, diaphragm ultrasound, and recording of transdiaphragmatic and gastric pressures following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. New York Heart Association (NYHA) class and 6-min walking distance (6MWD) were used to quantify exercise intolerance. Levels of circulating interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured using ELISAs. RESULTS: Compared with controls, both patient groups showed lower forced vital capacity (FVC) (p < 0.05), maximum inspiratory pressure (PImax), maximum expiratory pressure (PEmax) (p < 0.05), diaphragm thickening ratio (p = 0.01), and diaphragm strength (twitch transdiaphragmatic pressure in response to supramaximal cervical magnetic phrenic nerve stimulation) (p = 0.01). In patients with HFrEF, NYHA class and 6MWD were both inversely correlated with FVC, PImax, and PEmax. In those with HFpEF, there was an inverse correlation between amino terminal pro B-type natriuretic peptide levels and FVC (r = -0.77, p = 0.04). In all HF patients, IL-6 and TNF-α were statistically related to FVC. CONCLUSIONS: Irrespective of left ventricular ejection fraction, HF is associated with respiratory muscle dysfunction, which is associated with increased levels of circulating IL-6 and TNF-α.

Contribution of the neuronal sodium channel NaV1.8 to sodium- and calcium-dependent cellular proarrhythmia.

OBJECTIVE: In myocardial pathology such as heart failure a late sodium current (INaL) augmentation is known to be involved in conditions of arrhythmogenesis. However, the underlying mechanisms of the INaL generation are not entirely understood. By now evidence is growing that non-cardiac sodium channel isoforms could also be involved in the INaL generation. The present study investigates the contribution of the neuronal sodium channel isoform NaV1.8 to arrhythmogenesis in a clearly-defined setting of enhanced INaL by using anemone toxin II (ATX-II) in the absence of structural heart disease. METHODS: Electrophysiological experiments were performed in order to measure INaL, action potential duration (APD), SR-Ca2+-leak and cellular proarrhythmic triggers in ATX-II exposed wild-type (WT) and SCN10A-/- mice cardiomyocytes. In addition, WT cardiomyocytes were stimulated with ATX-II in the presence or absence of NaV1.8 inhibitors. INCX was measured by using the whole cell patch clamp method. RESULTS: In WT cardiomyocytes exposure to ATX-II augmented INaL, prolonged APD, increased SR-Ca2+-leak and induced proarrhythmic triggers such as early afterdepolarizations (EADs) and Ca2+-waves. All of them could be significantly reduced by applying NaV1.8 blockers PF-01247324 and A-803467. Both blockers had no relevant effects on cellular electrophysiology of SCN10A-/- cardiomyocytes. Moreover, in SCN10A-/--cardiomyocytes, the ATX-II-dependent increase in INaL, SR-Ca2+-leak and APD prolongation was less than in WT and comparable to the results which were obtained with WT cardiomyocytes being exposed to ATX-II and NaV1.8 inhibitors in parallel. Moreover, we found a decrease in reverse mode NCX current and reduced CaMKII-dependent RyR2-phosphorylation after application of PF-01247324 as an underlying explanation for the Na+-mediated Ca2+-dependent proarrhythmic triggers. CONCLUSION: The current findings demonstrate that NaV1.8 is a significant contributor for INaL-induced arrhythmic triggers. Therefore, NaV1.8 inhibition under conditions of an enhanced INaL constitutes a promising antiarrhythmic strategy which merits further investigation.

Inhibition of NaV1.8 prevents atrial arrhythmogenesis in human and mice.

Pharmacologic approaches for the treatment of atrial arrhythmias are limited due to side effects and low efficacy. Thus, the identification of new antiarrhythmic targets is of clinical interest. Recent genome studies suggested an involvement of SCN10A sodium channels (NaV1.8) in atrial electrophysiology. This study investigated the role and involvement of NaV1.8 (SCN10A) in arrhythmia generation in the human atria and in mice lacking NaV1.8. NaV1.8 mRNA and protein were detected in human atrial myocardium at a significant higher level compared to ventricular myocardium. Expression of NaV1.8 and NaV1.5 did not differ between myocardium from patients with atrial fibrillation and sinus rhythm. To determine the electrophysiological role of NaV1.8, we investigated isolated human atrial cardiomyocytes from patients with sinus rhythm stimulated with isoproterenol. Inhibition of NaV1.8 by A-803467 or PF-01247324 showed no effects on the human atrial action potential. However, we found that NaV1.8 significantly contributes to late Na+ current and consequently to an increased proarrhythmogenic diastolic sarcoplasmic reticulum Ca2+ leak in human atrial cardiomyocytes. Selective pharmacological inhibition of NaV1.8 potently reduced late Na+ current, proarrhythmic diastolic Ca2+ release, delayed afterdepolarizations as well as spontaneous action potentials. These findings could be confirmed in murine atrial cardiomyocytes from wild-type mice and also compared to SCN10A-/- mice (genetic ablation of NaV1.8). Pharmacological NaV1.8 inhibition showed no effects in SCN10A-/- mice. Importantly, in vivo experiments in SCN10A-/- mice showed that genetic ablation of NaV1.8 protects against atrial fibrillation induction. This study demonstrates that NaV1.8 is expressed in the murine and human atria and contributes to late Na+ current generation and cellular arrhythmogenesis. Blocking NaV1.8 selectively counteracts this pathomechanism and protects against atrial arrhythmias. Thus, our translational study reveals a new selective therapeutic target for treating atrial arrhythmias.

Inhibition of Late Sodium Current as an Innovative Antiarrhythmic Strategy.

PURPOSE OF REVIEW: Over the last years, evidence is accumulating that enhanced late sodium current (INaL) in cardiac pathologies has fundamental consequences for cellular electrophysiology. This review discusses the underlying mechanisms of INaL-induced arrhythmias and the significance of INaL-inhibition as a possible therapeutic approach. RECENT FINDINGS: Inhibition of enhanced INaL, e.g., by ranolazine, was shown to reverse these effects in different myocardial diseases including heart failure. The antianginal drug ranolazine has already been examined in larger clinical trials with promising antiarrhythmic actions. Enhanced INaL was found to be present in several cardiac pathologies like ischemia, long QT syndromes, hypertrophic cardiomyopathy, and heart failure. In settings of enhanced INaL, a sodium-dependent calcium overload leads to severe impairment of excitation-contraction coupling and therefore has a high proarrhythmogenic potential. Experimental data showed that inhibition of INaL has a high antiarrhythmic potential which could be confirmed in further clinical trials.

Case report of persistent atrial fibrillation with durably isolated pulmonary veins: what's next?

Background: Pulmonary vein isolation (PVI) has emerged as a safe and effective treatment for patients with paroxysmal and persistent atrial fibrillation. Nevertheless, in some patients, a relapse of atrial fibrillation occurs although pulmonary veins are durably isolated. For those patients, the underlying mechanisms of atrial fibrillation perpetuation are manifold and optimal treatment options are not yet defined. Case summary: We describe a case of a 55-year-old man with a history of atrial fibrillation and previous PVI presenting with persistent AF and arrhythmia induced cardiomyopathy. During the redo procedure, electro-anatomical mapping revealed durably isolated PV. Bipolar mapping showed large low-voltage areas at the posterior wall and the septum. As the patient was refractory to electrical cardioversion, it was decided to modify the large low-voltage areas as potential arrhythmic substrate. After performing additional ablation with isolation of the posterior wall and two anterior/septal lines, the patient spontaneously converted to sinus rhythm. Discussion: Ablation in patients with persistent AF despite durable PVI remains a challenge for the treating team. Individualized ablation approaches addressing additional arrhythmic substrates or extra-PV triggers can be considered to treat patients with persistent AF and durable PVI.

[Oral anticoagulation in supraventricular arrhythmia]. / Orale Antikoagulation bei supraventrikulären Rhythmusstörungen.

Atrial fibrillation represents the most frequent persistent cardiac arrhythmia and is associated with an increased morbidity and mortality. An important component of the holistic treatment of atrial fibrillation is oral anticoagulation (OAC) for the prevention of stroke. The CHA2DS2-VASc score as a risk score is recommended for estimation of the individual stroke risk and the concomitant need of OAC in these patients. In the majority of patients the OAC is nowadays carried out with direct oral anticoagulants (DOAC), which have proved to be effective with a moderate side effect profile and have replaced vitamin K antagonists as the standard substance. In the meantime, these principles have become established as the usual practice but some issues regarding OAC in patients with atrial fibrillation are still insufficiently answered. Furthermore, it is unclear whether OACs need to be continued after successful treatment of atrial fibrillation with pulmonary vein ablation or in some cases can even be discontinued. Unanswered questions also remain regarding the treatment of subclinical atrial fibrillation and atrial high-frequency episodes detected by implanted heart rhythm devices. Especially the duration of atrial high-frequency episodes that should trigger the initiation of OAC treatment is still under debate. Therefore, currently the benefits of stroke prevention must be carefully weighed up against the risk of bleeding complications.

Next-generation atrial fibrillation ablation: clinical performance of pulsed-field ablation and very high-power short-duration radiofrequency.

INTRODUCTION: Pulsed-field energy (PFA) and very high-power short-duration radiofrequency (vHPSD-RF) are two novel ablation methods for pulmonary vein isolation (PVI). Both PFA and vHPSD-RF show promise for improving efficacy, safety, and reducing procedure durations. However, direct comparisons between these two techniques are scarce. METHODS AND RESULTS: Retrospective analysis of 82 patients with symptomatic AF. Of these, 52 patients received PFA and 30 received vHPSD-RF (90 W, 4 s) as index procedure. At the 6-month follow-up, AF recurrence occurred in 4 patients following PFA and 5 patients following vHPSD-RF (p-value = 0.138). Significant improvements in the EHRA and NYHA stages were evident in both PFA (p < 0.001 and p = 0.047, respectively) and vHPSD-RF groups (p = 0.007 and p = 0.012, respectively). The total procedure duration and the left atrial dwell time were significantly shorter in the PFA group (64 ± 19 min vs. 99 ± 32 min, p < 0.001 and 41 ± 12 min vs. 62 ± 29 min, p < 0.001, respectively). The fluoroscopy time and dose area product were significantly higher in PFA (14 ± 6 vs. 9 ± 5 min, p < 0.001 and 14 ± 9 vs. 11 ± 9 Gy cm2, p = 0.046, respectively). One patient in the vHPSD-RF group suffered a stroke, not directly linked to the procedure (0 vs. 1 major complication, p = 0.366). CONCLUSION: Based on this retrospective single-center study, PFA and vHPSD-RF were associated with similar effectiveness and safety profiles. PFA was linked to shorter procedure times and higher radiation exposure compared to vHPSD-RF.

Metabolomic Profiling in Patients with Different Hemodynamic Subtypes of Severe Aortic Valve Stenosis.

Severe aortic stenosis (AS) is a common pathological condition in an ageing population imposing significant morbidity and mortality. Based on distinct hemodynamic features, i.e., ejection fraction (EF), transvalvular gradient and stroke volume, four different AS subtypes can be distinguished: (i) normal EF and high gradient, (ii) reduced EF and high gradient, (iii) reduced EF and low gradient, and (iv) normal EF and low gradient. These subtypes differ with respect to pathophysiological mechanisms, cardiac remodeling, and prognosis. However, little is known about metabolic changes in these different hemodynamic conditions of AS. Thus, we carried out metabolomic analyses in serum samples of 40 AS patients (n = 10 per subtype) and 10 healthy blood donors (controls) using ultrahigh-performance liquid chromatography-tandem mass spectroscopy. A total of 1293 biochemicals could be identified. Principal component analysis revealed different metabolic profiles in all of the subgroups of AS (All-AS) vs. controls. Out of the determined biochemicals, 48% (n = 620) were altered in All-AS vs. controls (p < 0.05). In this regard, levels of various acylcarnitines (e.g., myristoylcarnitine, fold-change 1.85, p < 0.05), ketone bodies (e.g., 3-hydroxybutyrate, fold-change 11.14, p < 0.05) as well as sugar metabolites (e.g., glucose, fold-change 1.22, p < 0.05) were predominantly increased, whereas amino acids (e.g., leucine, fold-change 0.8, p < 0.05) were mainly reduced in All-AS. Interestingly, these changes appeared to be consistent amongst all AS subtypes. Distinct differences between AS subtypes were found for metabolites belonging to hemoglobin metabolism, diacylglycerols, and dihydrosphingomyelins. These findings indicate that relevant changes in substrate utilization appear to be consistent for different hemodynamic subtypes of AS and may therefore reflect common mechanisms during AS-induced heart failure. Additionally, distinct metabolites could be identified to significantly differ between certain AS subtypes. Future studies need to define their pathophysiological implications.

Atrial Fibrillation and Heart Failure.

Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide and has a strong association with heart failure (HF). It often remains unclear if HF is the cause or consequence of AF due to the complexity of the processes that are involved in both the perpetuation of AF and the development of HF. To date, two therapeutic strategies are accepted as the standard of care in AF patients with heart failure. Rhythm control aims to permanently restore sinus rhythm, whereas a rate-control strategy aims to slow ventricular rate without the termination of AF. In the last 5 years a tremendous number of important studies have been published investigating the optimal therapeutic strategy in HF patients. This review highlights the important studies with respect to the involvement of AF in promoting left-ventricular dysfunction and discusses the optimal strategy in HF patients suffering from AF.

Impact of open-irrigated radiofrequency catheter with contact force measurement on the efficacy and safety of atrial fibrillation ablation: a single-center direct comparison.

BACKGROUND: In atrial fibrillation (AF) patients, catheter ablation of pulmonary veins (PVI) is the most effective therapeutic option to maintain sinus rhythm. To improve successful PVI, contact force-sensing (CF) catheters became routinely available. Previous studies did not clearly show superior clinical efficacy in comparison with non-CF catheters. METHODS: We investigated consecutive patients, who underwent index PVI for AF at our hospital between 2012 and 2018. Three hundred and fifty-four patients were ablated without CF. After availability of CF catheters in 2016, 317 patients were ablated using CF. In case of crossover between the groups, follow-up was censored. The primary endpoint was any documented atrial tachycardia (AT) or atrial fibrillation > 30 s after a 3-month blanking period. Secondary endpoints were procedural characteristics and periprocedural complications. RESULTS: There was no significant difference between the groups at baseline except hyperlipidemia. After 365 days of follow-up, 67% of patients in the CF group remained free from AF/AT recurrence compared to 59% in non-CF group (P = 0.038). In multivariable Cox regression analysis, non-CF ablation was an independent risk factor for AF recurrence besides age and persistent AF. Total fluoroscopy time (15 ± 7.6 vs. 28 ± 15.9 min) and total procedure time (114 ± 29.6 vs. 136 ± 38.5 min) were significantly lower for CF-guided PVI (P < 0.001). Complication rates did not differ between groups (P = 0.661). CONCLUSIONS: In our study, the AT/AF recurrence rate and pulmonary vein reconnection rate is lower after CF PVI with a similar complication rate but lower total procedure time and total fluoroscopy time compared to non-CF PVI.

Application of Pre-Trained Deep Learning Models for Clinical ECGs.

Automatic electrocardiogram (ECG) analysis has been one of the very early use cases for computer assisted diagnosis (CAD). Most ECG devices provide some level of automatic ECG analysis. In the recent years, Deep Learning (DL) is increasingly used for this task, with the first models that claim to perform better than human physicians. In this manuscript, a pilot study is conducted to evaluate the added value of such a DL model to existing built-in analysis with respect to clinical relevance. 29 12-lead ECGs have been analyzed with a published DL model and results are compared to build-in analysis and clinical diagnosis. We could not reproduce the results of the test data exactly, presumably due to a different runtime environment. However, the errors were in the order of rounding errors and did not affect the final classification. The excellent performance in detection of left bundle branch block and atrial fibrillation that was reported in the publication could be reproduced. The DL method and the built-in method performed similarly good for the chosen cases regarding clinical relevance. While benefit of the DL method for research can be attested and usage in training can be envisioned, evaluation of added value in clinical practice would require a more comprehensive study with further and more complex cases.

Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure.

An interplay between Ca2+/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na+ current (INaL) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform NaV1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of NaV1.8, we demonstrate that NaV1.8 contributes to INaL formation. In addition, we reveal a direct interaction between NaV1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of NaV1.8 and CaMKIIδc, we show that NaV1.8-driven INaL is CaMKIIδc-dependent and that NaV1.8-inhibtion reduces diastolic SR-Ca2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a NaV1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKIIδc downstream target which may constitute a prognostic and antiarrhythmic strategy.

Inspiratory muscle dysfunction and restrictive lung function impairment in congenital heart disease: Association with immune inflammatory response and exercise intolerance.

BACKGROUND: In adult patients with congenital heart disease (ACHD), both underlying disease and lung restriction contribute to exercise intolerance. In ACHD the yet incompletely understood mechanism underlying restricted ventilation may be inspiratory muscle weakness. Therefore, this study comprehensively evaluated inspiratory muscle function in ACHD and associations with systemic inflammation and the clinical severity of exercise intolerance. METHODS: 30 ACHD patients (21 men, 35 ± 12 years) and 30 healthy controls matched for age, gender and body mass index underwent spirometry, measurement of mouth occlusion pressures, and diaphragm ultrasound. Six-minute walking distance (6MWD) and New York Heart Association functional class were used to quantify exercise intolerance. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were measured using enzyme-linked immunosorbent assays. RESULTS: ACHD patients showed lower forced vital capacity (FVC), and maximum inspiratory (PImax) and expiratory (PEmax) pressures compared with controls (all p < 0.05). On ultrasound, ACHD patients showed a lower diaphragm thickening ratio (2.3 ± 0.5 vs. 2.8 ± 0.9, p < 0.01) and lower diaphragm excursion velocity during a voluntary sniff maneuver (5.7 ± 2.2 vs. 7.6 ± 2.0 cm/s, p < 0.01). Respiratory parameters, such as FVC (r = 0.53; p < 0.01) and PImax (r = 0.43; p = 0.02), correlated with 6MWD. Furthermore, amino terminal pro B-type natriuretic peptide levels were inversely correlated with FVC (r = -0.54; p < 0.01). Circulating pro-inflammatory cytokines were markedly increased, and IL-6 was correlated with 6MWD, dyspnea, and biomarkers of heart, lung and inspiratory muscle function (all p < 0.05). CONCLUSIONS: Our findings show that diaphragm dysfunction is present in ACHD and relates to restrictive ventilation disorder and exercise intolerance, possibly mediated by increased IL-6 levels.

Empagliflozin directly improves diastolic function in human heart failure.

AIMS: Empagliflozin, a clinically used oral antidiabetic drug that inhibits the sodium-dependent glucose co-transporter 2, has recently been evaluated for its cardiovascular safety. Surprisingly, empagliflozin reduced mortality and hospitalization for heart failure (HF) compared to placebo. However, the underlying mechanisms remain unclear. Therefore, our study aims to investigate whether empagliflozin may cause direct pleiotropic effects on the myocardium. METHODS AND RESULTS: In order to assess possible direct myocardial effects of empagliflozin, we performed contractility experiments with in toto-isolated human systolic end-stage HF ventricular trabeculae. Empagliflozin significantly reduced diastolic tension, whereas systolic force was not changed. These results were confirmed in murine myocardium from diabetic and non-diabetic mice, suggesting independent effects from diabetic conditions. In human HF cardiomyocytes, empagliflozin did not influence calcium transient amplitude or diastolic calcium level. The mechanisms underlying the improved diastolic function were further elucidated by studying myocardial fibres from patients and rats with diastolic HF (HF with preserved ejection fraction, HFpEF). Empagliflozin beneficially reduced myofilament passive stiffness by enhancing phosphorylation levels of myofilament regulatory proteins. Intravenous injection of empagliflozin in anaesthetized HFpEF rats significantly improved diastolic function measured by echocardiography, while systolic contractility was unaffected. CONCLUSION: Empagliflozin causes direct pleiotropic effects on the myocardium by improving diastolic stiffness and hence diastolic function. These effects were independent of diabetic conditions. Since pharmacological therapy of diastolic dysfunction and HF is an unmet need, our results provide a rationale for new translational studies and might also contribute to the understanding of the EMPA-REG OUTCOME trial.

Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart.

Aims: In heart failure (HF), enhanced persistent Na+ current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. However, the underlying regulatory mechanisms remain unclear. Our aim was to potentially investigate the regulation and electrophysiological contribution of neuronal sodium channel NaV1.8 in failing human heart and eventually to reveal a novel anti-arrhythmic therapy. Methods and results: By western blot, we found that NaV1.8 protein expression is significantly up-regulated, while of the predominant cardiac isoform NaV1.5 is inversely reduced in human HF. Furthermore, to investigate the relation of NaV1.8 regulation with the cellular proarrhythmic events, we performed comprehensive electrophysiology recordings and explore the effect of NaV1.8 on INaL, action potential duration (APD), Ca2+ spark frequency, and arrhythmia induction in human failing cardiomyocytes. NaV1.8 inhibition with the specific blockers A-803467 and PF-01247324 decreased INaL, abbreviated APD and reduced cellular-spontaneous Ca2+-release and proarrhythmic events in human failing cardiomyocytes. Consistently, in mouse cardiomyocytes stressed with isoproterenol, pharmacologic inhibition and genetically knockout of NaV1.8 (SCN10A-/-), were associated with reduced INaL and abbreviated APD. Conclusion: We provide first evidence of differential regulation of NaV1.8 and NaV1.5 in the failing human myocardium and their contribution to arrhythmogenesis due to generation of INaL. We propose inhibition of NaV1.8 thus constitutes a promising novel approach for selective anti-arrhythmic therapy in HF.