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An interplay between Ca 2+ /calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na + current (I NaL ) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na V 1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na V 1.8, we demonstrate that Na V 1.8 contributes to I NaL formation. In addition, we reveal a direct interaction between Na V 1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na V 1.8 and CaMKIIδc, we show that Na V 1.8-driven I NaL is CaMKIIδc-dependent and that Na V 1.8-inhibtion reduces diastolic SR-Ca 2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a Na V 1.8 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. In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel Na V 1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model.

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.

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.

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 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 CHA DS -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.

Abstract 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.

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.

IntroductionPulsed-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 resultsRetrospective 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).ConclusionBased 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.

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 (PI max ), maximum expiratory pressure (PE max ) (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, PI max , and PE max . 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.

Abstract BackgroundIn 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.MethodsWe 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.ResultsThere 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).ConclusionsIn 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.