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A 34-year-old man receiving his first dose of ampicillin-sulbactam for osteomyelitis in a hospital setting experienced fatal drug-induced anaphylaxis.

AimsIn atrial fibrillation, increased function of the Na+/Ca2+-exchanger (NCX) is one among several electrical remodeling mechanisms.Methods/resultsUsing the patch-clamp- and Ca2+ imaging-methods, we investigated atrial myocytes from NCX-homozygous-overexpressor (OE)- and heterozygous-knockout (KO)-mice and their corresponding wildtypes (WTOE; WTKO). NCX mediated Ca2+ extrusion capacity was reduced in KO and increased in OE. There was no evidence for structural or molecular remodeling. During a proarrhythmic pacing-protocol, the number of low amplitude delayed afterdepolarizations (DADs) was unaltered in OE vs. WTOE and KO vs. WTKO. However, DADs triggered full spontaneous action potentials (sAP) significantly more often in OE vs. WTOE (ratio sAP/DAD: OE:0.18±0.05; WTOE:0.02±0.02; p

Background. Kidney transplantation and dialysis are two major risk factors for severe forms of coronavirus disease 2019 (COVID-19). The dynamics of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in this population remain largely unknown. Methods. We report here the analysis of anti–SARS-CoV-2 antibody– and T cell–mediated immune responses in 26 kidney transplant recipients (KTRs) and 11 dialyzed patients (DPs) who recovered from COVID-19. Results. After a mean time of 83 ± 26 d post–symptom onset for KTRs and 97 ± 31 d for DPs, 20 KTRs (76.9%) and 10 DPs (90.9%) displayed anti-S1 immunoglobulin G SARS-CoV-2 antibodies (P = 0.34), at similar titers in both groups. SARS-CoV-2–specific interferon-γ–producing T cells were evidenced in 26 KTRs (100%) and 10 DPs (90.9%). Total numbers of SARS-CoV-2–reactive T cells were high and not statistically different between the 2 groups. No correlation between the severity of the disease and the number of reactive T cells was found in KTRs. In 5 KTRs, also evaluated 10 mo after COVID-19, weak or absent antibody response was observed, whereas specific memory T-cell response was detected in all cases. Conclusion. T-cell response persisted up to 3 mo post–symptom onset, even in KTRs in whom full immunosuppressive regimen was reinstated at recovery, and seems to be present up to 10 mo after infection. Our findings have implications in the understanding of the natural course of the disease in transplant patients and DPs.

Left atrial (LA) thrombus formation is the presumed origin of thromboembolic complications in patients with atrial fibrillation (AF). Beyond clinical risk factors, the factors causing formation of LA thrombi are not well known. In this case-control study, we analyzed clinical characteristics and genetic thrombophilia markers (factor V Leiden (FVL), prothrombin G20210A (FIIV), Tyr2561 variant of von Willebrand factor (VWF-V)) in 42 patients with AF and LA thrombus (LAT) and in 68 control patients with AF without LAT (CTR). Patients with LAT had more clinical conditions predisposing to stroke (mean CHA 2 DS 2 -VASc-score 3.4 ± 1.5 vs. 1.9 ± 1.4; P < 0.001), a higher LA volume (96 ± 32 vs. 76 ± 21 ml, P = 0.002) and lower LA appendage emptying velocity (0.21 ± 0.11vs. 0.43 ± 0.19 m/s, P < 0.001). Prevalence of FVL, FIIV and VWF-V mutations was not different, but in the subgroup of patients

Introduction: KRAS mutations are detected in 20% to 30% of NSCLC. However, KRAS mutation subtypes may differently influence the outcome of patients with advanced NSCLC. Methods: In the Biomarkers France study, 4894 KRAS mutations (26.2%) were detected in 4634 patients from the 17,664 enrolled patients with NSCLC. Survival and treatment data on noncurative stage III to IV NSCLC were available for 901 patients. First- and second-line treatment effects on progression-free survival and overall survival were analyzed according to the KRAS mutations subtype. Results: Over 95% of patients with KRAS mutation were smokers or former smokers who were white (99.5%), presenting with adenocarcinoma (82.5%). The most common KRAS mutation subtype was G12C (374 patients; 41.5%), followed by G12V (168; 18.6%), G12D (131; 14.5%), G12A (62; 6.9%), G13C (45; 5.0%), G13D (31; 3.4%), and others (10; 1%). Approximately 21% of patients had transition mutation and 68.2% had a transversion mutation. G12D and transition mutations were predominant in never-smokers. The median overall survival for patients with KRAS-mutated NSCLC was 8.1 months (95% confidence interval [CI]: 7.5–9.5), without any differences according to the different KRAS subtypes mutations. The median progression-free survival was 4.6 months (95% CI: 4.2–5.1) for first-line treatment and 4.8 months (95% CI: 4.3–6.8) for second-line treatment, without any differences according to the different KRAS subtypes mutations. Conclusions: KRAS mutation subtypes influenced neither treatment responses nor outcomes. The KRAS G12C mutation was detected in 41.5% of patients, who are now eligible for potent and specific G12C inhibitors.

Summary: Background: Insecticide-treated bednets (ITNs) are effective in preventing malaria where vectors primarily bite indoors and late at night, but their effectiveness is uncertain where vectors bite outdoors and earlier in the evening. We studied the effectiveness of ITNs following a mass distribution in Haiti from May to September, 2012, where the Anopheles albimanus vector bites primarily outdoors and often when people are awake. Methods: In this case-control study, we enrolled febrile patients presenting to outpatient departments at 17 health facilities throughout Haiti from Sept 4, 2012, to Feb 27, 2014, who were tested with malaria rapid diagnostic tests (RDTs), and administered questionnaires on ITN use and other risk factors. Cases were defined by positive RDT and controls were febrile patients from the same clinic with a negative RDT. Our primary analysis retrospectively matched cases and controls by age, sex, location, and date, and used conditional logistic regression on the matched sample. A sensitivity analysis used propensity scores to match patients on ITN use propensity and analyse malaria among ITN users and non-users. Additional ITN bioefficacy and entomological data were collected. Findings: We enrolled 9317 patients, including 378 (4%) RDT-positive cases. 1202 (13%) patients reported ITN use. Post-hoc matching of cases and controls yielded 362 cases and 1201 matched controls, 19% (333) of whom reported consistent campaign net use. After using propensity scores to match on consistent campaign ITN use, 2298 patients, including 138 (7%) RDT-positive cases, were included: 1149 consistent campaign ITN users and 1149 non-consistent campaign ITN users. Both analyses revealed that ITNs did not significantly protect against clinical malaria (odds ratio [OR]=0·95, 95% CI 0·68–1·32, p=0·745 for case-control analysis; OR=0·95, 95% CI 0·45–1·97, p=0·884 for propensity score analysis). ITN and entomological data indicated good ITN physical integrity and bioefficacy, and no permethrin resistance among local mosquitoes. Interpretation: We found no evidence that mass ITN campaigns reduce clinical malaria in this observational study in Haiti; alternative malaria control strategies should be prioritised. Funding: The Global Fund to Fight AIDS, Tuberculosis, and Malaria, and the US-based Centers for Disease Control and Prevention (CDC).

Aims: Pulsed-field ablation (PFA) is an emerging technology to perform pulmonary vein isolation (PVI). Initial data demonstrated high safety and efficacy. Data on long-term PVI durability and reconduction patterns in comparison to established energy sources for PVI are scarce. We compare findings in repeat ablation procedures after a first PFA to findings in repeat ablation procedures after a first cryoballoon ablation (CBA) based PVI., Methods and Result: A total of 550 consecutively enrolled patients underwent PFA or CBA index PVI. Repeat ablations in patients with symptomatic atrial arrhythmia recurrences were analysed. A total of 22/191 (12%) patients after index PFA-PVI and 44/359 (12%) after CBA-PVI underwent repeat ablation. Reconduction of any pulmonary vein (PV) was detected by multipolar spiral mapping catheter at each PV with careful evaluation of PV potentials and by 3D-mapping in 16/22 patients (73%) after PFA-PVI and in 33/44 (75%) after CBA-PVI (P = 1.000). Of 82 initially isolated PVs after PFA-PVI, 31 (38%) were reconducting; of 169 isolated PVs after CBA-PVI, 63 (37%) were reconducting (P = 0.936). Clinical atrial tachycardia occurred similarly in patients after PFA (5/22; 23%) and CBA (7/44; 16%; P = 0.515). Roof lines were set more often after PFA- (8/22; 36%) compared with CBA-PVI (5/44; 11%; P = 0.023). Repeat procedure duration [PFA: 87 (76, 123) min; CBA: 93 (75, 128) min; P = 0.446] was similar and fluoroscopy time [PFA: 11 (9, 14) min; CBA: 11 (8, 14) min; P = 0.739] equal between groups at repeat ablation., Conclusion: During repeat ablation after previous PFA- or CBA-based PVI, electrical PV-reconduction rates and patterns were similar., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Despite advances in efficacy and safety of pulmonary vein isolation (PVI), atrial fibrillation (AF) recurrence after PVI remains common. PV-reconnection is the main finding during repeat PVI procedures performed to treat recurrent AF., Objective: To analyze pulmonary vein (PV) reconnection patterns during repeat ablation procedures in a large cohort of consecutive patients undergoing radio frequency or cryoballoon-based PVI., Methods: Retrospective analysis of PV-reconnection patterns and analysis of re-ablation strategies in consecutive index RF- and CB-based PVI and their respective re-ablation procedures during concomitant usage of both energy sources at a single high-volume center in Germany., Results: A total of 610 first (06/2015-10/2022) and 133 s (01/2016-11/2022) repeat ablation procedures after 363 (60%) RF- and 247 (40%) CB-based index PVIs between 01/2015 and 12/2021 were analyzed. PV-reconnection was found in 509/610 (83%) patients at first and 74/133 (56%) patients at second repeat procedure. 465 of 968 (48%) initially via CB isolated PVs were reconnected at first re-ablation but 796 of 1422 initially RF-isolated PV (56%) were reconnected (OR: 0.73 [95% CI: 0.62-0.86]; p < .001). This was driven by fewer reconnections of the left PVs (LSPV: OR: 0.60 [95% CI: 0.42-0.86]; p = .005 and LSPV: 0.67 [0.47-0.95]; p = .026). PV-reconnection was more likely after longer, RF-based index PVI and in older females. Repeat procedures were shorter after CB-compared to after RF-PVI., Conclusions: Reconnection remains the most common reason for repeat AF ablation procedures after PVI. Our data suggest to preferentially use of the cryoballoon during index PVI, especially in older women., (© 2024 The Author(s). Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Aims: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4., Methods and Results: We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)]., Conclusion: Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org., Competing Interests: Conflict of interest: A.R.: Consultant fees, travel grants or lecture fees from Medtronic, Biosense Webster, Abbott, Boston Scientific, Ablamap, Philips, Cardiofocus, Bayer, Pfizer and Novartis, Edwards and Lifetech. Committee: German Society of Cardiology (Select-chair of EP community). L.E.: Grants/contracts: research support by the German heart foundation. Consulting fees Boston Scientific, lecture fees for various medical companies. Society, committee: German Society of Cardiology; European Society of Cardiology; European Heart Rhythm Society. K.B.: no COIs. J.C.: Participation on a data safety monitoring board: Anthos, Johnson and Johnson, Enso, Bayer, Charité. H.C.: Grants/contracts: ZonMw grant no. 104021005 RACE 9 Device-based rate vs. rhythm control treatment in patients with symptomatic recent-onset atrial fibrillation in the emergency department (RACE 9). Consulting fees: InCarda Therapeutics, Roche, Sanofi, Atricure. Payment or Honoraria: Medtronic. Participation on a data safety monitoring board or advisory board: Chair DSMB Decision trial. Committee/society: DZHK, German Centre for Cardiovascular research. A.G.: Grants/contracts: Maestria Grant EU 965286. Consulting fees: Sanofi-Aventis, Bayer, Astra Zeneca, Daiichi Sankyo, BMS/Pfizer, Viofor, Boston Scientific, Medtronic, Menarini. G.B.: Chair, advisory board to AFNET e.V., no payment. M.L.: No COIs. A.M.: Consulting fees: Medtronic, Johnson and Johnson, Boston Scientific, LifeTech. Lecture honoraria: Medtronic, Johnson and Johnson, Lifetech, Pfizer, Boston Scientific, Bayer, Bristol Meyer Squibb. L.R.: No COIs. U.S.: Grants/contracts: EU: CATCH ME, MAESTRIA, Personalize AF, REPAIR, Dutch Heart foundation, RACE V Embrace. Consulting fees: Roche advisory board, YourRhythmics BV. Payment or honoraria: Johnson and Johnson. Patents: non-invasive classification of AF with ECG. Society/Committee: Board of directors of AFNET. Stock or stock options: YourRhythmics BV. E.V.: Support for present manuscript: AFNET: payments made to my institution. Outside this work: Biotronik: payments made to my institution. K.W.: All support payment for manuscript: AFNET. Grants/contracts: Biotronik, Resmed. Payment/honoraria: Boston scientific, Novartis. A.Z.: Support for present manuscript: AFNET: payments made to my institution. Outside this work: Biotronik: payments made to my institution. Grants/contracts: Biotronik, Resmed. Payment/honoraria: Boston scientific. H.H.: Unconditional Research Grants through the University of Hassels and Antwerp: Abbott, Medtronic, Biotronik, Boston scientific, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Pfizer–BMS. Payment or honoraria: Bayer, Biotronik, Bristol Myers Squibb, Daiichi Sankyo, Milestone Pharmaceuticals, Centrix India, CTI Germany, European Society of Cardiology, Medscape, Springer healthcare. Participation on a data safety monitoring board or advisory board: Member, DSBM Prestige-AF. S.W.: Grants: Boston Scientific, Consulting fees: Boston Scientific, Abbott. Speakers Bureau: BSCI; Abbott, BMS, Medtronic. L.F.: Institutional government or charity research support: European Union Horizon 2020 MAESTRIA [grant agreement number 965286 (MAESTRIA)] European Union Horizon 2020 CATCH ME, [grant agreement number 633196 (CATCH ME), European Union Horizon 2020 AFFECT-EU, grant agreement number 847770 (AFFECT-EU)] Institutional governmental support, National Institute for Health and Care Research NIHR, Medical Research Council (UK), German Centre for Cardiovascular Research DZHK. Support for attending meetings: ESC, EHRA, and ESC working groups, ARVC patient organization (charity). Patents planned issued or pending: L.F. is listed as inventor of two patents (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). Society/committee: BHF project grant committee (charity). BHF chair committee visits (charity), AFNET steering committee (charity), ARVC patient organization (charity). Equipment and analytics to AFNET for AFNET 9: Preventicus, Trial costs to AFNET for AFNET 9: Daiichi Sankyo. R.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under the grant agreement No 648131, from the European Union’s Horizon 2020 research and innovation programme under the grant agreement no. 847770 (AFFECT-EU) and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103 and 81Z0710114); German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239). Wolfgang Seefried project funding German Heart Foundation. Lecture fees and advisory board fees from BMS/Pfizer and Bayer. Society/committee: ESC stroke council nucleus member. C.M.: Grants or contracts: Research funding from German Center for Cardiovascular Research (Promotion of women scientists programme; FKZ 81X3710112); Deutsche Stiftung für Herzforschung; Dr. Rolf M. Schwiete Stiftung; NDD; Loewenstein Medical. Payment or honoraria: AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Bayer, Pfizer, Sanofi, Aventis, Apontis, Abbott. Support for attending meetings: AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Novo Nordisk. Participation on a data safety monitoring board or advisory board: Boehringer Ingelheim/Lilly; Novo Nordisk. P.K.: P.K. was partially supported by European Union AFFECT-AF (grant agreement 847770), and MAESTRIA (grant agreement 965286), British Heart Foundation (PG/17/30/32961; PG/20/22/35093; AA/18/2/34218), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers DZHK FKZ 81X2800182, 81Z0710116, and 81Z0710110), German Research Foundation (Ki 509167694), and Leducq Foundation. P.K. receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation. P.K. is listed as inventor on two issued patents held by University of Hamburg (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). P.K. receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Center for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last 3 years. P.K. is board member of the ESC and speaker of the board AFNET., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Atrial fibrillation (AF) and heart failure (HF) coexist, increasing morbidity and mortality. Studies have demonstrated improved outcomes following AF ablation in HF patients with reduced ejection fraction (EF)., Objective: This study sought to assess the outcomes of pulsed field ablation (PFA) in HF., Methods: MANIFEST-PF (Multi-National Survey on the Methods, Efficacy, and Safety on the Post-Approval Clinical Use of Pulsed Field Ablation) is a multicenter, patient-level registry of consecutive patients undergoing PFA for paroxysmal AF or persistent AF (PerAF). In this substudy, patients were stratified as no history of HF (no-HF), HF with preserved EF (HFpEF) (left ventricular EF of ≥50%) or HF with reduced/mildly reduced EF (HFmr/rEF) (left ventricular EF of <50%). The primary effectiveness and safety endpoints were freedom from documented atrial arrhythmias lasting ≥30 seconds and major adverse events, respectively., Results: Of the 1,381 patients, 85% (n = 1,174) were no-HF, 6.2% (n = 87) were HFpEF, and 8.6% (n = 120) were HFmr/rEF. No-HF patients had less PerAF than patients with HF (P < 0.001), with no difference between HF subtypes (P = >0.99). The 1-year freedom from atrial arrhythmia was significantly higher in no-HF patients than in those with HFpEF or HFmr/rEF (79.9%, 71.3%, and 67.5%, respectively; P < 0.001) but similar between patients with HFmr/rEF and HFpEF (P = 0.26). However, there was no significant difference in freedom from atrial arrhythmia among patients with no-HF vs HFpEF vs HFmr/rEF for those with paroxysmal AF (82.8%, 82.4%, and 71.7%, respectively; P = 0.09) and PerAF (73.3%, 64.2%, and 64.9%, respectively; P = 0.14). Major adverse event rates were similar between the no-HF, HFpEF, and HFmr/rEF groups (1.9%, 0%, and 2.5%, respectively)., Conclusions: PFA appears to be potentially safe and effective in AF patients with HF. Freedom from atrial arrhythmia post-PFA was higher in patients without a history of HF, with no significant difference between HF subtypes., Competing Interests: Funding Support and Author Disclosures Boston Scientific provided a grant to help fund data collection but was not otherwise involved with study design or analysis and did not have access to this manuscript before submission. Dr Turagam has received consulting fees from Biosense Webster, Boston Scientific Inc, and AltaThera and speaker honoraria from Sanofi and Medtronic. Dr Neuzil has received a grant from the Ministry of Health, Czech Republic, Development of Research Organizations (DRO), Na Homolka Hospital (NHH) (0023884). Dr Schmidt has received speaker fees and research grants from Boston Scientific/Farapulse, Medtronic, Biosense Webster, and Abbott. Dr Reichlin has received research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the sitem insel support fund; speaker/consulting honoraria or travel support from Abbott/SJM, Bayer, Biosense Webster, Biotronik, Boston Scientific, Daiichi Sankyo, Medtronic, and Pfizer-BMS; and support for his institution’s fellowship program from Abbott/SJM, Biosense Webster, Biotronik, Boston Journal Pre-proof 21 Scientific, and Medtronic. Dr Neven has received speaker fees from Farapulse, Inc. Dr Metzner has received a research grant and fees from Farapulse. Dr Hansen has received speaker fees and grant support from Biosense Webster and Medtronic. Dr Blaauw has received research grants from Medtronic and Atricure and consulting fees from Abbott, Biosense Webster, Boston Scientific. Dr Sommer has served as a member of the Advisory Board for Abbott, Biosense Webster, Boston Scientific, and Medtronic. He has received modest honoraria from Medtronic. Dr Anic has received consultant fees from Farapulse Inc, Boston Scientific Inc, Galaxy Medical Inc, and Biosense Webster and has performed contracted research for Farapulse Inc, Boston Scientific Inc, Galaxy Medical Inc, and Biosense Webster. Dr Anselme has received consulting fees from Boston Scientific, Medtronic, and Microport CRM. Dr Boveda has received consulting fees from Medtronic, Boston Scientific, Microport, Zoll, and BMS. Dr Deneke has received speaker honoraria from Galaxy Medical, Abbott, and Biotronik, has been a consultant to Farapulse, and has served on a Clinical Events Committee for Boston Scientific. Dr Willems has received grants and personal fees from Abbott, Boston Scientific, and Medtronic and personal fees from Boehringer Ingelheim, Brystol Myers Squibb, Bayer Vital, Accutus, Daiichi, and Farapulse Inc. Dr Tilz has received consulting fees from Boston Scientific, Abbott Medical, Biotronik, and Biosense Webster and speaker honoraria from Boston Scientific, Abbott Medical, Biotronik, and Biosense Webster. Dr Scherr has received an educational grant from Farapulse Inc and is a consultant for Boston Scientific Inc. Dr Wakili has received investigator-initiated funding for research projects (initiated by him) from Bristol Myers Squibb, Pfizer, and Boston Scientific and speaking honoraria from Boston Scientific, Biotronik, and Medtronic. Dr Steven has received speaker fees from Pfizer, Bayer, Abbott, Johnson & Johnson, and Medtronic; grants from Abbott, Johnson & Johnson, and Boston Scientific; and consulting fees from Boston Scientific and Johnson & Johnson. Dr Kautzner has received personal fees from Bayer, Biosense Webster, Boehringer Ingelheim, Medtronic, and Abbott for participation in Scientific Advisory Boards and speaker honoraria from Bayer, Biosense Webster, Biotronik, Boehringer Ingelheim, CathVision, Medtronic, Mylan, Pfizer, ProMed, and Abbott. Dr Jais has received partial funding from L'institut Des Maladies Du Rythme Cardiaque, LIRYC ANR-10-IAHU-04, equity from Farapulse, and consulting fees and a grant from Boston Scientific. Dr Chun has received speaker fees and research grants from Boston Scientific/Farapulse, Medtronic, Biosense Webster, and Abbott. Dr Roten has received research grants from Medtronic, the Swiss National Foundation, the Swiss Heart Foundation, the Immanuel and Ilse Straub Foundation, and the Sitem Insel Support Fund and speaker fees/honoraria from Biosense Webster, Boston Scientific, Abbott, and Medtronic. Dr Lemoine has received a research grant from Farapulse. Dr Rollin has received a research grant from Farapulse. Dr Gunawardene has received grants from Farapulse Inc and Abbott. Dr Heeger has received travel grants and research grants from Boston Scientific, Lifetech, Biosense Webster, and Cardiofocus and speaker honoraria from Boston Scientific, Lifetech. Biosense Webster, Bayer, and Cardiofocus and he has served as a consultant for Medtronic, Journal Pre-proof 22 Lifetech, Boston Scientific, Biosense Webster, and Cardiofocus. Dr Manninger has received speaker fees from Bayer, Biosense Webster, Biotronik, Amomed, AOP Orphan, Boston Scientific, Daiichi Sankyo, and BMS/Pfizer and research grants from Biosense Webster and Abbott. Dr Sultan has received lecture and consulting honoraria from Medtronic, Abbott, and Bayer. Dr Derval has received receiving consulting fees from Boston Scientific. Dr Reddy has received consulting fees (and equity—now divested) from Farapulse Inc; has served as a consultant for Boston Scientific Inc; unrelated to this manuscript, has also served as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Anumana, Apama Medical–Boston Scientific, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, Cardiofocus, CardioNXT/AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics–Medtronic, EpiEP, Eximo, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, Laminar Medical, LuxMed, Medlumics, Middlepeak, Neutrace, Nuvera–Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, and Valcare; unrelated to this work, has served as a consultant for Abbott, Adagio Medical, Append Medical, AtriAN, Biosense Webster, BioTel Heart, Biotronik, Cairdac, Cardionomic, CoreMap, Fire1, Gore & Associates, Impulse Dynamics, Medtronic, Novartis, Novo Nordisk, Philips, Pulse Biosciences; and unrelated to this work, has equity in Atraverse, DRS Vascular, Manual Surgical Sciences, Newpace, Nyra Medical, Soundcath, Surecor, and Vizaramed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary vein isolation (PVI) alone is insufficient to treat many patients with persistent atrial fibrillation (PersAF). Adjunctive left atrial posterior wall (LAPW) ablation with thermal technologies has revealed lack of efficacy, perhaps limited by the difficulty in achieving lesion durability amid concerns of esophageal injury., Objectives: This study aims to compare the safety and effectiveness of PVI + LAPW ablation vs PVI in patients with PersAF using pulsed-field ablation (PFA)., Methods: In a retrospective analysis of the MANIFEST-PF (Multi-National Survey on the Methods, Efficacy, and Safety on the Post-approval Clinical Use of Pulsed Field Ablation) registry, we studied consecutive PersAF patients undergoing post-approval treatment with a pentaspline PFA catheter. The primary effectiveness outcome was freedom from any atrial arrhythmia of ≥30 seconds. Safety outcomes included the composite of acute and chronic major adverse events., Results: Of the 547 patients with PersAF who underwent PFA, 131 (24%) received adjunctive LAPW ablation. Compared to PVI-alone, patients receiving adjunctive LAPW ablation were younger (65 vs 67 years of age, P = 0.08), had a lower CHA 2 DS 2 -VASc score (2.3 ± 1.6 vs 2.6 ± 1.6, P = 0.08), and were more likely to receive electroanatomical mapping (48.1% vs 39.0%, P = 0.07) and intracardiac echocardiography imaging (46.1% vs 17.1%, P < 0.001). The 1-year Kaplan-Meier estimate for freedom from atrial arrhythmias was not statistically different between groups in the full (PVI + LAPW: 66.4%; 95% CI: 57.6%-74.4% vs PVI: 73.1%; 95% CI: 68.5%-77.2%; P = 0.68) and propensity-matched cohorts (PVI + LAPW: 71.7% vs PVI: 68.5%; P = 0.34). There was also no significant difference in major adverse events between the groups (2.2% vs 1.4%, respectively, P = 0.51)., Conclusions: In patients with PersAF undergoing PFA, as compared to PVI-alone, adjunctive LAPW ablation did not improve freedom from atrial arrhythmia at 12 months., Competing Interests: Funding Support and Author Disclosures Boston Scientific provided a grant to help fund data collection but was not otherwise involved with study design or analysis nor did they have access to this manuscript before submission. Dr Turagam has received consulting fees from Biosense Webster; and has received speaker honorarium from Sanofi and Medtronic. Dr Neuzil has received grants from the Ministry of Health, Czech Republic, DRO (NHH, 00023884). Dr Schmidt has received speaker fees and research grants from Boston Scientific/Farapulse, Medtronic, Biosense Webster, and Abbott. Dr Reichlin has received grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the sitem insel support fund; has received speaker/consulting honoraria or travel support from Abbott/SJM, Bayer, Biosense Webster, Biotronik, Boston Scientific, Daiichi Sankyo, Medtronic, and Pfizer-BMS; and has received support for his institution’s fellowship program from Abbott/SJM, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. Dr Metzner has received grants and fees from Farapulse. Dr Hansen has received speaker fees and grant support from Biosense Webster and Medtronic. Dr Blaauw has received grants from Medtronic and Atricure; and has received consulting fees from Abbott, Biosense Webster, and Boston Scientific. Dr Sommer has been a member of the advisory boards for Abbott, Biosense Webster, Boston Scientific, and Medtronic. Dr Anic has received consultant fees from Farapulse Inc, Boston Scientific Inc, Galaxy Medical Inc, Biosense Webster; and has performed contracted research for Farapulse Inc, Boston Scientific Inc, Galaxy Medical Inc, and Biosense Webster. Dr Anselme has received consulting fees from Boston Scientific, Medtronic, and Microport CRM. Dr Boveda has received consulting fees from Medtronic, Boston Scientific, Microport, Zoll, and BMS. Dr Deneke has received speaker honoraria from Galaxy Medical, Abbott, and Biotronik; has received consulting fees from Farapulse; and has served on a Clinical Events Committee for Boston Scientific. Dr Willems has received grants and personal fees from Abbott, Boston Scientific, and Medtronic; and has received personal fees from Boehringer Ingelheim, Brystol Myers Squibb, Bayer Vital, Accutus, Daiichi, and Farapulse Inc. Dr Tilz reports receiving consulting fees from Boston Scientific, Abbott Medical, Biotronik, Biosense Webster and speaker honorarium from Boston Scientific, Abbott Medical, Biotronik, Biosense Webster. Dr Scherr has received an educational grant from Farapulse Inc; and is a consultant For Boston Scientific Inc. Dr Wakili has received consulting fees and travel expenses from Boston Scientific and Biotronik; has received investigator-initiated funding for research projects (initiated by him) from Bristol-Myers Squibb, Pfizer, and Boston Scientific; and has received speaking honoraria from Boston Scientific, Biotronik, and Medtronic. Dr Scherr has received speaking fees from Pfizer, Bayer, Abbott, Johnson & Johnson, and Medtronic; has received grants from Abbott, Johnson & Johnson, and Boston Scientific; and has received consulting fees from Boston Scientific and Johnson & Johnson. Dr Kautzner has received personal fees from Bayer, Biosense Webster, Boehringer Ingelheim, Medtronic, and Abbott for participation in scientific advisory boards; and has received speaker honoraria from Bayer, Biosense Webster, Biotronik, Boehringer Ingelheim, CathVision, Medtronic, Mylan, Pfizer, ProMed, and Abbott. Dr Jais has received partial funding from IHU LIRYC ANR-10-IAHU-04; has received equity from Farapulse; and has received consulting fees and grants from Boston Scientific. Dr Chun has received speaker fees and research grants from Boston Scientific/Farapulse, Medtronic, Biosense Webster, and Abbott. Dr Roten has received speaker honoraria from Abbott/SJM; has received consulting honoraria from Medtronic; and has received research funding to the institution from Medtronic. Dr Lemoine has received grants from Farapulse. Dr Rollin has received grants from Farapulse. Dr Nentwich has received speaker fees from Farapulse, Inc. Dr Gunawardine has received grants from Farapulse Inc and Abbott. Dr Heeger has received travel grants and research grants from Boston Scientific, Lifetech, Biosense Webster, and Cardiofocus; has received speaker honoraria from Boston Scientific, Lifetech, Biosense Webster, Bayer, and Cardiofocus; and has received consulting fees from Medtronic, Lifetech, Boston Scientific, Biosense Webster, and Cardiofocus. Dr Manninger has received speaker fees from Bayer, Biosense Webster, Biotronik, Amomed, AOP Orphan, Boston Scientific, Daiichi Sankyo, and BMS/Pfizer; and has received grants from Biosense Webster and Abbott. Dr Sultan has received lecture and consulting honoraria from Medtronic, Abbott, and Bayer. Dr Derval has received consulting fees from Boston Scientific. Dr Reddy has received consulting fees (and equity – now divested) from Farapulse Inc; has received consulting fees from Boston Scientific Inc; and, unrelated to this manuscript, has served as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Apama Medical-Boston Scientific, Anumana, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, CardioNXT/AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics-Medtronic, EpiEP, Eximo, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, Laminar, LuxMed, Medlumics, Middlepeak, Neutrace, Nuvera-Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, Valcare; also unrelated to this work, he has received consulting fees from AtriAN, Biosense-Webster, BioTel Heart, Biotronik, Cairdac, Cardiofocus, Cardionomic, CoreMap, Fire1, Gore & Associates, Impulse Dynamics, Medtronic, Novartis, Philips, and Pulse Biosciences; and he has equity in Manual Surgical Sciences, Newpace, Nyra Medical, Surecor, and Vizaramed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Pulsed-field ablation (PFA) is a nonthermal energy source for ablation of cardiac arrhythmias. This study investigated the prospective outcomes of a novel PFA generator in conjunction with a commercially available, contact force-sensing, focal ablation catheter., Objective: The purpose of this study was to assess the feasibility, safety, and lesion characteristics of point-by-point PFA in consecutive patients undergoing repeat ablation of atrial fibrillation (AF)., Methods: The study involved reisolation of pulmonary veins (PVs) with electrical reconnection and the creation of an anterior line (AL) in patients with anterior substrate or durable pulmonary vein isolation (PVI)., Results: In 24 patients (46% female; mean age 67 ± 10 years; 67% persistent AF), successful reisolation of 27 of 27 reconnected PVs (100%) was performed. In 19 patients, AL ablation was performed, with bidirectional block in 16 (84%), median ablation time 26 [21, 33] minutes, and first-pass bidirectional block in 13 patients (68%). Acute AL reconduction occurred in 8 of 19 patients (42%). Among these 8 patients, a subsequent sustained block of the AL was achieved in 5 (63%). Ultra-high-density electroanatomic mapping revealed homogeneous but relatively large low-voltage areas in the ablated regions. Median procedural, left atrial dwell, and fluoroscopy times were 100 [90, 109] minutes, 83 [75, 98] minutes, and 10 [8, 13] minutes, respectively. No major or minor complications occurred., Conclusion: This study demonstrated feasibility, acute efficacy, and safety of point-by-point PFA for repeat PVI and AL ablation. Further studies are warranted to assess the long-term durability and comparison with established ablation methods., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Importance: Previous studies evaluating the association of patient sex with clinical outcomes using conventional thermal ablative modalities for atrial fibrillation (AF) such as radiofrequency or cryoablation are controversial due to mixed results. Pulsed field ablation (PFA) is a novel AF ablation energy modality that has demonstrated preferential myocardial tissue ablation with a unique safety profile., Objective: To compare sex differences in patients undergoing PFA for AF in the Multinational Survey on the Methods, Efficacy, and Safety on the Postapproval Clinical Use of Pulsed Field Ablation (MANIFEST-PF) registry., Design, Setting, and Participants: This was a retrospective cohort study of MANIFEST-PF registry data, which included consecutive patients undergoing postregulatory approval treatment with PFA to treat AF between March 2021 and May 2022 with a median follow-up of 1 year. MANIFEST-PF is a multinational, retrospectively analyzed, prospectively enrolled patient-level registry including 24 European centers. The study included all consecutive registry patients (age ≥18 years) who underwent first-ever PFA for paroxysmal or persistent AF., Exposure: PFA was performed on patients with AF. All patients underwent pulmonary vein isolation and additional ablation, which was performed at the discretion of the operator., Main Outcomes and Measures: The primary effectiveness outcome was freedom from clinically documented atrial arrhythmia for 30 seconds or longer after a 3-month blanking period. The primary safety outcome was the composite of acute (<7 days postprocedure) and chronic (>7 days) major adverse events (MAEs)., Results: Of 1568 patients (mean [SD] age, 64.5 [11.5] years; 1015 male [64.7%]) with AF who underwent PFA, female patients, as compared with male patients, were older (mean [SD] age, 68 [10] years vs 62 [12] years; P < .001), had more paroxysmal AF (70.2% [388 of 553] vs 62.4% [633 of 1015]; P = .002) but had fewer comorbidities such as coronary disease (9% [38 of 553] vs 15.9% [129 of 1015]; P < .001), heart failure (10.5% [58 of 553] vs 16.6% [168 of 1015]; P = .001), and sleep apnea (4.7% [18 of 553] vs 11.7% [84 of 1015]; P < .001). Pulmonary vein isolation was performed in 99.8% of female (552 of 553) and 98.9% of male (1004 of 1015; P = .90) patients. Additional ablation was performed in 22.4% of female (124 of 553) and 23.1% of male (235 of 1015; P = .79) patients. The 1-year Kaplan-Meier estimate for freedom from atrial arrhythmia was similar in male and female patients (79.0%; 95% CI, 76.3%-81.5% vs 76.3%; 95% CI, 72.5%-79.8%; P = .28). There was also no significant difference in acute major AEs between groups (male, 1.5% [16 of 1015] vs female, 2.5% [14 of 553]; P = .19)., Conclusion and Relevance: Results of this cohort study suggest that after PFA for AF, there were no significant sex differences in clinical effectiveness or safety events.

Competing Interests: Disclosures Dr Wenzel received funding from the German Foundation of Heart Research (F/29/19) and travel grants from Boston Scientific in each case unrelated to this project. Dr Lemoine received a research grant from Farapulse and was supported by the Research Promotion Fund of the Faculty of Medicine unrelated to this project. Dr Metzner received speaker’s honoraria and travel grants from Medtronic, Biosense Webster, Boston Scientific, and EPD Solutions/Philips and a research grant from Farapulse. Dr Rillig received travel grants, speaker fees, and consultant fees from Biosense Webster, Medtronic, Cardiofocus, Ablamap, and EPD Solutions/Philips (KODEX-EPD). Dr Reissmann received speaker’s honoraria and travel grants from Medtronic. The other authors report no conflicts.

Introduction: Pulsed-field ablation (PFA) and the multielectrode radiofrequency balloon (RFB) are two novel ablation technologies to perform pulmonary vein isolation (PVI). It is currently unknown whether these technologies differ in lesion formation and lesion extent. We compared the acute lesion extent after PVI induced by PFA and RFB by measuring low-voltage area in high-density maps and the release of biomolecules reflecting cardiac injury., Methods: PVI was performed with a pentaspline catheter (FARAPULSE) applying PFA or with the compliant multielectrode RFB (HELIOSTAR). Before and after PVI high-density mapping with CARTO 3 was performed. In addition, blood samples were taken before transseptal puncture and after post-PVI remapping and serum concentrations of high-sensitive Troponin I were quantified by immunoassay., Results: Sixty patients undergoing PVI by PFA (n = 28, age 69 ± 12 year, 60% males, 39.3% persistent atrial fibrillation [AF]) or RFB (n = 32, age 65 ± 13 year, 53% males, 21.9% persistent AF) were evaluated. Acute PVI was achieved in all patients in both groups. Mean number of PFA pulses was 34.2 ± 4.5 and mean number RFB applications was 8.5 ± 3 per patient. Total posterior ablation area was significantly larger in PFA (20.7 ± 7.7 cm²) than in RFB (7.1 ± 2.09 cm²; p < .001). Accordingly, posterior ablation area for each PV resulted in larger lesions after PFA versus RFB (LSPV 5.2 ± 2.7 vs. 1.9 ± 0.8 cm², LIPV 5.5 ± 2.3 vs. 1.9 ± 0.8 cm², RSPV 4.7 ± 1.9 vs. 1.6 ± 0.5 cm², RIPV 5.3 ± 2.1 vs. 1.6 ± 0.7 cm,² respectively; p < .001). In a subset of 38 patients, increase of hsTropI was higher after PFA (625 ± 138 pg/mL, n = 28) versus RFB (148 ± 36 pg/mL, n = 10; p = .049) supporting the evidence of larger lesion extent by PFA., Conclusion: PFA delivers larger acute lesion areas and higher troponin release upon successful PVI than multielectrode RFB-based PVI in this single-center series., (© 2023 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Background: Pulsed field ablation is a novel nonthermal cardiac ablation modality using ultra-rapid electrical pulses to cause cell death by a mechanism of irreversible electroporation. Unlike the traditional ablation energy sources, pulsed field ablation has demonstrated significant preferentiality to myocardial tissue ablation, and thus avoids certain thermally mediated complications. However, its safety and effectiveness remain unknown in usual clinical care., Methods: MANIFEST-PF (Multi-National Survey on the Methods, Efficacy, and Safety on the Post-Approval Clinical Use of Pulsed Field Ablation) is a retrospective, multinational, patient-level registry wherein patients at each center were prospectively included in their respective center registries. The registry included all patients undergoing postapproval treatment with a multielectrode 5-spline pulsed field ablation catheter to treat atrial fibrillation (AF) between March 1, 2021, and May 30, 2022. The primary effectiveness outcome was freedom from clinical documented atrial arrhythmia (AF/atrial flutter/atrial tachycardia) of ≥30 seconds on the basis of electrocardiographic data after a 3-month blanking period (on or off antiarrhythmic drugs). Safety outcomes included the composite of acute (<7 days postprocedure) and latent (>7 days) major adverse events., Results: At 24 European centers (77 operators) pulsed field ablation was performed in 1568 patients with AF: age 64.5±11.5 years, female 35%, paroxysmal/persistent AF 65%/32%, CHA 2 DS 2 -VASc 2.2±1.6, median left ventricular ejection fraction 60%, and left atrial diameter 42 mm. Pulmonary vein isolation was achieved in 99.2% of patients. After a median (interquartile range) follow-up of 367 (289-421) days, the 1-year Kaplan-Meier estimate for freedom from atrial arrhythmia was 78.1% (95% CI, 76.0%-80.0%); clinical effectiveness was more common in patients with paroxysmal AF versus persistent AF (81.6% versus 71.5%; P =0.001). Acute major adverse events occurred in 1.9% of patients., Conclusions: In this large observational registry of the postapproval clinical use of pulsed field technology to treat AF, catheter ablation using pulsed field energy was clinically effective in 78% of patients with AF., Competing Interests: Disclosures Dr Reddy reports receiving consulting fees (and equity—now divested) from Farapulse Inc. and is a consultant for Boston Scientific Inc; unrelated to this manuscript, Dr Reddy also serves as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Apama Medical-Boston Scientific, Anumana, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, CardioNXT/ AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics-Medtronic, EpiEP, Eximo, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, LuxMed, Medlumics, Middlepeak, Neutrace, Nuvera-Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, Valcare; unrelated to this work, has served as a consultant for AtriAN, Biosense-Webster, BioTel Heart, Biotronik, Cairdac, Cardiofocus, Cardionomic, CoreMap, Fire1, Gore & Associates, Impulse Dynamics, Medtronic, Novartis, Philips, Pulse Biosciences; and has equity in Manual Surgical Sciences, Newpace, Nyra Medical, Surecor, and Vizaramed. Dr Schmidt reports receiving speaker’s fees and research grants from Boston Scientific/Farapulse, Medtronic, Biosense Webster, and Abbott. Dr Reichlin reports research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the sitem insel Support Fund. Speaker/consulting honoraria or travel support from Abbott/SJM, Bayer, Biosense Webster, Biotronik, Boston Scientific, Daiichi Sankyo, Medtronic, and Pfizer-BMS. Support for his institution’s fellowship programme from Abbott/SJM, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. Dr Roten reports receiving speaker honoraria from Abbott/SJM, consulting honoraria from Medtronic, and research funding to the institution from Medtronic. Dr Neven reports speaker’s fees from Farapulse, Inc. Dr Metzner reports research grant and fees from Farapulse. Dr Rollin reports receiving research grant from Farapulse. Dr Lemoine reports receiving research grant from Farapulse. Dr Hansen reports receiving speaker fees and grant support from Biosense Webster, and Medtronic. Dr Blaauw reports receiving research grants from Medtronic and Atricure and consulting fees from Abbott, Biosense Webster, Boston Scientific. Dr Sommer reports member of the advisory board for Abbott, Biosense Webster, Boston Scientific, and Medtronic. Dr Anic reports receiving consultant fees from Farapulse Inc., Boston Scientific Inc., Galaxy Medical Inc., Biosense Webster, and performs contracted research for Farapulse Inc., Boston Scientific Inc., Galaxy Medical Inc., and Biosense Webster. Dr Anselme reports receiving consulting fees from Boston Scientific, Medtronic, and Microport CRM. Dr Boveda reports receiving consulting fees from Medtronic, Boston Scientific, Microport, Zoll, and BMS. Dr Deneke reports receiving speaker honoraria from Galaxy Medical, Abbott, and Biotronik, being a consultant to Farapulse, and serving on a Clinical Events Committee for Boston Scientific. Dr Willems reports receiving grants and personal fees from Abbott, Boston Scientific, Medtronic, and personal fees from Boehringer Ingelheim, Brystol Myers Squibb, Bayer Vital, Accutus, Daiichi, and Farapulse Inc. Dr Gunawardene reports grants from Farapulse Inc. and Abbott. Dr Tilz reports receiving consulting fees from Boston Scientific, Abbott Medical, Biotronik, Biosense Webster and speaker honorarium from Boston Scientific, Abbott Medical, Biotronik, and Biosense Webster. Dr Heeger received travel grants and research grants by Boston Scientific, Lifetech, Biosense Webster, and Cardiofocus and Speaker´s Honoraria from Boston Scientific, Lifetech. Biosense Webster, Bayer, and Cardiofocus. He is a consultant of Medtronic, Lifetech, Boston Scientific, Biosense Webster, and Cardiofocus. Dr Scheer reports receiving an educational grant from Farapulse Inc. and is a consultant for Boston Scientific Inc. Dr Wakili reports receiving consultant fees and travel expenses from Boston Scientific and Biotronik; investigator-initiated funding for research projects (initiated by him) from Bristol-Myers Squibb, Pfizer, and Boston Scientific; and speaking honoraria from Boston Scientific, Biotronik, and Medtronic. Dr Steven reports receiving speaking fees from Pfizer, Bayer, Abbott, Johnson & Johnson, and Medtronic; grants from Abbott, Johnson & Johnson, and Boston Scientific; and consulting fees from Boston Scientific and Johnson & Johnson. Dr Sultan reports receiving lecture and consulting honoraria from Medtronic, Abbott, and Bayer. Dr Kautzner reports personal fees from Bayer, Biosense Webster, Boehringer Ingelheim, Medtronic, and Abbott for participation in scientific advisory boards, and has received speaker honoraria from Bayer, Biosense Webster, Biotronik, Boehringer Ingelheim, CathVision, Medtronic, Mylan, Pfizer, ProMed, and Abbott. Dr Jais reports receiving equity from Farapulse and consulting fees and grant from Boston Scientific. Dr Derval reports receiving consulting fees from Boston scientific. Dr Chun reports receiving speaker’s fees and research grants from Boston Scientific/Farapulse, Medtronic, Biosense Webster, and Abbott. Dr Neuzil reports receiving grants from the Ministry of Health, Czech Republic, DRO (NHH, 00023884). Dr Manninger reports receiving speaker fees from Bayer, Biosense Webster, Biotronik, Amomed, AOP Orphan, Boston Scientific, Daiichi Sankyo, BMS/Pfizer and research grants from Biosense Webster and Abbott. All remaining authors have declared no conflict of interest.

Purpose: Pulsed-field ablation (PFA) is a new energy source to achieve pulmonary vein isolation (PVI) by targeted electroporation of cardiomyocytes. Experimental and controlled clinical trial data suggest good efficacy of PFA-based PVI. We aimed to assess efficacy, safety and follow-up of PFA-based PVI in an early adopter routine care setting., Methods: Consecutive patients with symptomatic paroxysmal or persistent atrial fibrillation (AF) underwent PVI using the Farawave® PFA ablation catheter in conjunction with three-dimensional mapping at two German high-volume ablation centers. PVI was achieved by applying 8 PFA applications in each PV., Results: A total of 138 patients undergoing a first PVI (67 ± 12 years, 66% male, 62% persistent AF) were treated. PVI was achieved in all patients by deploying 4563 applications in 546 PVs (8.4 ± 1.0/PV). Disappearance of PV signals after the first application was demonstrated in 544/546 PVs (99.6%). More than eight PFA applications were performed in 29/546 PVs (6%) following adapted catheter positioning or due to reconnection as assessed during remapping. Mean procedure time was 78 ± 22 min including pre- and post PVI high-density voltage mapping. PFA catheter LA dwell-time was 23 ± 9 min. Total fluoroscopy time and dose area product were 16 ± 7 min and 505 [275;747] cGy*cm 2 . One pericardial tamponade (0.7%), one transient ST-elevation (0.7%) and three groin complications (2.2%) occurred. 1-year follow-up showed freedom of arrhythmia in 90% in patients with paroxysmal AF (n = 47) and 60% in patients with persistent AF (n = 82, p = 0.015)., Conclusions: PFA-based PVI is acutely highly effective and associated with a beneficial safety and low recurrence rate., (© 2022. The Author(s).)

Background: Electrical remodeling in human persistent atrial fibrillation is believed to result from rapid electrical activation of the atria, but underlying genetic causes may contribute. Indeed, common gene variants in an enhancer region close to PITX2 (paired-like homeodomain transcription factor 2) are strongly associated with atrial fibrillation, but the mechanism behind this association remains unknown. This study evaluated the consequences of PITX2 deletion (PITX2 -/- ) in human induced pluripotent stem cell-derived atrial cardiomyocytes., Methods: CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) was used to delete PITX2 in a healthy human iPSC line that served as isogenic control. Human induced pluripotent stem cell-derived atrial cardiomyocytes were differentiated with unfiltered retinoic acid and cultured in atrial engineered heart tissue. Force and action potential were measured in atrial engineered heart tissues. Single human induced pluripotent stem cell-derived atrial cardiomyocytes were isolated from atrial engineered heart tissue for ion current measurements., Results: PITX2 -/- atrial engineered heart tissue beats slightly slower than isogenic control without irregularity. Force was lower in PITX2 -/- than in isogenic control (0.053±0.015 versus 0.131±0.017 mN, n=28/3 versus n=28/4, PITX2 -/- versus isogenic control; P <0.0001), accompanied by lower expression of CACNA1C and lower L-type Ca 2+ current density. Early repolarization was weaker (action potential duration at 20% repolarization; 45.5±13.2 versus 8.6±5.3 ms, n=18/3 versus n=12/4, PITX2 -/- versus isogenic control; P <0.0001), and maximum diastolic potential was more negative (-78.3±3.1 versus -69.7±0.6 mV, n=18/3 versus n=12/4, PITX2 -/- versus isogenic control; P =0.001), despite normal inward rectifier currents (both I K1 and I K,ACh ) and carbachol-induced shortening of action potential duration., Conclusions: Complete PITX2 deficiency in human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulates some findings of electrical remodeling of atrial fibrillation in the absence of fast beating, indicating that these abnormalities could be primary consequences of lower PITX2 levels.

Aims: Cardiac arrhythmia originating from the papillary muscle (PM) can trigger ventricular fibrillation (VF) and cause sudden cardiac death even in the absence of structural heart disease. Most premature ventricular contractions, however, are benign and hitherto difficult to distinguish from a potentially fatal arrhythmia. Altered repolarization characteristics are associated with electrical instability, but electrophysiological changes which precede degeneration into VF are still not fully understood., Methods and Results: Ventricular arrhythmia (VA) was induced by aconitine injection into PMs of healthy sheep. To investigate mechanisms of degeneration of stable VA into VF in structurally healthy hearts, endocardial high-density and epicardial mapping was performed during sinus rhythm (SR) and VA. The electrical restitution curve, modelling the relation of diastolic interval and activation recovery interval (a surrogate parameter for action potential duration), is steeper in VA than in non-arrhythmia (ventricular pacing and SR). Steeper restitution curves reflect electrical instability and propensity to degenerate into VF. Importantly, we find the parameter repolarization time in relation to cycle length (RT/CL) to differentiate self-limiting from degenerating arrhythmia with high specificity and sensitivity., Conclusion: RT/CL may serve as a simple index to aid differentiation between self-limiting and electrically instable arrhythmia with the propensity to degenerate to VF. RT/CL is independent of cycle length and could easily be measured to identify electrical instability in patients., Competing Interests: Conflict of interest: P.M. received travel grant and fellowship programme by Biotronik. C.M. received compensation for participation as consultant for Biotronik, Biosense Webster, Boston Scientific, and on speaker’s bureau for Abbott, Biotronik, Boston Scientific, and Medtronic. All remaining authors have declared no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Genetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) ACTN2 gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut presents a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray, and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this ACTN2 variant, which may contribute to human ACTN2 -associated cardiomyopathies.

The physiological importance of NCX in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is not well characterized but may depend on the relative strength of the current, compared to adult cardiomyocytes, and on the exact spatial arrangement of proteins involved in Ca2+ extrusion. Here, we determined NCX currents and its contribution to action potential and force in hiPSC-CMs cultured in engineered heart tissue (EHT). The results were compared with data from rat and human left ventricular tissue. The NCX currents in hiPSC-CMs were larger than in ventricular cardiomyocytes isolated from human left ventricles (1.3 ± 0.2 pA/pF and 3.2 ± 0.2 pA/pF for human ventricle and EHT, respectively, p < 0.05). SEA0400 (10 µM) markedly shortened the APD90 in EHT (by 26.6 ± 5%, p < 0.05) and, to a lesser extent, in rat ventricular tissue (by 10.7 ± 1.6%, p < 0.05). Shortening in human left ventricular preparations was small and not different from time-matched controls (TMCs; p > 0.05). Force was increased by the NCX block in rat ventricle (by 31 ± 5.4%, p < 0.05) and EHT (by 20.8 ± 3.9%, p < 0.05), but not in human left ventricular preparations. In conclusion, hiPSC-CMs possess NCX currents not smaller than human left ventricular tissue. Robust NCX block-induced APD shortening and inotropy makes EHT an attractive pharmacological model.

Background: Hybrid activation mapping is a novel tool to correct for spatial displacement of the mapping catheter due to asymmetrical contraction of myocardium during premature ventricular contractions (PVC). The aim of this study is to describe and improve our understanding of spatial displacement during PVC mapping as well as options for correction using hybrid activation mapping., Methods and Results: We analyzed 5798 hybrid mapping points in 40 acquired hybrid maps of 22 consecutive patients (age 63 ± 16 years, 45% female) treated for premature ventricular contractions (PVCs). Median PVC-coupling interval was 552 ms (IQR 83 ms). Spatial displacement was determined by measuring the dislocation of the catheter tip during PVC compared to the preceding sinus beat. Mean spatial displacement was 3.8 ± 1.5 mm for all maps. The displacement was 1.3 ± 0.4 mm larger for PVCs with non-outflow-tract origin compared to PVCs originating from the ventricular outflow tracts (RVOT/LVOT; p = 0.045). Demographic parameters, PVC-coupling-interval and chamber of origin had no significant influence on the extent of spatial displacement., Conclusion: Ectopic activation of the ventricular myocardium during PVCs results in spatial displacement of mapping points that is significantly larger for PVCs with non-outflow-tract origin. The correction for spatial displacement may improve accuracy of radiofrequency current (RFC)-application in catheter ablation of PVCs., (© 2022. The Author(s).)

Ultra-high-density (UHD) mapping can improve scar area detection and fast activation mapping in patients undergoing catheter ablation of ventricular tachycardia (VT). The aim of the present study was to compare the outcome after VT ablation guided by UHD and conventional point-by-point 3D-mapping. The acute and long-term ablation outcome of 61 consecutive patients with UHD mapping (64-electrode mini-basket catheter) was compared to 61 consecutive patients with conventional point-by-point 3D-mapping using a 3.5 mm tip catheter. Patients, whose ablation was guided by UHD mapping had an improved 24-months outcome in comparison to patients with conventional mapping (cumulative incidence estimate of the combination of recurrence or disease-related death of 52.4% (95% confidence interval (CI) [36.9-65.7]; recurrence: n = 25; disease-related death: n = 4) versus 69.6% (95% CI [55.9-79.8]); recurrence: n = 31; disease-related death n = 11). In a cause-specific Cox proportional hazards model, UHD mapping (hazard ratio (HR) 0.623; 95% CI [0.390-0.995]; P = 0.048) and left ventricular ejection fraction > 30% (HR 0.485; 95% CI [0.290-0.813]; P = 0.006) were independently associated with lower rates of recurrence or disease-related death. Other procedural parameters were similar in both groups. In conclusion, UHD mapping during VT ablation was associated with fewer VT recurrences or disease-related deaths during long-term follow-up in comparison to conventional point-by-point mapping. Complication rates and other procedural parameters were similar in both groups., (© 2022. The Author(s).)

Introduction: Catheter ablation of ventricular arrhythmias emerging from the ventricular outflow tracts and adjacent structures is very effective and considered almost curative in patients without structural heart disease (SHD). Outcomes of patients with SHD undergoing ablation of outflow tract arrhythmias are not known., Methods: Consecutive patients (2019-2021) undergoing catheter ablation of ventricular arrhythmias in a single high-volume center were retrospectively analyzed. Patients with ablation of outflow tract arrhythmias were identified and divided in individuals with and without SHD. Procedural parameters and acute outcome were compared., Results: We identified 215 patients with outflow tract arrhythmias (35.3% female, mean age 58.3 ± 16.0 years). Of those, 93 (43.3%) had SHD. Patients with SHD and outflow tract arrhythmias were older (65.0 ± 12.8 vs. 53.3 ± 16.3 years; p < 0.001), more often male (82.8 vs. 50.0%; p < 0.001) and had more comorbidities than patients without SHD (arterial hypertension: 62.4 vs. 34.4%, p < 0.001; diabetes: 22.6 vs. 8.2%, p = 0.005; chronic lung disease: 20.4 vs. 7.4%, p = 0.007). Outflow tract arrhythmias in patients with SHD had their origin more often in the left ventricle (68.8 vs. 53.3%, p = 0.025). The acute success rate was similar in both patient groups (93.4 vs. 94.2%, p = 0.781). Patients with SHD were discharged later {median length of hospital stay with SHD 5 [6 (interquartile range)] days, without SHD 2 [4] days, p < 0.001}. Periprocedural complications were numerically more frequent in patients with SHD [with SHD 12 (12.9%), without SHD 8 (6.6%), p = 0.154]., Conclusion: Outflow tract arrhythmia ablation has a high success rate irrespective of the presence of SHD. Longer hospital stay and potentially a higher risk of periprocedural complications should be considered when discussing this treatment option with patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schleberger, Riess, Brauer, Pinnschmidt, Rottner, Moser, Moser, Kany, My, Lemoine, Reissmann, Meyer, Metzner, Ouyang, Kirchhof and Rillig.)

Background: One third of heart failure patients exhibit dyssynchronized electromechanical activity of the heart (evidenced by a broad QRS-complex). Cardiac resynchronization therapy (CRT) in the form of biventricular pacing improves cardiac output and clinical outcome of responding patients. Technically demanding and laborious large animal models have been developed to better predict responders of CRT and to investigate molecular mechanisms of dyssynchrony and CRT. The aim of this study was to establish a first humanized in vitro model of dyssynchrony and CRT., Methods: Cardiomyocytes were differentiated from human induced pluripotent stem cells and cast into a fibrin matrix to produce engineered heart tissue (EHT). EHTs were either field stimulated in their entirety (symmetrically) or excited locally from one end (asymmetrically) or they were allowed to beat spontaneously., Results: Asymmetrical pacing led to a depolarization wave from one end to the other end, which was visualized in human EHT transduced with a fast genetic Ca 2+ -sensor (GCaMP6f) arguing for dyssynchronous excitation. Symmetrical pacing in contrast led to an instantaneous (synchronized) Ca 2+ -signal throughout the EHT. To investigate acute and long-term functional effects, spontaneously beating human EHTs (0.5-0.8 Hz) were divided into a non-paced control group, a symmetrically and an asymmetrically paced group, each stimulated at 1 Hz. Symmetrical pacing was clearly superior to asymmetrical pacing or no pacing regarding contractile force both acutely and even more pronounced after weeks of continuous stimulation. Contractile dysfunction that can be evoked by an increased afterload was aggravated in the asymmetrically paced group. Consistent with reports from paced dogs, p38MAPK and CaMKII-abundance was higher under asymmetrical than under symmetrical pacing while pAKT was considerably lower., Conclusions: This model allows for long-term pacing experiments mimicking electrical dyssynchrony vs. synchrony in vitro. Combined with force measurement and afterload stimulus manipulation, it provides a robust new tool to gain insight into the biology of dyssynchrony and CRT., (Copyright © 2021. Published by Elsevier Ltd.)

Hypertrophic cardiomyopathy (HCM) patients are at increased risk of ventricular arrhythmias and sudden cardiac death, which can occur even in the absence of structural changes of the heart. HCM mouse models suggest mutations in myofilament components to affect Ca 2+ homeostasis and thereby favor arrhythmia development. Additionally, some of them show indications of pro-arrhythmic changes in cardiac electrophysiology. In this study, we explored arrhythmia mechanisms in mice carrying a HCM mutation in Mybpc3 (Mybpc3-KI) and tested the translatability of our findings in human engineered heart tissues (EHTs) derived from CRISPR/Cas9-generated homozygous MYBPC3 mutant (MYBPC3hom) in induced pluripotent stem cells (iPSC) and to left ventricular septum samples obtained from HCM patients. We observed higher arrhythmia susceptibility in contractility measurements of field-stimulated intact cardiomyocytes and ventricular muscle strips as well as in electromyogram recordings of Langendorff-perfused hearts from adult Mybpc3-KI mice than in wild-type (WT) controls. The latter only occurred in homozygous (Hom-KI) but not in heterozygous (Het-KI) mouse hearts. Both Het- and Hom-KI are known to display pro-arrhythmic increased Ca 2+ myofilament sensitivity as a direct consequence of the mutation. In the electrophysiological characterization of the model, we observed smaller repolarizing K + currents in single cell patch clamp, longer ventricular action potentials in sharp microelectrode recordings and longer ventricular refractory periods in Langendorff-perfused hearts in Hom-KI, but not Het-KI. Interestingly, reduced K + channel subunit transcript levels and prolonged action potentials were already detectable in newborn, pre-hypertrophic Hom-KI mice. Human iPSC-derived MYBPC3hom EHTs, which genetically mimicked the Hom-KI mice, did exhibit lower mutant mRNA and protein levels, lower force, beating frequency and relaxation time, but no significant alteration of the force-Ca 2+ relation in skinned EHTs. Furthermore, MYBPC3hom EHTs did show higher spontaneous arrhythmic behavior, whereas action potentials measured by sharp microelectrode did not differ to isogenic controls. Action potentials measured in septal myectomy samples did not differ between patients with HCM and patients with aortic stenosis, except for the only sample with a MYBPC3 mutation. The data demonstrate that increased myofilament Ca 2+ sensitivity is not sufficient to induce arrhythmias in the Mybpc3-KI mouse model and suggest that reduced K + currents can be a pro-arrhythmic trigger in Hom-KI mice, probably already in early disease stages. However, neither data from EHTs nor from left ventricular samples indicate relevant reduction of K + currents in human HCM. Therefore, our study highlights the species difference between mouse and human and emphasizes the importance of research in human samples and human-like models., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Human engineered heart tissue (EHT) transplantation represents a potential regenerative strategy for patients with heart failure and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices, and determination of the effective dose., Methods: Cardiomyocytes were differentiated from 3 different human induced pluripotent stem cell lines including one reprogrammed under good manufacturing practice conditions. Protocols for human induced pluripotent stem cell expansion, cardiomyocyte differentiation, and EHT generation were adapted to substances available in good manufacturing practice quality. EHT geometry was modified to generate patches suitable for transplantation in a small-animal model and perspectively humans. Repair efficacy was evaluated at 3 doses in a cryo-injury guinea pig model. Human-scale patches were epicardially transplanted onto healthy hearts in pigs to assess technical feasibility., Results: We created mesh-structured tissue patches for transplantation in guinea pigs (1.5×2.5 cm, 9-15×10 6 cardiomyocytes) and pigs (5×7 cm, 450×10 6 cardiomyocytes). EHT patches coherently beat in culture and developed high force (mean 4.6 mN). Cardiomyocytes matured, aligned along the force lines, and demonstrated advanced sarcomeric structure and action potential characteristics closely resembling human ventricular tissue. EHT patches containing ≈4.5, 8.5, 12×10 6 , or no cells were transplanted 7 days after cryo-injury (n=18-19 per group). EHT transplantation resulted in a dose-dependent remuscularization (graft size: 0%-12% of the scar). Only high-dose patches improved left ventricular function (+8% absolute, +24% relative increase). The grafts showed time-dependent cardiomyocyte proliferation. Although standard EHT patches did not withstand transplantation in pigs, the human-scale patch enabled successful patch transplantation., Conclusions: EHT patch transplantation resulted in a partial remuscularization of the injured heart and improved left ventricular function in a dose-dependent manner in a guinea pig injury model. Human-scale patches were successfully transplanted in pigs in a proof-of-principle study.

Competing Interests: The authors report no conflicts of interest.

Left atrial (LA) thrombus formation is the presumed origin of thromboembolic complications in patients with atrial fibrillation (AF). Beyond clinical risk factors, the factors causing formation of LA thrombi are not well known. In this case-control study, we analyzed clinical characteristics and genetic thrombophilia markers (factor V Leiden (FVL), prothrombin G20210A (FIIV), Tyr2561 variant of von Willebrand factor (VWF-V)) in 42 patients with AF and LA thrombus (LAT) and in 68 control patients with AF without LAT (CTR). Patients with LAT had more clinical conditions predisposing to stroke (mean CHA 2 DS 2 -VASc-score 3.4 ± 1.5 vs. 1.9 ± 1.4; P < 0.001), a higher LA volume (96 ± 32 vs. 76 ± 21 ml, P = 0.002) and lower LA appendage emptying velocity (0.21 ± 0.11vs. 0.43 ± 0.19 m/s, P < 0.001). Prevalence of FVL, FIIV and VWF-V mutations was not different, but in the subgroup of patients <65 years (y) there was a tendency for a higher incidence of VWF-V with a prevalence of 27% (LAT <65 y) vs. 7% (CTR <65 y, P = 0.066). These findings warrant further investigation of the VWF-V as a risk factor for LA thrombogenesis in younger patients.

Abstract: Atrial tachypacing is an accepted model for atrial fibrillation (AF) in large animals and in cellular models. Human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CM) provide a novel human source to model cardiovascular diseases. Here, we investigated whether optogenetic tachypacing of atrial-like hiPSC-CMs grown into engineered heart tissue (aEHT) can induce AF-remodeling. After differentiation of atrial-like cardiomyocytes from hiPSCs using retinoic acid, aEHTs were generated from ∼1 million atrial-like hiPSC-CMs per aEHT. AEHTs were transduced with lentivirus expressing channelrhodopsin-2 to enable optogenetic stimulation by blue light pulses. AEHTs underwent optical tachypacing at 5 Hz for 15 seconds twice a minute over 3 weeks and compared with transduced spontaneously beating isogenic aEHTs (1.95 ± 0.07 Hz). Force and action potential duration did not differ between spontaneously beating and tachypaced aEHTs. Action potentials in tachypaced aEHTs showed higher upstroke velocity (138 ± 15 vs. 87 ± 11 V/s, n = 15-13/3; P = 0.018), possibly corresponding to a tendency for more negative diastolic potentials (73.0 ± 1.8 vs. 68.0 ± 1.9 mV; P = 0.07). Tachypaced aEHTs exhibited a more irregular spontaneous beating pattern (beat-to-beat scatter: 0.07 ± 0.01 vs. 0.03 ± 0.004 seconds, n = 15-13/3; P = 0.008). Targeted expression analysis showed higher RNA levels of KCNJ12 [Kir2.2, inward rectifier (IK1); 69 ± 7 vs. 44 ± 4, P = 0.014] and NPPB (NT-proBNP; 39,690 ± 4834 vs. 23,671 ± 3691; P = 0.024). Intermittent tachypacing in aEHTs induces some electrical alterations found in AF and induces an arrhythmic spontaneous beating pattern, but does not affect resting force. Further studies using longer, continuous, or more aggressive stimulation may clarify the contribution of different rate patterns on the changes in aEHT mimicking the remodeling process from paroxysmal to persistent atrial fibrillation., Competing Interests: T. Eschenhagen and A. Hansen are co-founders of EHT Technologies, Hamburg. The other authors report no conflicts of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are commercially available, and cardiac differentiation established routine. Systematic evaluation of several control hiPSC-CM is lacking. We investigated 10 different control hiPSC-CM lines and analyzed function and suitability for drug screening. Five commercial and 5 academic hPSC-CM lines were casted in engineered heart tissue (EHT) format. Spontaneous and stimulated EHT contractions were analyzed, and 7 inotropic indicator compounds investigated on 8 cell lines. Baseline contractile force, kinetics, and rate varied widely among the different lines (e.g., relaxation time range: 118-471 ms). In contrast, the qualitative correctness of responses to BayK-8644, nifedipine, EMD-57033, isoprenaline, and digoxin in terms of force and kinetics varied only between 80% and 93%. Large baseline differences between control cell lines support the request for isogenic controls in disease modeling. Variability appears less relevant for drug screening but needs to be considered, arguing for studies with more than one line., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Chronic tachypacing is commonly used in animals to induce cardiac dysfunction and to study mechanisms of heart failure and arrhythmogenesis. Human induced pluripotent stem cells (hiPSC) may replace animal models to overcome species differences and ethical problems. Here, 3D engineered heart tissue (EHT) was used to investigate the effect of chronic tachypacing on hiPSC-cardiomyocytes (hiPSC-CMs)., Methods and Results: To avoid cell toxicity by electrical pacing, we developed an optogenetic approach. EHTs were transduced with lentivirus expressing channelrhodopsin-2 (H134R) and stimulated by 15 s bursts of blue light pulses (0.3 mW/mm2, 30 ms, 3 Hz) separated by 15 s without pacing for 3 weeks. Chronic optical tachypacing did not affect contractile peak force, but induced faster contraction kinetics, shorter action potentials, and shorter effective refractory periods. This electrical remodelling increased vulnerability to tachycardia episodes upon electrical burst pacing. Lower calsequestrin 2 protein levels, faster diastolic depolarization (DD) and efficacy of JTV-519 (46% at 1 µmol/L) to terminate tachycardia indicate alterations of Ca2+ handling being part of the underlying mechanism. However, other antiarrhythmic compounds like flecainide (69% at 1 µmol/L) and E-4031 (100% at 1 µmol/L) were also effective, but not ivabradine (1 µmol/L) or SEA0400 (10 µmol/L)., Conclusion: We demonstrated a high vulnerability to tachycardia of optically tachypaced hiPSC-CMs in EHT and the effective termination by ryanodine receptor stabilization, sodium or hERG potassium channel inhibition. This new model might serve as a preclinical tool to test antiarrhythmic drugs increasing the insight in treating ventricular tachycardia., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Catheter ablation of non-reentrant, commonly termed "idiopathic" ventricular arrhythmias (VA) is highly effective in patients without structural heart disease (SHD). Meanwhile, the outcome of catheter ablation of these arrhythmias in patients with SHD remains unclear. This study sought to characterize the outcome of patients with and without SHD undergoing catheter ablation of non-reentrant VA., Methods: In this single-centre study the acute and long-term outcome of 266 consecutive patients undergoing catheter ablation of non-reentrant VA was investigated. In 41.0% of patients a SHD was present (n = 109, 80.7% male, age 59.1 ± 14.7 years), 59.0% had no SHD (n = 157; 44.0% male, age 49.9 ± 16.5 years)., Results: Acute procedural success (absence of spontaneous or provoked VA at the end of procedure and within 48 h after the procedure) was achieved in 89.9% of patients with SHD vs. 94.3% without SHD (p = 0.238). During a mean follow-up of 34.7 ± 15.1 months a repeat catheter ablation was performed in 19.6% of patients with SHD vs. 13.0% without SHD (p = 0.179). Patients with dilated cardiomyopathy (DCM) were the most likely to require a repeat ablation procedure (32.0% of patients with DCM vs. 13.0% without SHD; p = 0.022). Periprocedural complications occurred in 5.5% of patients with SHD vs. 5.7% without SHD (p > 0.999). All complications were managed without sequelae., Conclusions: The outcome of catheter ablation of non-reentrant VA in patients with SHD appears good and is comparable to patients without SHD. A slightly higher rate of repeat ablations was observed in patients with DCM.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent an unlimited source of human CMs that could be a standard tool in drug research. However, there is concern whether hiPSC-CMs express all cardiac ion channels at physiological level and whether they might express non-cardiac ion channels. In a control hiPSC line, we found large, "noisy" outward K + currents, when we measured outward potassium currents in isolated hiPSC-CMs. Currents were sensitive to iberiotoxin, the selective blocker of big conductance Ca 2+ -activated K + current (I BK,Ca ). Seven of 16 individual differentiation batches showed a strong initial repolarization in the action potentials (AP) recorded from engineered heart tissue (EHT) followed by very early afterdepolarizations, sometimes even with consecutive oscillations. Iberiotoxin stopped oscillations and normalized AP shape, but had no effect in other EHTs without oscillations or in human left ventricular tissue (LV). Expression levels of the alpha-subunit (K Ca 1.1) of the BK Ca correlated with the presence of oscillations in hiPSC-CMs and was not detectable in LV. Taken together, individual batches of hiPSC-CMs can express sarcolemmal ion channels that are otherwise not found in the human heart, resulting in oscillating afterdepolarizations in the AP. HiPSC-CMs should be screened for expression of non-cardiac ion channels before being applied to drug research.

Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease accompanied by structural and contractile alterations. We identified a rare c.740C>T (p.T247M) mutation in ACTN2, encoding α-actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstruction, and atrial fibrillation. We generated patient-derived human-induced pluripotent stem cells (hiPSCs) and show that hiPSC-derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks of HCM, such as hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and higher myofilament Ca 2+ sensitivity, and also prolonged action potential duration and enhanced L-type Ca 2+ current. The L-type Ca 2+ channel blocker diltiazem reduced force amplitude, relaxation, and action potential duration to a greater extent in HCM than in isogenic control. We translated our findings to patient care and showed that diltiazem application ameliorated the prolonged QTc interval in HCM-affected son and sister of the index patient. These data provide evidence for this ACTN2 mutation to be disease-causing in cardiomyocytes, guiding clinical therapy in this HCM family. This study may serve as a proof-of-principle for the use of hiPSC for personalized treatment of cardiomyopathies., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

Biological pacemakers could be a promising alternative to electronic pacemakers and human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) may represent a suitable source for implantable cells. To further unravel this potential a thorough understanding of pacemaker function with regard to coupling processes both in the physiological and in the graft-host context is required. Here we developed a 2-component cardiac organoid model with a hiPSC-CM embryoid body (EB) as trigger casted into a rat engineered heart tissue (EHT) as arrhythmic beating substrate. Contractility recordings revealed that the EB controlled the beating activity of the EHT, leading to a regular hiPSC-CM-like beating pattern instead of the irregular beating typically seen in rat EHT. Connectivity was observed with action potential (AP) measurements and calcium transients transmitting from the EB directly into the rat EHT. Immunohistochemistry and genetically labeled hiPSC-CMs demonstrated that EB-derived and rat cells intermingled and formed a transitional zone. Connexin 43 expression followed the same pattern as histological and computer models have indicated for the human sinoatrial node. In conclusion, hiPSC-CM EBs function as a biological pacemaker in a 2-component cardiac organoid model, which provides the possibility to study electrophysiological and structural coupling mechanisms underlying propagation of pacemaker activity., (Copyright © 2019. Published by Elsevier Ltd.)

Atrial fibrillation (AF), the most common sustained heart rhythm disorder worldwide, is linked to dysfunction of the intrinsic cardiac autonomic nervous system (ICNS). The role of ICNS damage occurring during catheter-based treatment of AF, which is the therapy of choice for many patients, remains controversial. We show here that the neuronal injury marker S100B is expressed in cardiac glia throughout the ICNS and is released specifically upon catheter ablation of AF. Patients with higher S100B release were more likely to be AF free during follow-up. Subsequent in vitro studies revealed that murine intracardiac neurons react to S100B with diminished action potential firing and increased neurite growth. This suggests that release of S100B from cardiac glia upon catheter-based treatment of AF is a hallmark of acute neural damage that contributes to nerve sprouting and can be used to assess ICNS damage., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)