Atrial tachycardias (AT) represent an increasingly common cause of morbidity and mortality. Driven by substantial advances in mapping and ablation technologies, the mechanistic understanding and therapeutic strategies for AT management have evolved rapidly in recent years, and catheter ablation is now regarded as the most effective strategy for maintaining sinus rhythm. Against this background, the recently published international clinical consensus statement on the management of patients with AT introduces, for the first time, a structured 10-point plan for "SMART-AT care" as a framework for the diagnosis and treatment of regular AT. This review highlights key developments and clinical implications, taking into account recent changes within the healthcare system.

Atriale Tachykardien (AT) sind eine zunehmend häufige Ursache für Morbidität und Mortalität. Aufgrund substanzieller Fortschritte in Mapping- und Ablationstechnologien haben sich das elektrophysiologische Verständnis und die therapeutischen Konzepte im Rahmen der Behandlung von AT in den vergangenen Jahren rasch weiterentwickelt, sodass die Katheterablation heute als effektivste Methode zum Rhythmuserhalt gilt. Vor diesem Hintergrund legt das kürzlich veröffentlichte, von internationalen Fachgesellschaften erarbeitete Konsensusdokument zum Management von Patienten mit AT erstmals einen strukturierten 10-Punkte-Plan für „SMART-AT care“ als Rahmen für Diagnostik und Therapie regulärer AT vor. In der vorliegenden Übersicht werden wesentliche Neuerungen sowie klinische Implikationen unter Berücksichtigung aktueller Entwicklungen im Gesundheitssystem beleuchtet.

BACKGROUND AND AIMS:Stroke and systemic embolism are recognized but poorly characterized complications of atrial fibrillation (AF) and left atrial flutter (AFL) catheter ablation. Their incidence, outcomes, and procedural associations remain insufficiently defined. METHODS:Retrospective global registry was initiated by the European Heart Rhythm Association Scientific Committee. A secure database captured data from ablation centres worldwide on general AF and left AFL ablation activity, as well as detailed information on patients with symptomatic embolic events between 2017 and 2024. RESULTS:Overall, 204 centres reported 335 743 ablation procedures and 550 embolic events (incidence 0.16%). Centre-level rate ranged from 0% to 3.1%. Most events were cerebral (94%), followed by peripheral (5%), and combined (1%). Coronary air embolism accounted for 62% of all peripheral events. Intraprocedural events occurred in 93 patients (17%), within 72 h in 357 (78%) and beyond 72 h in 100 (22%); 128 cases (23%) were diagnosed after hospital discharge. Nonparoxysmal AF (0.23% vs 0.15%; P < .001), centre experience, and ablation energy source (radiofrequency, 0.16%; cryoballoon, 0.16%; pulsed field ablation, 0.25%; laserballoon, 0.88%; P < .001) were associated with embolic risk. Median NIHSS score after stroke was 4 (interquartile range, 2-9). Three-month follow-up was available for 518 patients with embolism (95%): 181 (35%) had sequelae and 16 (3%) died. CONCLUSIONS:Symptomatic embolic events are infrequent but associated with significant morbidity and mortality. Most events occur early, though a substantial proportion arise later. Higher event rates were observed with laser and possibly with pulsed field ablation. A greater centre experience was associated with a lower embolism incidence.

Das aktualisierte Positionspapier der DGK zur Katheterablation von Vorhofflimmern (AF) [1] stellt die aktuelle Evidenz, Techniken und Qualitätsstandards dar, die sich seit 2017 gemeinsam mit Indikation, Technik und Rolle der Ablation in der Therapie deutlich gewandelt haben. Die Pulmonalvenenisolation (PVI) bleibt zentraler Bestandteil der AF-Ablation. Neben etablierten Verfahren wie Radiofrequenz- und Kryoablation gewinnt die Pulsed-Field-Ablation (PFA) an Bedeutung. Bei persistierendem AF fehlen klare Empfehlungen über die PVI hinaus, trotz zunehmender Daten für ergänzende Ablationsstrategien. Die Versorgungssituation zeigt eine starke Zunahme der Ablationen, wobei die tagesgleiche Entlassung nur für selektierte Patienten empfohlen wird. Die präzise Patientenselektion, inklusive Anamnese, Risikofaktoren und Bildgebung sind entscheidend für den Erfolg und die Sicherheit. Die Bedeutung von periprozeduralem Management und strukturierter Nachsorge wird hervorgehoben. Komplikationen wie Perikardtamponade, Schlaganfall und Phrenikusparese erfordern strukturierte Abläufe und erfahrene Teams. Besonders bei Patienten mit Herzinsuffizienz zeigt sich die Ablation als potenziell prognoseverbessernd. Die Zertifizierung von Zentren durch die DGK dient der Qualitätssicherung. Neue Entwicklungen wie KI-gestützte Ablationsplanung und Studien zur OAK-Strategie nach Ablation werden die Praxis weiter verändern.

Abstract This study demonstrates the successful production and injection of human induced pluripotent stem cell cardiomyocyte aggregates into infarcted cynomolgus monkey hearts, resulting in substantial, structured human grafts three months after cell transplantation. Transient graft-induced arrhythmias decreased over time. Both the arrhythmogenicity and the substantial heart function recovery in vivo notably seemed to correlate with induced pluripotent stem cell clone-dependent contractile and electrophysiological cardiomyocyte properties in vitro. Overexpression of a red fluorescent reporter protein led to a dysregulated conduction and contraction machinery in yet engraftment competent cardiomyocytes, providing an important tool to mechanistically understand and improve induced pluripotent stem cell-based heart repair in preclinical models. We demonstrate the logistically important, temporal uncoupling of cardiomyocyte production from transplantation. Cardiomyocyte aggregate transplantation yielded results comparable to the reported transplantation of 10-20-fold higher numbers of dissociated human embryonic stem cell- cardiomyocytes and suggests a higher degree of cell/ tissue maturation in cardiac grafts. Our study promotes reduced cell production costs, highlights the need for an in vitro potency assay, and shows a pragmatic new avenue for the clinical translation of human induced pluripotent stem cell-based heart repair.

BACKGROUND AND AIMS:Stereotactic arrhythmia radioablation (STAR) is increasingly used for refractory ventricular tachycardia (VT), yet prospective multicentre outcome data remain limited. Here, the planned interim analysis of the prospective Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary (STOPSTORM) registry is reported. METHODS:STOPSTORM is a European prospective, international, multicentre registry of patients treated with STAR. The primary efficacy endpoint was the change in sustained VT episode burden comparing the 6 months before versus the 6 months after STAR. The primary safety endpoint was the occurrence of serious adverse events (SAEs) adjudicated as possibly or probably treatment-related. Overall survival was assessed using time-to-event methods. RESULTS:Across 28 centres, 193 patients were included (mean age 68±9 years; 88% male; 53% non-ischaemic cardiomyopathy). Median follow-up was 19 months. Among 107 evaluable patients with ≥6-month follow-up, the median VT episode burden was reduced by 80% after STAR. Among patients surviving ≥6 months, 72% were free from implantable cardioverter-defibrillator (ICD) shock. In the full cohort, 12 SAEs were adjudicated as possibly or probably treatment-related, including pericardial effusion, coronary events, and early post-treatment ventricular arrhythmia. Overall survival probability was 77% at 12 months. CONCLUSIONS:In the largest prospective multicentre cohort reported to date, STAR was associated with a substantial reduction in VT burden and ICD shocks, with a low frequency of possibly or probably treatment-related SAEs.

The updated German Society of Cardiology (DGK) position paper on catheter ablation of atrial fibrillation (AF) [1] presents the current evidence, techniques, and quality standards, which have evolved significantly since 2017 alongside indications, technology, and the role of ablation in therapy. Pulmonary vein isolation (PVI) remains the cornerstone of AF ablation. In addition to established procedures such as radiofrequency and cryoballoon ablation, pulsed field ablation (PFA) is gaining importance. For persistent AF, clear recommendations beyond PVI are still lacking, despite growing evidence supporting adjunctive ablation strategies. The healthcare landscape shows a marked increase in ablations, with same day discharge procedures recommended only for carefully selected patients. Precise patient selection-including medical history, risk factors, and imaging-is critical for procedural success and safety. The importance of periprocedural management and structured follow-up is emphasized. Complications such as pericardial tamponade, stroke, and phrenic nerve injury require structured protocols and experienced teams. Particularly in patients with heart failure, ablation may offer prognostic benefits. Certification of centers by the DGK supports quality assurance. New developments, such as artificial intelligence (AI)-assisted ablation planning and studies on postablation anticoagulation strategies, are expected to further influence clinical practice.

Background:Esophageal fistula (EF) is a rare but devastating complication following atrial fibrillation (AF) ablation. Data regarding the impact of age on EF are scarce. Objective:To study the impact of age on the management and prognosis of EF following catheter ablation for AF. Methods:The POTTER-AF study is a worldwide registry on EF following catheter ablation for AF. A total of 553,729 patients underwent AF ablation in 214 centers between 1996 and 2022. Of them, 138 patients experienced EF, and data regarding age, management, and prognosis were available in 113 patients. The population was divided based on the median age. Results:The median age was 63 years; 54 patients were <63 years old (Group 1), and 59 patients were ≥63 years old (Group 2). The groups were similar regarding procedural characteristics. The older population had a shorter time to symptom onset [15.0 (6.0, 21.0) vs. 21.0 (10.0, 25.3) days; p = 0.031]. Group 2 was less likely to receive a brain CT or MRI for diagnosis (25.9% vs. 45.3%; p = 0.046). The older population was more likely to undergo endoscopic treatment without surgery (27.6% vs. 11.3%; p = 0.035). Conservative and surgical treatments were used in similar proportions. A trend toward higher fatality was noted in the older patients (72.9% vs. 56.6%; p = 0.078). Conclusion:The older population had a shorter time to symptom onset, was less likely to receive a brain CT or MRI, and more likely to be treated by an endoscopic approach only. The older patient group showed a trend toward a higher fatality.

BACKGROUND:Numerous algorithms predict the origin of idiopathic premature ventricular contractions (PVCs) with an inferior axis using the electrocardiogram (ECG), especially trying to differentiate between PVCs from the left and right ventricular outflow tract (LVOT and RVOT). Although evaluating the PVC origin goes along with evaluating risks and benefits of catheter ablation, this approach is complex for non-electrophysiology (EP) experts and shows limited reliability. As an additional strategy to guide decision-making, we sought to find simple ECG criteria that predict outcome of catheter ablation directly rather than origin. METHODS:Patients undergoing catheter ablation of idiopathic PVCs with an inferior axis at our center between 2012 and 2020 were included. Procedural data assessed included complete suppression of the PVC at the end of the procedure, ECG analysis included assessment of Q-, R-, and S-amplitudes, -durations and derived parameters. RESULTS:104 patients (54% male, 54 ± 17 years) were included. Overall ablation success was 81%. Two ECG features - a more leftward PVC axis in the limb leads and an earlier precordial transition in the chest leads - independently predicted ablation failure. Using ROC statistics, we suggest combining the following two criteria to predict ablation success with a positive predictive value of 95% with no major complications: (1) PVC axis ≥ 75° (lead III ≥ (neg) aVR) and (2) TZ-score > 2 (V2 net negative, p < 0.001). If either parameter was not met, success rate was only 60% and major complication rate was 7%. Considering the PVC origin underlying these findings, the two criteria were inversely associated with a parahisian and LV summit origin, while no differences in ablation success or procedural data were observed between RVOT and LVOT origins. CONCLUSION:While catheter ablation of LVOT and RVOT PVCs show similarly high success rates, two simple ECG criteria based on PVC axis and precordial transition independently predict ablation outcome due to complex PVC foci. These should be considered when evaluating patients with idiopathic PVCs with an inferior axis for catheter ablation.

BACKGROUND:Until the late 1980s, dextro-transposition of the great arteries (d-TGA) was primarily treated with Mustard or Senning (M/S) atrial redirection surgery. Common long-term complications in these patients include atrial tachyarrhythmias, yet data on catheter ablation in this population remain limited. OBJECTIVE:This study aimed to assess procedural characteristics, acute success, and long-term outcomes. METHODS:We retrospectively analyzed all patients with d-TGA after M/S surgery who underwent electrophysiologic procedures for atrial tachyarrhythmia at a tertiary referral center between June 2001 and June 2023. RESULTS:97 patients (35% female; 50 Mustard) underwent 160 electrophysiological procedures. A total of 111 tachyarrhythmias were identified. Cavotricuspid isthmus (CTI)-dependent macro-reentrant atrial tachycardia was the most common substrate and was successfully treated in 90% of procedures. Localized reentrant atrial tachycardia was the second most frequent arrhythmia with an age-dependent increase in relative frequency. Overall, 86% of substrate-guided ablations were acutely successful. In procedures with non-inducible or non-sustained arrhythmias, strategic CTI ablation was performed routinely. During a median follow-up of 6.0 years, 95 tachyarrhythmias occurred, of which 13% represented recurrences of previously ablated arrhythmias. Strategic CTI ablation was not associated with a statistically significant increase in subsequent arrhythmias compared with substrate-guided ablations. Arrhythmias during follow-up were more common after Mustard than Senning surgery (hazard ratio, 1.87; 95% confidence interval, 1.06-3.31; P = .030). CONCLUSION:Catheter ablation in patients with d-TGA with M/S surgery is feasible and highly effective, with durable results for targeted arrhythmias. However, the high incidence of de novo arrhythmias underscores the persistent risk for arrhythmias in this population and highlights the need for adjusted long-term management strategies.

Aims SCN5A-E1784K (c.5350G>A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. Methods and results We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. 'Lethal events' were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. 'Cardiac events' were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Conclusion Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.

AIMS:Digitoxin reduced the composite of death or worsening heart failure in DIGIT-HF, but whether these benefits translate into economic value remains unknown. We assessed its cost-effectiveness as add-on therapy for heart failure with reduced ejection fraction (HFrEF) across all 27 European Union Member States (EU-27) and the United States (US). METHODS:We developed a DIGIT-HF-informed, multi-jurisdictional three-state Markov cost-utility model projecting 10-year and lifetime outcomes. Clinical risks and intention-to-treat effects were held constant; hospitalization costs, EQ-5D-5L utilities, digitoxin costs, discounting, and willingness-to-pay (WTP) thresholds varied by jurisdiction. Uncertainty was assessed using 10 000 probabilistic simulations. RESULTS:Across the EU-27, digitoxin was cost-effective at 10 years, with incremental costs of -€338 to +€25 per patient, incremental quality-adjusted life-years (QALYs) of 0.188-0.231, and a maximum incremental cost-effectiveness ratio (ICER) of €120/QALY. Over lifetime, corresponding ranges were -€79 to +€72, 0.373-0.453 QALYs, and a maximum ICER of €174/QALY. At €50 000/QALY, cost-effectiveness probability was 92%. Digitoxin was cost-saving in 24 of 27 Member States at 10 years and 10 of 27 over lifetime. In the USA, it was cost-saving (lifetime savings US$405 per patient; 0.43 QALYs; 93.4% probability of cost-effectiveness). CONCLUSION:Digitoxin generated clinically meaningful health benefits at negligible incremental cost and remained cost-effective across every evaluated EU-27 healthcare system and the USA. Economic value emerged earliest within the first decade and in higher-cost hospital systems, while lifetime analysis captured larger cumulative gains in quality-adjusted survival.

The updated position paper of the German Cardiac Society (DGK) on catheter ablation of atrial fibrillation (AF) presents the current evidence, techniques and quality standards, which have clearly evolved since 2017 together with the indications, techniques and the role of ablation in treatment. Pulmonary vein isolation (PVI) remains the cornerstone of AF ablation. In addition to established procedures, such as radiofrequency and cryoballoon ablation, pulsed field ablation (PFA) is gaining in importance. For persistent AF clear recommendations beyond PVI are lacking, despite growing evidence supporting adjunctive ablation strategies. The healthcare landscape shows a marked increase in ablation, with same day discharge procedures recommended only for carefully selected patients. Precise patient selection, including medical history, risk factors and imaging, is critical for procedural success and safety. The importance of periprocedural management and structured follow-up is emphasized. Complications such as pericardial tamponade, stroke and phrenic nerve paresis require structured protocols and experienced teams. Ablation can potentially improve the prognosis, particularly in patients with heart failure. Certification of centers by the DGK supports quality assurance. New developments, such as artificial intelligence (AI)-assisted ablation planning and studies on postablation oral anticoagulation strategies, are expected to further influence clinical practice.

DIGIT-HF is a multicentre, randomized, double-blind, placebo-controlled trial designed to investigate the effect of digitoxin versus placebo on the composite primary endpoint of time to all-cause death and hospital admission for worsening heart failure (HFH) (whichever occurs first) in patients with heart failure (HF) and reduced ejection fraction (HFrEF).1 The DIGIT-HF trial is conducted in compliance with the German Drug Law (AMG), the German Good Clinical Practice (GCP) ordinance, ICH GCP guidelines, and other applicable ethical and regulatory requirements. The DIGIT-HF trial is registered at EudraCT (2013-005326-38). Since recruitment of the first patient in May 2015, seven key protocol amendments have been implemented to specify and clarify its content, particularly to improve the recruitment to reach the required number of primary endpoint events (Figure 1; for details see online supplementary Table S1). Due to the lower than expected recruitment rate, a blinded sample size/trial duration re-estimation was conducted 40 months after beginning of recruitment. It was estimated that the study duration needed to be extended to observe the required number of 734 primary endpoint events. Consequently, the required number of patients was reduced from 2190 to 1653. Following successful application for continued funding, the trial conduct was extended until the end of 2024 with an increased number of recruitment sites. The main challenge of the trial was the lower than expected recruitment, which was probably due to the initial overestimation of the number of patients to be recruited per trial site, although the observed pooled event rate for the primary endpoint was similar as assumed in the sample size calculation. Therefore, the number of trial sites was increased from initially 40 to finally 65. This included extension of the trial to motivated investigators in Austria and Serbia.2 In addition, several competing clinical trials recruiting HFrEF populations funded by pharmaceutical companies (e.g. DAPA-HF, EMPEROR-Reduced)3, 4 started during the DIGIT-HF trial period, which probably impaired recruitment into DIGIT-HF as well. The COVID-19 pandemic also affected recruitment because screening/baseline visits intended to be performed in presence could not be scheduled. Furthermore, trial extension to Serbia was strongly delayed by COVID-19 pandemic just after solving all regulatory issues (e.g. digitoxin is not available and approved in Serbia) mandatory for starting the trial at 10 study sites in Serbia, which significantly affected final recruitment numbers. Overall, the COVID-19 pandemic did affect the study conduct by for example, changing the in-person visits to telephone visits, which may have significantly impaired collection of events, in particular HFH events. To explore potential impact of COVID-19 on the study results, COVID-related data (e.g. respiratory infections, vaccinations) have been collected and will be analysed. Further COVID-related supplementary analyses may be conducted, for example, separately analysing the pre-COVID-19 data. A second blind review of trial data in December 2022 revealed that the required number of 367 primary endpoint events for the pre-planned interim analysis had not been achieved. Because the probability for early trial termination due to overwhelming efficacy was very low, the initially planned interim analysis was not performed. Consequently, the full alpha of 0.05 can be used for the final analysis and 716 primary endpoint events need to be observed to demonstrate the expected hazard ratio of 0.811 with a power of 80%. The most recent protocol amendment (Version 8.0, date 20 July 2023, in online supplementary material) re-defined the key secondary endpoints of all-cause death, HFH and (recurrent) HFH. Analysis of time to first HFH alone is not of high clinical relevance as it ignores the fatal worsening event death, which constitutes about 30% of the primary endpoint events in the current trial (based on a blind review). Furthermore, censoring patients who had not experienced HFH before death is statistically inappropriate, as this leads to informative censoring. Therefore, including death as a fatal worsening event is more meaningful from both clinical and statistical aspects. As this coincides with the primary endpoint, time to first HFH was removed from the list of key secondary endpoints. The absolute and relative frequency of the first HFH as a component of the primary endpoint will be presented. Analysis of recurrent HFH would have similar problems if death is ignored. Furthermore, including death as an additional event may better prevent a potential type I error inflation associated with the analysis of recurrent HFH alone.5 Therefore, the composite of recurrent HFH and all-cause death instead of recurrent HFH was defined as a new key secondary endpoint. To control the overall type I error, a hierarchical testing procedure for the primary and key secondary endpoints was pre-specified with the following testing order: (1) superiority of digitoxin versus placebo in the primary endpoint, (2) non-inferiority of digitoxin versus placebo regarding time to all-cause death, (3) superiority of digitoxin versus placebo regarding the composite of recurrent HFH and all-cause death. The testing order reflects the relative clinical relevance/importance of the endpoints and implies the clinical decision-making process. For example, all-cause mortality is the first key secondary endpoint after the primary endpoint, since the most important component of the composite endpoint should not be negatively impacted by the experimental treatment. Composite recurrent HFH endpoint is the second key secondary endpoint after all-cause mortality. As indicated in the European Medicines Agency chronic HF guideline,6 the main challenge in the analysis and interpretation of recurrent event endpoints is the presence of terminal events (e.g. death), which limit the number of events per subject. In consequence, a lower number of events in one as compared to the other treatment group may simply be the result of an increased mortality in the former treatment group. Thus, excluding a detrimental effect on all-cause mortality in the first step is a pre-requisite for concluding a positive effect on the composite recurrent HFH endpoint. If all confirmatory null hypotheses of the main study can successfully be rejected, substudies will be assessed confirmatory in the pre-defined order. Otherwise, substudies will be evaluated descriptively with a two-sided alpha of 5%. The primary analysis will be conducted on the intention-to-treat (ITT) population including all randomized patients who took at least one dose of the study drug. Patients will be analysed as randomized regardless of their actual treatment (digitoxin or placebo). Initially, the per-protocol population was specified to all patients who achieved the target serum concentration of digitoxin (preferably 8–18 ng/ml [10.5–23.6 nmol/L]), complied with the study protocol until the end of the observational period, and remained in the treatment arm to which they were allocated by randomization. This was further refined to all patients of the ITT population that had attended visit 3 (12 months ± 7 days), achieved digitoxin serum concentrations of <2.5 nmol/L (if randomized to placebo) or had a digitoxin serum concentration of 5–30 nmol/L (if randomized to digitoxin), and experienced no active decision against the randomized therapy. As various win ratio analyses have been performed in recent HF trials, we further pre-specified secondary analyses of (1) hierarchical composite of all-cause death, number of HFH, and time to first HFH, and (2) hierarchical composite of all-cause death, number of HFH, time to first HFH, change from baseline in New York Heart Association class and change from baseline in quality of life, both assessed using a win ratio method, to provide additional insights into the understanding of the treatment effect (statistical analysis plan, sections S2.4 and S10 in online supplementary material). During the recruitment phase of DIGIT-HF, recommendations of the European Society of Cardiology for pharmacological treatment of HFrEF were extended to also include angiotensin receptor–neprilysin inhibitors and sodium–glucose cotransporter 2 inhibitors.7, 8 Because the aim of the trial was to investigate a potential benefit of digitoxin in HFrEF patients on top of standard of care based on guideline recommendations, standard of care for study participants in the trial protocol was extended by these substance classes. The principal findings of the DIGIT-HF trial are anticipated to be made available in 2025, potentially offering important new insights into the efficacy and safety of cardiac glycosides, specifically digitoxin, in the treatment of advanced HFrEF. Open Access funding enabled and organized by Projekt DEAL. The DIGIT-HF study is funded by the Federal Ministry of Education and Research, Germany (BMBF: 01KG1303 and 01KG1907) the Braukmann-Wittenberg-Herzstiftung, and the German Heart Foundation. Conflict of interest: U.B. and J.B. represent the study heads of the DIGIT-HF-study and applied for funding of DIGIT-HF described above. U.B., J.B., A.K., H.v.d.L., C.V., S.S., and M.B. are members of the DIGIT-HF trial steering committee. U.B. received travel support and honoraria for lectures/consulting from Alnylam Pharmaceutical, Amgen, AstraZeneca, Bayer Vital, Novartis, and Pfizer and institutional research support from Alnylam Pharmaceuticals, all not related to the current manuscript. D.B. was competitively selected for 'CORE100Pilot', which is an advanced clinician-scientist programme co-funded by the Else Kröner Fresenius Foundation and the Ministry for Science and Culture of the State of Lower Saxony. D.B. received honoraria for lectures/consulting from Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Edwards Lifesciences, Pfizer, all not related to the current manuscript. P.M.B reports personal fees from AstraZeneca, Ingelheim Boehringer and the German Research Foundation, all not related to the current manuscript. C.V. reports honorary for lectures or consulting from Abbott, Medtronic, BMS and Zoll. M.B. is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939) and reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Edwards, Medtronic, Novartis, ReCor, Servier and Vifor during the conduct of the study. J.B. received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, BMS, Amgen, Corvia, Norgine, Edwards, Roche not related to this article; and research support for the department from Zoll, CVRx, Abiomed, Norgine, Roche, all not related to the current manuscript. All other authors have nothing to disclose. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.