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Background: The Heart Failure Collaboratory (HFC) score integrates types and dosages of guideline-directed pharmacotherapies for heart failure (HF) with reduced ejection fraction (HFrEF). We examined the effects of cardioverter-defibrillator (ICD) implantation according to the modified HFC (mHFC) score in 1116 patients with nonischemic HFrEF from the Danish Study to Assess the Efficacy of ICDs in Patients with Nonischemic Systolic HF on Mortality (DANISH)., Methods and Results: Patients were assigned scores for renin-angiotensin-system inhibitors, beta-blockers and mineralocorticoid receptor antagonists (0, no use; 1, < 50% of maximum dosage; 2, ≥ 50% of maximum dosage). The maximum score was 6, corresponding to ≥ 50% of maximum dosage for all therapies. The median baseline mHFC score was 4, and the median follow-up was 9.5 years. Compared with an mHFC score of 3-4, an mHFC score of 1-2 was associated with a higher rate of all-cause death (mHFC = 1-2: adjusted HR 1.67 [95% CI, 1.23-2.28]; mHFC = 3-4, reference; mHFC = 5-6: adjusted HR 1.07 [95% CI, 0.87-1.31]). ICD implantation did not reduce all-cause death compared with control (reference) (HR 0.89 [95% CI, 0.74-1.08]), regardless of mHFC score (mHFC = 1-2: HR 0.98 [95% CI, 0.56-1.71]; mHFC = 3-4: HR 0.89 [95% CI,0.66-1.20]; mHFC = 5-6: HR 0.85 [95% CI, 0.64-1.12]; P interaction , 0.65). Similarly, ICD implantation did not reduce cardiovascular death (HR 0.87 [95% CI, 0.70-1.09]), regardless of mHFC score (P interaction , 0.59). The ICD group had a lower rate of sudden cardiovascular death (HR, 0.60 [95% CI,0.40-0.92]); this association was not modified by mHFC score (P interaction , 0.35)., Conclusions: Lower mHFC scores were associated with higher rates of all-cause death. ICD implantation did not result in an overall survival benefit in patients with nonischemic HFrEF, regardless of mHFC score., Competing Interests: Disclosures JJT reports speaker's fees from Astra Zeneca and BMS and travel grants from AstraZeneca. JCN reports grants from the Novo Nordisk Foundation and Danish Heart Foundation outside the submitted work. NEB reports grants from the Novo Nordisk Foundation, the Augustinus Foundation, Health Insurance Denmark, and the Kaj Hansen Foundation, not related to this work. FG is an aAdvisor to Abbott, Ionis, Alnylam, AstraZeneca, Bayer, and Pfizer and is a speaker at Novartis. CH reports research grants from the Novo Nordisk Foundation, Lundbeck Foundation, and the Danish Heart Foundation (not related to this work). JHS reports a research grant from Medtronic (outside of this work) and speaker's fee from Medtronic and is a member of the Advisory Board for Medtronic and for Vital Beats. SP reports a travel grant from Abbott. LK reports speaker's honoraria from AstraZeneca, Bayer, Boehringer, Novartis, and Novo Nordisk. JHB reports advisory board honoraria from AstraZeneca and Bayer, consultant honoraria from Novartis and AstraZeneca and travel grants from AstraZeneca. All other authors have no disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose To assess long-term geometric changes of the mitral valve apparatus using cardiac CT in individuals who underwent cardiac resynchronization therapy (CRT). Materials and Methods Participants from a randomized controlled trial with cardiac CT examinations before CRT implantation and at 6 months follow-up (Clinicaltrials.gov identifier NCT01323686) were invited to undergo an additional long-term follow-up cardiac CT examination. The geometry of the mitral valve apparatus, including mitral valve annulus area, A2 leaflet angle, tenting height, and interpapillary muscle distances, were assessed. Geometric changes at the long-term follow-up examination were reported as mean differences (95% CI), and the Pearson correlation test was used to assess correlation between statistically significant geometric changes and left ventricular (LV) volumes and function. Results Thirty participants (mean age, 68 years ± 9 [SD]; 25 male participants) underwent cardiac CT imaging after a median long-term follow-up of 9.0 years (IQR, 8.4-9.4). There were reductions in end-systolic A2 leaflet angle (-4° [95% CI: -7, -2]), end-systolic tenting height (-1 mm [95% CI: -2, -1]), and end-systolic and end-diastolic interpapillary muscle distances (-4 mm [95% CI: -6, -2]) compared with pre-CRT implantation values. The mitral valve annulus area remained unchanged. LV end-diastolic and end-systolic volumes decreased (-68 mL [95% CI: -99, -37] and -67 mL [95% CI: -96, -39], respectively), and LV ejection fraction increased (13% [95% CI: 7, 19]) at the long-term follow-up examination. Changes in interpapillary muscle distances showed moderate to strong correlations with LV volumes ( r = 0.42-0.72; P < .05), while A2 leaflet angle and tenting height were not correlated to LV volumes or function. Conclusion Among the various geometric changes in the mitral valve apparatus after long-term CRT, the reduction in interpapillary muscle distances correlated with LV volumes while the reduced A2 leaflet angle and tenting height did not correlate with LV volumes. Keywords: Mitral Valve Apparatus, Cardiac Resynchronization Therapy, Cardiac CT Supplemental material is available for this article. © RSNA, 2024.

Aims: Although body mass index (BMI) is the most commonly used anthropometric measure to assess adiposity, alternative indices such as the waist-to-height ratio may better reflect the location and amount of ectopic fat as well as the weight of the skeleton., Methods and Results: The prognostic value of several alternative anthropometric measures was compared with that of BMI in 1116 patients with non-ischaemic heart failure with reduced ejection fraction (HFrEF) enrolled in DANISH. The association between anthropometric measures and all-cause death was adjusted for prognostic variables, including natriuretic peptides. Median follow-up was 9.5 years (25th-75th percentile, 7.9-10.9). Compared to patients with a BMI 18.5-24.9 kg/m 2 (n = 363), those with a BMI ≥25 kg/m 2 had a higher risk of all-cause and cardiovascular death, although this association was only statistically significant for a BMI ≥35 kg/m 2 (n = 91) (all-cause death: hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.28-2.48; cardiovascular death: HR 2.46, 95% CI 1.69-3.58). Compared to a BMI 18.5-24.9 kg/m 2 , a BMI <18.5 kg/m 2 (n = 24) was associated with a numerically, but not a significantly, higher risk of all-cause and cardiovascular death. Greater waist-to-height ratio (as an exemplar of indices not incorporating weight) was also associated with a higher risk of all-cause and cardiovascular death (HR for the highest vs. the lowest quintile: all-cause death: HR 2.11, 95% CI 1.53-2.92; cardiovascular death: HR 2.17, 95% CI 1.49-3.15)., Conclusion: In patients with non-ischaemic HFrEF, there was a clear association between greater adiposity and higher long-term mortality., Clinical Trial Registration: ClinicalTrials.gov NCT00542945., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: We aimed to evaluate the association between atrial fibrillation (AF) burden, duration and number of episodes with healthcare utilisation and quality of life in patients with early paroxysmal AF without a history of AF., Methods: In this observational cohort study, we included 417 patients with paroxysmal AF from the Reappraisal of Atrial Fibrillation: interaction between hyperCoagulability, Electrical remodelling and Vascular destabilisation in the progression of AF (RACE V) Study. Patients were monitored with an insertable cardiac monitor for 1 year. Outcomes collected were healthcare utilisation, and quality of life assessed using the Atrial Fibrillation Severity Scale and EuroQol EQ-5D-5L questionnaires., Results: During 1 year of follow-up, 63 973 AF episodes were detected in 353 (85%) patients. The median AF burden was 0.7% (IQR 0.1-4.0%). AF ablation was performed more frequently in patients with intermediate-to-high AF burdens (>0.2%) (16.2% vs 5.9%, p=0.01) and longer AF episode duration (>1 hour) (15.8% vs 2.0%, p=0.01), whereas cardioversions were more frequent in patients with longer episode duration (>1 hour) (9.5% vs 0%, p=0.04) and intermediate (0.2-1.9%) (but not high) AF burdens (13.6% vs 4.2%, p=0.01). Patients with many episodes (>147) reported higher symptom severity (p=0.001). No differences in symptom severity nor in EQ-5D-5L scores according to AF burden or duration were observed., Conclusion: In patients with early paroxysmal AF, higher AF burden and longer episode duration were associated with increased rates of healthcare utilisation but not with symptoms and quality of life. Patients with a higher number of episodes experienced more severe symptoms., Trial Registration Number: NCT02726698., Competing Interests: Competing interests: MHJPF received consulting fees from Medtronic outside this work. MBK received speaker’s honoraria from Abbott outside this work. JCN was supported by a grant from the Novo Nordisk Foundation (NNF16OC0018658). MR received consultancy fees from Bayer and InCarda Therapeutics (to the institution). MDM is an employee of Medtronic Bakken Research Center. RGT reports grants and personal fees from Medtronic and grants from St Jude Medical outside this work. In addition, RGT has a patent as co-inventor of the MyDiagnostick issued. The remaining authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aim: There are a paucity of studies investigating workforce affiliation in connection with first-time implantable cardioverter defibrillator (ICD)-implantation. This study explored workforce affiliation and risk markers associated with not returning to work in patients with ICDs., Methods: Using the nationwide Danish registers, patients with a first-time ICD-implantation between 2007 and 2017 and of working age (30-65 years) were identified. Descriptive statistic and logistic regression models were used to describe workforce affiliation and to estimate risk markers associated with not returning to work, respectively. All analyses were stratified by indication for implantation (primary and secondary prevention)., Results: Of the 4659 ICD-patients of working age, 3300 patients (71%) were members of the workforce (employed, on sick leave or unemployed) (primary: 1428 (43%); secondary:1872 (57%)). At baseline, 842 primary and 1477 secondary prevention ICD-patients were employed. Of those employed at baseline, 81% primary and 75% secondary prevention ICD-patients returned to work within 1 year, whereof more than 80% remained employed the following year. Among patients receiving sick leave benefits at baseline, 25% were employed after 1 year. Risk markers of not returning to work were 'younger age' in primary prevention ICD-patients, while 'female sex', left ventricular ejection fraction 'LVEF ≤40', 'lower income', and '≥3 comorbidities' were risk markers in secondary prevention ICD-patients. Lower educational level was a risk marker in both patient groups., Conclusion: High return-to-work proportions following ICD-implantation, with a subsequent high level of employment maintenance were found. Several significant risk markers of not returning to work were identified including 'lower educational level' that posed a risk in both patient groups., Trial Registration Number: Capital Region of Denmark, P-2019-051., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Current guidelines recommend implantable cardioverter-defibrillator (ICD) therapy in patients with heart failure, a left ventricular ejection fraction of ≤35%, and New York Heart Association (NYHA) class II-III. However, the evidence regarding the benefit of primary prevention ICD is less consistent in patients with NYHA class III. We investigated the long-term effects of primary prevention ICD implantation according to NYHA class in an extended follow-up study of the DANISH trial., Methods and Results: The DANISH trial randomized 1116 patients with non-ischaemic heart failure with reduced ejection fraction (HFrEF) to ICD implantation or usual care. Outcomes were analysed according to NYHA class at baseline (NYHA class II and III/IV). The primary outcome was all-cause mortality. Of the 1116 patients randomized in the DANISH trial, 597 (53.5%) were in NYHA class II at baseline, 505 (45.3%) in NYHA class III, and 14 (1.3%) in NYHA class IV. During a median follow-up of 9.5 years, NYHA class III/IV, compared with NYHA class II, were associated with a greater long-term rate of all-cause mortality (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.20-1.93) and cardiovascular death (HR 1.95 [1.47-2.60]). ICD implantation, compared with usual care, did not reduce the long-term rate of all-cause mortality (all participants: HR 0.89 [95% CI 0.74-1.08]; NYHA class II: HR 0.85 [0.64-1.13]; NYHA class III/IV: HR 0.89 [0.69-1.14]; p interaction  = 0.78) or cardiovascular death (all participants: HR 0.87 [95% CI 0.70-1.09]; NYHA class II: HR 0.78 [0.54-1.12]; NYHA class III/IV: HR 0.89 [0.67-1.19]; p interaction  = 0.58), irrespective of NYHA class. Similarly, NYHA class did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (all participants: HR 0.60 [95% CI 0.40-0.92]; NYHA class II: HR 0.73 [0.40-1.36]; NYHA class III/IV: HR 0.52 [0.29-0.94]; p interaction  = 0.39)., Conclusions: In patients with non-ischaemic HFrEF, ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce sudden cardiovascular death, regardless of baseline NYHA class., Clinical Trial Registration: ClinicalTrials.gov NCT00542945., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Voltage mapping to detect ventricular scar is important for guiding catheter ablation, but the field-of-view of unipolar, bipolar, conventional, and microelectrodes as it relates to the extent of viable myocardium (VM) is not well defined., Objectives: The purpose of this study was to evaluate electroanatomic voltage-mapping (EAVM) with different-size electrodes for identifying VM, validated against high-resolution ex-vivo cardiac magnetic resonance (HR-LGE-CMR)., Methods: A total of 9 swine with early-reperfusion myocardial infarction were mapped with the QDOT microcatheter. HR-LGE-CMR (0.3-mm slices) were merged with EAVM. At each EAVM point, the underlying VM in multisize transmural cylinders and spheres was quantified from ex vivo CMR and related to unipolar and bipolar voltages recorded from conventional and microelectrodes., Results: In each swine, 220 mapping points (Q1, Q3: 216, 260 mapping points) were collected. Infarcts were heterogeneous and nontransmural. Unipolar and bipolar voltage increased with VM volumes from >175 mm 3 up to >525 mm 3 (equivalent to a 5-mm radius cylinder with height >6.69 mm). VM volumes in subendocardial cylinders with 1- or 3-mm depth correlated poorly with all voltages. Unipolar voltages recorded with conventional and microelectrodes were similar (difference 0.17 ± 2.66 mV) and correlated best to VM within a sphere of radius 10 and 8 mm, respectively. Distance-weighting did not improve the correlation., Conclusions: Voltage increases with transmural volume of VM but correlates poorly with small amounts of VM, which limits EAVM in defining heterogeneous scar. Microelectrodes cannot distinguish thin from thick areas of subendocardial VM. The field-of-view for unipolar recordings for microelectrodes and conventional electrodes appears to be 8 to 10 mm, respectively, and unexpectedly similar., Competing Interests: Funding Support and Author Disclosures This study was partially supported by an investigator-initiated grant from Biosense Webster (a Johnson and Johnson company). Dr Tofig has received research support from the Arvid Nilssons Foundation. Mr Leenknegt was funded by FWO-Flanders grant number G025820N and KU Leuven grant STG/19/007. Outside this work, Dr Nielsen has received research support from the Novo Nordisk Foundation (grants NNF16OC0018658 and NNF17OC0029148). Dr Lukac has received an institutional grant from Abbott Denmark and Biosense Webster. All other authors have reported that they have no relationships to disclose that are relevant to the contents of this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Changes in QRS duration (∆QRS) are often used in the clinical setting to evaluate the effect of cardiac resynchronization therapy (CRT), although an association between ∆QRS and outcomes is not firmly established. We aimed to assess the association between mortality and ∆QRS after CRT in patients from the DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-Ischemic Systolic Heart Failure on Mortality) study., Methods: We included all patients from DANISH who received a CRT device and had available QRS duration data before and after implantation. Cox proportional hazards models were used to assess associations between ∆QRS (post-CRT QRS minus pre-CRT QRS) and mortality., Results: Complete data were available in 572 patients. Median baseline QRS duration was 160 ms (IQR [146;180]). Post-CRT QRS was recorded a median of 48 days (IQR [33;86]) after implantation, and the median ∆QRS was -14 ms (IQR [-38;-3]). During a median follow-up of 4.1 years (IQR [2.5;5.8]), 106 patients died. In crude Cox regression, all-cause mortality was reduced by 6% per 10 ms shortening of QRS (HR 0.94; CI: 0.88-1.00, p = 0.04). The effect did not remain significant after multivariable adjustment (HR 1.01, CI: 0.93-1.10, p = 0.77). Further, no association was found between ∆QRS and improvement of New York Heart Association functional class at 6 months (OR 1.03, CI: 0.96-1.10, p = 0.42)., Conclusion: In a large cohort of patients with non-ischemic cardiomyopathy, reduction of QRS duration after CRT was not associated with changes in mortality during long-term follow-up., Competing Interests: Declaration of competing interest Casper Lund-Andersen has received a grant from Innovation fund Denmark and has received travel grants from St. Jude Medical and Medtronic (outside of this study). Adelina Yafasova has received a grant from the Foundation of Rigshospitalet (outside of this study). Jesper Hastrup Svendsen has received grants from Medtronic outside this study and is a member of an advisory board in Medtronic. Jens Cosedis Nielsen has received a grant from the Novo Nordisk Foundation outside of this study (NNF16OC0018658). Lars Køber has received grants from Astra Zeneca, Bayer, Boehringer, Novartis and Novo Nordisk. Finn Gustafsson has received speaker's fees from Pfizer and Novartis and is a member of advisory boards in Abbott, Ionis, Alnylam, AstraZeneca, and Bayer. All remaining authors have declared no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: A growing number of patients with tetralogy of Fallot develop left ventricular systolic dysfunction and heart failure, in addition to right ventricular dysfunction. Although cardiac resynchronization therapy (CRT) is an established treatment option, the effect of CRT in this population is still not well defined. This study aimed to investigate the early and late efficacy, survival, and safety of CRT in patients with tetralogy of Fallot., Methods: Data were analyzed from an observational, retrospective, multicenter cohort, initiated jointly by the Pediatric and Congenital Electrophysiology Society and the International Society of Adult Congenital Heart Disease. Twelve centers contributed baseline and longitudinal data, including vital status, left ventricular ejection fraction (LVEF), QRS duration, and NYHA functional class. Outcomes were analyzed at early (3 months), intermediate (1 year), and late follow-up (≥2 years) after CRT implantation., Results: A total of 44 patients (40.3±19.2 years) with tetralogy of Fallot and CRT were enrolled. Twenty-nine (65.9%) patients had right ventricular pacing before CRT upgrade. The left ventricular ejection fraction improved from 32% [24%-44%] at baseline to 42% [32%-50%] at early follow-up ( P <0.001) and remained improved from baseline thereafter ( P ≤0.002). The QRS duration decreased from 180 [160-205] ms at baseline to 152 [133-182] ms at early follow-up ( P <0.001) and remained decreased at intermediate and late follow-up ( P ≤0.001). Patients with upgraded CRT had consistent improvement in left ventricular ejection fraction and QRS duration at each time point ( P ≤0.004). Patients had a significantly improved New York Heart Association functional class after CRT implantation at each time point compared with baseline ( P ≤0.002). The transplant-free survival rates at 3, 5, and 8 years after CRT implantation were 85%, 79%, and 73%., Conclusions: In patients with tetralogy of Fallot treated with CRT consistent improvement in QRS duration, left ventricular ejection fraction, New York Heart Association functional class, and reasonable long-term survival were observed. The findings from this multicenter study support the consideration of CRT in this unique population., Competing Interests: Disclosures None.

Background: Patients with heart failure and chronic kidney disease (CKD) may have an increased risk of death from causes competing with arrhythmic death, which could have implications for the efficacy of implantable cardioverter-defibrillators (ICDs). We examined the long-term effects of primary prophylactic ICD implantation, compared with usual care, according to baseline CKD status in an extended follow-up study of DANISH (Danish Study to Assess the Efficacy of ICDs in Patients With Nonischemic Systolic Heart Failure on Mortality)., Methods and Results: In the DANISH trial, 1116 patients with nonischemic heart failure with reduced ejection fraction were randomized to receive an ICD (N=556) or usual care (N=550). Outcomes were analyzed according to CKD status (estimated glomerular filtration rate ≥/<60 mL/min per 1.73 m 2 ) at baseline. In total, 1113 patients had an available estimated glomerular filtration rate measurement at baseline (median estimated glomerular filtration rate 73 mL/min per 1.73 m 2 ), and 316 (28%) had CKD. During a median follow-up of 9.5 years, ICD implantation, compared with usual care, did not reduce the rate of all-cause mortality (no CKD, HR, 0.82 [95% CI, 0.64-1.04]; CKD, HR, 1.02 [95% CI, 0.75-1.38]; P interaction =0.31) or cardiovascular death (no CKD, HR, 0.77 [95% CI, 0.58-1.03]; CKD, HR, 1.05 [95% CI, 0.73-1.51]; P interaction =0.20), irrespective of baseline CKD status. Similarly, baseline CKD status did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (no CKD, HR, 0.57 [95% CI, 0.32-1.00]; CKD, HR, 0.65 [95% CI, 0.34-1.24]; P interaction =0.70)., Conclusions: ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce the rate of sudden cardiovascular death, regardless of baseline kidney function in patients with nonischemic heart failure with reduced ejection fraction., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00542945.

Background: Atrial fibrillation is the most common cardiac arrhythmia and a major global health burden. Updated trends in the epidemiology of atrial fibrillation or flutter (AF) are needed., Methods: Using the Danish Heart Statistics, we investigated nationwide trends 2009-2018 in incidence rate and prevalence of AF according to age as well as age-standardized incidence rate (ASIR) and prevalence (ASP) of AF according to sex, ethnicity, educational level, and area of residence. Comparing year 2018 to 2009, we calculated stratum-specific ASIR ratios (ASIRR) and changes in ASP., Results: During 2009-2015 the ASIR for AF increased for both men and women, followed by a decline from 2015-2018. Overall, this resulted in a 9% increase among men (ASIRR: 1.09, 95% CI: 1.06-1.12), but no change among women (ASIRR: 1.00, 95% CI: 0.97-1.04). The ASP increased by 29% among men and 26% among women. An increase in ASIR was observed in all ethnic groups except men of Far Eastern ethnicity. Lower educational level was associated with greater increases in both ASIR and ASP. ASIR and ASP differed slightly between the Danish regions but increased in all of them., Conclusions: During 2009-2018 the incidence and prevalence of AF in Denmark increased although the increase in incidence was transient among women. Factors associated with higher incidence were male sex, higher age, Danish and Western ethnicity as well as Middle Eastern/North African ethnicity among women, and lower educational level. Within Denmark, we observed only minor regional differences in AF incidence and prevalence.

Competing Interests: Disclosures Dr Butt reports advisory board honoraria from Bayer and AstraZeneca, consultant honoraria from Novartis and AstraZeneca, and travel grants from AstraZeneca outside this work. Dr Nielsen reports grant from the Novo Nordisk Foundation (NNF16OC0018658 and NNF17OC0029148) outside this work. Dr Brandes reports lecture honoraria from Boehringer Ingelheim and Bristol-Myers Squibb, as well as research grants from Theravance, the Zealand Region, Canadian Institutes of Health Research, and the Danish Heart Foundation outside this work. Dr Svendsen reports institutional research grants from Medtronic, speaker fees from Medtronic, and membership in a Medtronic advisory board outside this work. Dr Hassager reports research grants from Novo Nordisk Foundation, Lundbeck Foundation, and The Danish Heart Foundation outside this work. Dr Gustafsson reports advisory roles for Abbott, Alnylam, Ionis, Pfizer, Bayer, FineHeart, and Corwave and speaker fees from Orion pharma, AstraZeneca, and Novartis outside this work. Dr Pehrson reports lecture fees from Bayer, BMS, and Abbott, as well as travel grants from Johnson & Johnson. The other authors report no conflicts.

Aims: Standardized data definitions are essential for monitoring and assessment of care and outcomes in observational studies and randomized controlled trials (RCTs). The European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart) project of the European Society of Cardiology aimed to develop contemporary data standards for atrial fibrillation/flutter (AF/AFL) and catheter ablation., Methods and Results: We used the EuroHeart methodology for the development of data standards and formed a Working Group comprising 23 experts in AF/AFL and catheter ablation registries, as well as representatives from the European Heart Rhythm Association and EuroHeart. We conducted a systematic literature review of AF/AFL and catheter ablation registries and data standard documents to generate candidate variables. We used a modified Delphi method to reach a consensus on a final variable set. For each variable, the Working Group developed permissible values and definitions, and agreed as to whether the variable was mandatory (Level 1) or additional (Level 2). In total, 70 Level 1 and 92 Level 2 variables were selected and reviewed by a wider Reference Group of 42 experts from 24 countries. The Level 1 variables were implemented into the EuroHeart IT platform as the basis for continuous registration of individual patient data., Conclusion: By means of a structured process and working with international stakeholders, harmonized data standards for AF/AFL and catheter ablation for AF/AFL were developed. In the context of the EuroHeart project, this will facilitate country-level quality of care improvement, international observational research, registry-based RCTs, and post-marketing surveillance of devices and pharmacotherapies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Beyond 1 year after percutaneous coronary intervention (PCI), guidelines recommend anticoagulant monotherapy in patients with atrial fibrillation (AF) rather than dual therapy with an anticoagulant and an antiplatelet drug. The risks and benefits of this strategy, however, remain uncertain. We examined hospitalization for bleeding and ischaemic risk beyond 1 year after PCI in patients with AF treated with monotherapy vs. dual therapy. Furthermore, among patients treated with monotherapy, we compared direct oral anticoagulant (DOAC) therapy and vitamin K antagonist (VKA) therapy., Methods and Results: We included all patients with AF undergoing first-time PCI between 2003 and 2017 from the Western Denmark Heart Registry and followed them for up to 4 years. Follow-up started 15 months after PCI to enable assessment of medical treatment after 12 months. Using a Cox regression model, we computed weighted hazard ratios (HRw) of hospitalization for bleeding and major adverse cardiac events (MACEs). Analyses comparing monotherapy vs. dual therapy included 3331 patients, and analyses comparing DOAC vs. VKA monotherapy included 1275 patients. Risks of hospitalization for bleeding [HRw 0.90, 95% confidence interval (CI) 0.75-1.09] and MACE (HRw 1.04, 95% CI 0.90-1.19) were similar with monotherapy and dual therapy. Similarly, risks of hospitalization for bleeding (HRw 1.27, 95% CI 0.84-1.92) and MACE (HRw 1.15, 95% CI 0.87-1.50) were equal with DOAC and VKA monotherapy., Conclusion: Our results support long-term OAC monotherapy beyond 1 year after PCI in patients with atrial fibrillation and suggest that DOAC monotherapy is as safe and effective as VKA monotherapy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Dyssynchrony-associated left ventricular systolic dysfunction is a major contributor to heart failure in congenital heart disease (CHD). Although conventional cardiac resynchronization therapy (CRT) has shown benefit, the comparative efficacy of cardiac conduction system pacing (CSP) is unknown., Objectives: The purpose of this study was compare the clinical outcomes of CSP vs conventional CRT in CHD with biventricular, systemic left ventricular anatomy., Methods: Retrospective CSP data from 7 centers were compared with propensity score-matched conventional CRT control subjects. Outcomes were lead performance, change in left ventricular ejection fraction (LVEF), and QRS duration at 12 months., Results: A total of 65 CSP cases were identified (mean age 37 ± 21 years, 46% men). The most common CHDs were tetralogy of Fallot (n = 12 [19%]) and ventricular septal defect (n = 12 [19%]). CSP was achieved after a mean of 2.5 ± 1.6 attempts per procedure (38 patients with left bundle branch pacing, 17 with HBP, 10 with left ventricular septal myocardial). Left bundle branch area pacing [LBBAP] vs HBP was associated with a smaller increase in pacing threshold (Δ pacing threshold 0.2 V vs 0.8 V; P = 0.05) and similar sensing parameters at follow-up. For 25 CSP cases and control subjects with baseline left ventricular systolic dysfunction, improvement in LVEF was non-inferior (Δ LVEF 9.0% vs 6.0%; P = 0.30; 95% confidence limits: -2.9% to 10.0%) and narrowing of QRS duration was more pronounced for CSP (Δ QRS duration 35 ms vs 14 ms; P = 0.04). Complications were similar (3 [12%] CSP, 4 [16%] conventional CRT; P = 1.00)., Conclusions: CSP can be reliably achieved in biventricular, systemic left ventricular CHD patients with similar improvement in LVEF and greater QRS narrowing for CSP vs conventional CRT at 1 year. Among CSP patients, pacing electrical parameters were superior for LBBAP vs HBP., Competing Interests: Funding Support and Author Disclosures Dr Cano has received consultant fees from Medtronic, Biotronik, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Objective: The aim of this study was to explore cardiac nurses' experiences with a comprehensive web-based intervention for patients with an implantable cardioverter defibrillator., Methods: We conducted an explorative qualitative study based on individual semi-structured interviews with 9 cardiac nurses from 5 Danish university hospitals., Results: We found one overall theme: "Between traditional nursing and modern eHealth". This theme was derived from the following six categories: (1) comprehensive content in the intervention, (2) patient-related differences in engagement, (3) following the protocol is a balancing act, (4) online communication challenges patient contact, (5) professional collaboration varies, and (6) an intervention with potential. Cardiac nurses were positive towards the web-based intervention and believe it holds a large potential. However, they felt challenged by not having in-person and face-to-face contact with patients, which they found valuable for assessing patients' wellbeing and psychological distress., Conclusion: Specific training in eHealth communication seems necessary as web-based care entails a shift in the nursing role and requires a different way of communication. Innovation Focusing on the user experience in web-based care from the perspective of cardiac nurses is innovative, and by applying implementation science this leads to new knowledge to consider when developing and implementing web-based care., Competing Interests: Susanne S Pedersen reports financial support was provided by Lundbeck Foundation. Susanne S Pedersen reports financial support was provided by TrygFonden., (© 2022 The Authors.)

Background The objective of this international multicenter study was to investigate both early and late outcomes of cardiac resynchronization therapy (CRT) in patients with a systemic right ventricle (SRV) and to identify predictors for congestive heart failure readmissions and mortality. Methods and Results This retrospective international multicenter study included 13 centers. The study population comprised 80 adult patients with SRV (48.9% women) with a mean age of 45±14 (range, 18-77) years at initiation of CRT. Median follow-up time was 4.1 (25th-75th percentile, 1.3-8.3) years. Underlying congenital heart disease consisted of congenitally corrected transposition of the great arteries and dextro-transposition of the great arteries in 63 (78.8%) and 17 (21.3%) patients, respectively. CRT resulted in significant improvement in functional class (before CRT: III, 25th-75th percentile, II-III; after CRT: II, 25th-75th percentile, II-III; P =0.005) and QRS duration (before CRT: 176±27; after CRT: 150±24 milliseconds; P =0.003) in patients with pre-CRT ventricular pacing who underwent an upgrade to a CRT device (n=49). These improvements persisted during long-term follow-up with a marginal but significant increase in SRV function (before CRT; 30%, 25th-75th percentile, 25-35; after CRT: 31%, 25th-75th percentile, 21-38; P =0.049). In contrast, no beneficial change in the above-mentioned variables was observed in patients who underwent de novo CRT (n=31). A quarter of all patients were readmitted for heart failure during follow-up, and mortality at latest follow-up was 21.3%. Conclusions This international experience with CRT in patients with an SRV demonstrated that CRT in selected patients with SRV dysfunction and pacing-induced dyssynchrony yielded consistent improvement in QRS duration and New York Heart Association functional status, with a marginal increase in SRV function.

Background: Men and women may respond differently to certain therapies for heart failure with reduced ejection fraction, including implantable cardioverter defibrillators (ICD). In an extended follow-up study of the DANISH trial (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heart Failure on Mortality), adding 4 years of additional follow-up, we examined the effect of ICD implantation according to sex., Methods: In the DANISH trial, 1116 patients with nonischemic systolic heart failure were randomized to receive an ICD (N=556) or usual clinical care (N=550). The primary outcome was all-cause mortality., Results: Of the 1116 patients randomized in the DANISH trial, 307 (27.5%) were women. During a median follow-up of 9.5 years, women had a lower associated rate of all-cause mortality (hazard ratio [HR], 0.60 [95% CI, 0.47-0.78]) cardiovascular death (HR, 0.62 [95% CI, 0.46-0.84]), nonsudden cardiovascular death (HR, 0.59 [95% CI, 0.42-0.85]), and a numerically lower rate of sudden cardiovascular death (HR, 0.70 [95% CI, 0.40-1.25]), compared with men. Compared with usual clinical care, ICD implantation did not reduce the rate of all-cause mortality, irrespective of sex (men, HR, 0.85 [95% CI, 0.69-1.06]; women, HR, 0.98 [95% CI, 0.64-1.50]; P interaction=0.51). In addition, sex did not modify the effect of ICD implantation on sudden cardiovascular death (men, HR, 0.57 [95% CI, 0.36-0.92]; women, HR, 0.68 [95% CI, 0.26-1.77]; P interaction=0.76)., Conclusions: In patients with nonischemic systolic heart failure, ICD implantation did not provide an overall survival benefit, but reduced sudden cardiovascular death, irrespective of sex., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT00542945.

Objective: To examine associations between baseline anxiety and depression and occurrence of ICD shocks and risk of mortality in patients with an implantable cardioverter defibrillator (ICD)., Method: We systematically searched EMBASE, PubMed, PsycINFO, and CINAHL for eligible studies fulfilling the predefined criteria., Results: We included 37 studies based on 25 different cohorts following 35,003 participants for up to seven years. We observed no association between baseline anxiety nor depression and the occurrence of ICD shocks. More than half of the identified studies (respectively 56% and 60%) indicated a significant association between baseline anxiety or depression and increased risk of mortality (anxiety: n = 5, ranging from Hazard ratios (HR):1.02 [Confidence intervals (CI) 95% 1.00-1.03] to HR:3.45 [CI 95% 1.57-7.60]; depression: n = 6, ranging from HR:1.03 [CI 95% 1.00-1.06] to HR:2.10 [CI 95% 1.44-3.05]). We found a significant association between high methodological quality of the primary study and the detection of a significant association (p < 0.01)., Conclusions: Baseline anxiety and depression are associated with increased risk of mortality in patients with an ICD, but not with occurrence of ICD shocks. Inclusion of baseline anxiety and depression in risk stratification of mortality may be warranted., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Prophylactic implantable cardioverter-defibrillators (ICD) reduce mortality in patients with ischaemic heart failure (HF), whereas the effect of ICD in patients with non-ischaemic HF is less clear. We aimed to investigate the association between concomitant coronary atherosclerosis and mortality in patients with non-ischaemic HF and the effect of ICD implantation in these patients., Methods and Results: Patients were included from DANISH (Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-Ischaemic Systolic Heart Failure on Mortality), randomizing patients to ICD or control. Study inclusion criteria for HF were left ventricular ejection fraction ≤ 35% and increased levels (>200 pg/mL) of N-terminal pro-brain natriuretic peptide. Of the 1116 patients from DANISH, 838 (75%) patients had available data from coronary angiogram and were included in this subgroup analysis. We used Cox regression to assess the relationship between coronary atherosclerosis and mortality and the effect of ICD implantation. Of the included patients, 266 (32%) had coronary atherosclerosis. Of these, 216 (81%) had atherosclerosis without significant stenoses, and 50 (19%) had significant stenosis. Patients with atherosclerosis were significantly older {67 [interquartile range (IQR) 61-73] vs. 61 [IQR 54-68] years; P < 0.0001}, and more were men (77% vs. 70%; P = 0.03). During a median follow-up of 64.3 months (IQR 47-82), 174 (21%) of the patients died. The effect of ICD on all-cause mortality was not modified by coronary atherosclerosis [hazard ratio (HR) 0.94; 0.58-1.52; P = 0.79 vs. HR 0.82; 0.56-1.20; P = 0.30], P for interaction = 0.67. In univariable analysis, coronary atherosclerosis was a significant predictor of all-cause mortality [HR, 1.41; 95% confidence interval (CI), 1.04-1.91; P = 0.03]. However, this association disappeared when adjusting for cardiovascular risk factors (age, gender, diabetes, hypertension, smoking, and estimated glomerular filtration rate) (HR 1.05, 0.76-1.45, P = 0.76)., Conclusions: In patients with non-ischaemic systolic heart failure, ICD implantation did not reduce all-cause mortality in patients either with or without concomitant coronary atherosclerosis. The concomitant presence of coronary atherosclerosis was associated with increased mortality. However, this association was explained by other risk factors., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Identification of patients with nonischemic cardiomyopathy who may benefit from prophylactic implantation of a cardioverter-defibrillator. We hypothesized that periodic repolarization dynamics (PRD), a marker of repolarization instability associated with sympathetic activity, could be used to identify patients who will benefit from prophylactic implantable cardioverter defibrillator (ICD) implantation., Methods: We performed a post hoc analysis of DANISH (Danish ICD Study in Patients With Dilated Cardiomyopathy), in which patients with nonischemic cardiomyopathy, left ventricular ejection fraction (LVEF) ≤35%, and elevated NT-proBNP (N-terminal probrain natriuretic peptides) were randomized to ICD implantation or control group. Patients were included in the PRD substudy if they had a 24-hour Holter monitor recording at baseline with technically acceptable ECG signals during the night hours (00:00-06:00). PRD was assessed using wavelet analysis according to previously validated methods. The primary end point was all-cause mortality. Cox regression models were adjusted for age, sex, NT-proBNP, estimated glomerular filtration rate, LVEF, atrial fibrillation, ventricular pacing, diabetes, cardiac resynchronization therapy, and mean heart rate. We proposed PRD ≥10 deg 2 as an exploratory cut-off value for ICD implantation., Results: A total of 748 of the 1116 patients in DANISH qualified for the PRD substudy. During a mean follow-up period of 5.1±2.0 years, 82 of 385 patients died in the ICD group and 85 of 363 patients died in the control group ( P =0.40). In Cox regression analysis, PRD was independently associated with mortality (hazard ratio [HR], 1.28 [95% CI, 1.09-1.50] per SD increase; P =0.003). PRD was significantly associated with mortality in the control group (HR, 1.51 [95% CI, 1.25-1.81]; P <0.001) but not in the ICD group (HR, 1.04 [95% CI, 0.83-1.54]; P =0.71). There was a significant interaction between PRD and the effect of ICD implantation on mortality ( P =0.008), with patients with higher PRD having greater benefit in terms of mortality reduction. ICD implantation was associated with an absolute mortality reduction of 17.5% in the 280 patients with PRD ≥10 deg 2 (HR, 0.54 [95% CI, 0.34-0.84]; P =0.006; number needed to treat=6), but not in the 468 patients with PRD <10 deg 2 (HR, 1.17 [95% CI, 0.77-1.78]; P =0.46; P for interaction=0.01)., Conclusions: Increased PRD identified patients with nonischemic cardiomyopathy in whom prophylactic ICD implantation led to significant mortality reduction.

Objectives: In this extended follow-up study of the DANISH (Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality) trial, adding 4 years of additional follow-up, we examined the effect of implantable cardioverter-defibrillator (ICD) implantation according to baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) level., Background: In the DANISH trial, NT-proBNP level at baseline appeared to modify the response to ICD implantation., Methods: In the DANISH trial, 1,116 patients with nonischemic systolic HF were randomized to receive an ICD (N = 556) or usual clinical care (N = 550). Outcomes were analyzed according to NT-proBNP levels (below/above median) at baseline. The primary outcome was death from any cause., Results: All 1,116 patients in the DANISH trial had an available NT-proBNP measurement at baseline (median: 1,177 pg/mL; range: 200-22,918 pg/mL). There was a trend toward a reduction in all-cause death with ICD implantation, compared with usual clinical care, in patients with NT-proBNP levels lower than the median (HR: 0.75 [95% CI: 0.55-1.03]), but not in those with higher NT-proBNP levels (HR: 0.95 [95% CI: 0.74-1.21]) (P interaction  = 0.28). Similarly, ICD implantation significantly reduced the rate of cardiovascular (CV) and sudden cardiovascular death (SCD) in patients with NT-proBNP levels lower than the median (CV death, HR: 0.69 [95% CI: 0.47-1.00]; SCD, HR: 0.37 [95% CI: 0.19-0.75]), but not in those with higher levels (CV death, HR: 0.94 [95% CI: 0.70-1.25]; SCD, HR: 0.86 [95% CI: 0.49-1.51]) (P interaction  = 0.20 and 0.08 for CV death and SCD, respectively)., Conclusions: Lower baseline NT-proBNP levels could identify patients with nonischemic systolic HF who may derive benefit from ICD implantation. (Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality [DANISH]; NCT00542945)., Competing Interests: Funding Support and Author Disclosures Dr Butt has received advisory board honoraria from Bayer, outside the submitted work. Dr Nielsen is supported by a grant from the Novo Nordisk Foundation (NNF16OC0018658) outside this work. Dr Bruun has received funding from the Novo Nordisk Foundation, the Augustinus Foundation, the Kaj Hansen Foundation, and from Health Insurance Denmark outside this work. Dr Brandes has received a research grant from Theravance and the Regions of Southern Denmark and Zealand; has received speaker honoraria from Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb; and has received a travel grant from Biotronik outside this work. Dr Gustafsson has received speaker honorarium from Orion, Novartis, and Vifor Pharma; and has received advisory board honorarium from Abott, Bayer, Alnylam, Ionis, Pfizer, Corvia, and Pharmacosmos. Dr Hassager has received speaker honorarium from Abiomed. Dr Svendsen has received speaker honorarium from Medtronic. Dr Pehrson has received lecture fees from Abbott, Bristol Myers Squibb, and AstraZeneca. Dr Køber has received speaker honorarium from Novartis, AstraZeneca, Boehringer, and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: DANISH (The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators [ICDs] in Patients With Nonischemic Systolic Heart Failure on Mortality) found that primary-prevention ICD implantation was not associated with an overall survival benefit in patients with nonischemic systolic heart failure during a median follow-up of 5.6 years, although there was a beneficial effect on all-cause mortality in patients ≤70 years. This study presents an additional 4 years of follow-up data from DANISH., Methods: In DANISH, 556 patients with nonischemic systolic heart failure were randomized to receive an ICD and 560 to receive usual clinical care and followed until June 30, 2016. In this long-term follow-up study, patients were followed until May 18, 2020. Analyses were conducted for the overall population and according to age (≤70 and >70 years)., Results: During a median follow-up of 9.5 years (25th-75th percentile, 7.9-10.9 years), 208/556 patients (37%) in the ICD group and 226/560 patients (40%) in the control group died. Compared with the control group, the ICD group did not have significantly lower all-cause mortality (hazard ratio [HR] 0.89, [95% CI, 0.74-1.08]; P = 0.24). In patients ≤70 years (n = 829), all-cause mortality was lower in the ICD group than the control group (117/389 [30%] versus 158/440 [36%]; HR, 0.78 [95% CI, 0.61-0.99]; P = 0.04), whereas in patients >70 years (n = 287), all-cause mortality was not significantly different between the ICD and control group (91/167 [54%] versus 68/120 [57%]; HR, 0.92 [95% CI, 0.67-1.28]; P = 0.75). Cardiovascular death showed similar trends (overall, 147/556 [26%] versus 164/560 [29%]; HR, 0.87 [95% CI, 0.70-1.09]; P = 0.20; ≤70 years, 87/389 [22%] versus 122/440 [28%]; HR, 0.75 [95% CI, 0.57-0.98]; P = 0.04; >70 years, 60/167 [36%] versus 42/120 [35%]; HR, 0.97 [95% CI, 0.65-1.45]; P = 0.91). The ICD group had a significantly lower incidence of sudden cardiovascular death in the overall population (35/556 [6%] versus 57/560 [10%]; HR, 0.60 [95% CI, 0.40-0.92]; P = 0.02) and in patients ≤70 years (19/389 [5%] versus 49/440 [11%]; HR, 0.42 [95% CI, 0.24-0.71]; P = 0.0008), but not in patients >70 years (16/167 [10%] versus 8/120 [7%]; HR, 1.34 [95% CI, 0.56-3.19]; P = 0.39)., Conclusions: During a median follow-up of 9.5 years, ICD implantation did not provide an overall survival benefit in patients with nonischemic systolic heart failure. In patients ≤70 years, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00542945.

This paper presents methods for continuous condition monitoring of railway switches and crossings (S&C, turnout) via sleeper-mounted accelerometers at the crossing transition. The methods are developed from concurrently measured sleeper accelerations and scanned crossing geometries from six in situ crossing panels. These measurements combined with a multi-body simulation (MBS) model with a structural track model and implemented scanned crossing geometries are used to derive the link between the crossing geometry condition and the resulting track excitation. From this analysis, a crossing condition indicator Cλ1-λ2,&nbsp;γ is proposed. The indicator is defined as the root mean square (RMS) of a track response signal γ that has been band-passed between frequencies corresponding to track deformation wavelength bounds of λ1 and λ2 for the vehicle passing speed ( f = v /&nbsp;λ). In this way, the indicator ignores the quasi-static track response with wavelengths predominantly above λ1 and targets the dynamic track response caused by the kinematic wheel-crossing interaction governed by the crossing geometry. For the studied crossing panels, the indicator C1-0.2&nbsp;m,&nbsp;γ (λ1=1 and λ2=0.2) was evaluated for γ = u , v , or a as in displacements, velocities, and accelerations, respectively. It is shown that this condition indicator has a strong correlation with vertical wheel-rail contact forces that is sustained for various track conditions. Further, model calibrations were performed to measured sleeper displacements for the six investigated crossing panels. The calibrated models show (1) a good agreement between measured and simulated sleeper displacements for the lower frequency quasi-static track response and (2) improved agreement for the dynamic track response at higher frequencies. The calibration also improved the agreement between measurements and simulation for the crossing condition indicator demonstrating the value of model calibration for condition monitoring purposes.

The current understanding of molecular mechanisms driving diabetic kidney disease (DKD) is limited, partly due to the complex structure of the kidney. To identify genes and signalling pathways involved in the progression of DKD, we compared kidney cortical versus glomerular transcriptome profiles in uninephrectomized (UNx) db/db mouse models of early-stage (UNx only) and advanced [UNxplus adeno-associated virus-mediated renin-1 overexpression (UNx-Renin)] DKD using RNAseq. Compared to normoglycemic db/m mice, db/db UNx and db/db UNx-Renin mice showed marked changes in their kidney cortical and glomerular gene expression profiles. UNx-Renin mice displayed more marked perturbations in gene components associated with the activation of the immune system and enhanced extracellular matrix remodelling, supporting histological hallmarks of progressive DKD in this model. Single-nucleus RNAseq enabled the linking of transcriptome profiles to specific kidney cell types. In conclusion, integration of RNAseq at the cortical, glomerular and single-nucleus level provides an enhanced resolution of molecular signalling pathways associated with disease progression in preclinical models of DKD, and may thus be advantageous for identifying novel therapeutic targets in DKD., Competing Interests: Competing interests F.E.S., H.M.Æ., J.C.N., T.S., M.V.Ø., K.T.G.R. and L.N.F. are employees of Gubra ApS. N.V. and J.J. are owners of Gubra ApS., (© 2021. Published by The Company of Biologists Ltd.)

Aims: Atrioventricular block (AVB) of unknown aetiology is rare in the young, and outcome in these patients is unknown. We aimed to assess long-term morbidity and mortality in young patients with AVB of unknown aetiology., Methods and Results: We identified all Danish patients younger than 50 years receiving a first pacemaker due to AVB between January 1996 and December 2015. By reviewing medical records, we included patients with AVB of unknown aetiology. A matched control cohort was established. Follow-up was performed using national registries. The primary outcome was a composite endpoint consisting of death, heart failure hospitalization, ventricular tachyarrhythmia, and cardiac arrest with successful resuscitation. We included 517 patients, and 5170 controls. Median age at first pacemaker implantation was 41.3 years [interquartile range (IQR) 32.7-46.2 years]. After a median follow-up of 9.8 years (IQR 5.7-14.5 years), the primary endpoint had occurred in 14.9% of patients and 3.2% of controls [hazard ratio (HR) 3.8; 95% confidence interval (CI) 2.9-5.1; P < 0.001]. Patients with persistent AVB at time of diagnosis had a higher risk of the primary endpoint (HR 10.6; 95% CI 5.7-20.0; P < 0.001), and risk was highest early in the follow-up period (HR 6.8; 95% CI 4.6-10.0; P < 0.001, during 0-5 years of follow-up)., Conclusion: Atrioventricular block of unknown aetiology presenting before the age of 50 years and treated with pacemaker implantation was associated with a three- to four-fold higher rate of the composite endpoint of death or hospitalization for heart failure, ventricular tachyarrhythmia, or cardiac arrest with successful resuscitation. Patients with persistent AVB were at higher risk. These findings warrant improved follow-up strategies for young patients with AVB of unknown aetiology., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Improved risk stratification to identify non-ischaemic heart failure patients who will benefit from primary prophylactic implantable cardioverter-defibrillator (ICD) is needed. We examined the potential of ventricular arrhythmia to identify patients who could benefit from an ICD., Methods and Results: A total of 850 non-ischaemic systolic heart failure patients with left ventricle ≤35% and elevated N-terminal pro-brain natriuretic peptides had a 24-h Holter monitor recording performed. We examined present non-sustained ventricular tachycardia (NSVT), defined as ≥3 consecutive premature ventricular contractions (PVCs) with a rate of ≥100/min, and number of PVCs per hour stratified into low (<30) and high burden (≥30) groups. Outcome measures were overall mortality, sudden cardiac death (SCD), and cardiovascular death (CVD). In total, 193 patients died, 49 from SCD and 125 from CVD. Non-sustained ventricular tachycardia (365 patients) was significantly associated with increased all-cause mortality [hazard ratio (HR) 1.47; 95% confidence interval (CI) 1.07-2.03; P = 0.02] and to CVD (HR 1.89; CI 1.25-2.87; P = 0.003). High burden PVC (352 patients) was associated with increased all-cause mortality (HR1.38; CI 1.00-1.90; P = 0.046) and with CVD (HR 1.78; CI 1.19-2.66; P = 0.005). There was no statistically significant association with SCD for neither NSVT nor PVC. In interaction analyses, neither NSVT (P = 0.56) nor high burden of PVC (P = 0.97) was associated with survival benefit from ICD implantation., Conclusion: Ventricular arrhythmia in non-ischaemic heart failure patients was associated with a worse prognosis but could not be used to stratify patients to ICD implantation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Atrial fibrillation (AF) in heart failure (HF) patients has been associated with a worse outcome. Similarly, excessive supraventricular ectopic activity (ESVEA) has been linked to development of AF, stroke, and death. This study aimed to investigate AF and ESVEA's association with outcomes and effect of prophylactic implantable cardioverter defibrillator (ICD) implantation in nonischemic HF patients., Methods: A total of 850 patients with nonischemic HF, left ventricle ejection fraction ≤35%, and elevated N-terminal pro-brain natriuretic peptides underwent 24 hours Holter recording. The presence of AF (≥30 seconds) and ESVEA (≥30 supraventricular ectopic complexes (SVEC) per hour or run of SVEC ≥20 beats) were registered. Outcomes were all-cause mortality, cardiovascular death (CVD), and sudden cardiac death (SCD)., Results: AF was identified in 188 patients (22%) and ESVEA in 84 patients (10%). After 4 years and 11 months of follow-up, a total of 193 patients (23%) had died. AF was associated with all-cause mortality (hazard ratio [HR] 1.44; confidence interval [CI] 1.04-1.99; P = .03) and CVD (HR 1.59; CI 1.07-2.36; P = .02). ESVEA was associated with all-cause mortality (HR 1.73; CI 1.16-2.57; P = .0073) and CVD (HR 1.76; CI 1.06-2.92; P = .03). Neither AF nor ESVEA was associated with SCD. ICD implantation was not associated with an improved prognosis for neither AF (P value for interaction = .17), nor ESVEA (P value for interaction = .68)., Conclusions: Both AF and ESVEA were associated with worsened prognosis in nonischemic HF. However, ICD implantation was not associated with an improved prognosis for either group., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Studies have shown an association between the outcome in cardiac resynchronization therapy (CRT) and longer interventricular delay at the site of the left ventricular (LV) lead. Targeted LV lead placement at the latest electrically activated segment increases LV function further as compared with standard treatment. We aimed to determine reproducibility and repeatability of identifying the latest electrically activated segment during mapping of all available coronary sinus (CS) branches in patients receiving CRT., Methods: We included 35 patients who underwent CRT implantation with protocolled mapping guided LV lead implantation aiming for the site of the latest electrical activation. Three different doctors experienced in electrophysiology and implantation of CRT devices independently measured time interval from the local bipolar right ventricular (RV) electrogram (EGM) to the local unipolar LV EGM at all mapped sites (RV-LV). The segment with the latest electrical activation was defined as the target segment (TS) and the CS tributary containing TS was defined as the target vein (TV). Weighted κ statistics with 95% confidence intervals were computed to assess intra- and interobserver agreement for TS and TV., Results: We mapped 258 segments within 131 veins. Weighted κ values for repeatability were 0.85 (0.81-0.89) for TS and 0.92 (0.89-0.93) for TV, and weighted κ values of interobserver agreement ranged from 0.70 (0.61-0.73) to 0.80 (0.76-0.83) for TS and 0.73 (0.64-0.78) to 0.86 (0.83-0.89) for TV among all three observers., Conclusion: The reproducibility and repeatability of identifying the latest electrically activated segment during mapping of all available CS branches in patients receiving CRT range from good to very good., (© 2020 Wiley Periodicals LLC.)

Objective: To examine the gradual association between self-reported health status and mortality in patients with heart failure (HF) as current research has focused on poor health status and increased risk of mortality., Method: This is a substudy of the DANISH (Defibrillator Implantation in Patients with Nonischemic Systolic HF) trial in which 1116 patients were randomized to receive or not receive an implantable cardioverter-defibrillator. Health status was assessed by a single question of the Short-Form 36. Patients were classified as having excellent/very good, good, fair (reference) or poor health status. We assessed the association between health status and mortality using multivariable Cox proportional hazard models., Results: Self-reported health status was completed by 943 (84%) patients at randomization with a median follow-up of 67 months and a health status distribution of; excellent/very good (n = 79, 8%), good (n = 369, 39%), fair (n = 409, 43%), and poor (n = 86, 9%). All-cause mortality (death events/ 100 person-years) occurred with gradual differences according to health status from excellent/ very good (2.14), good (3.74), fair (5.21) to poor health status (5.57). The gradual difference yielded a crude hazard ratio (HR) of 0.40, 95% CI 0.20-0.80 (adjusted HR 0.47 (95% CI 0.23-0.95) for excellent/ very good health status, HR 0.71, 95% CI 0.52-0.97 (adjusted HR 0.78 (95% CI 0.56-1.08) for good health status. Poor being worse than fair health status yielded a crude HR of 1.07, 95% CI 0.67-1.69., Conclusion: Excellent/very good self-reported health status as assessed by a single question was associated with lower long-term mortality in patients with HF., Competing Interests: Declaration of Competing Interest CTP reports study grants from Bayer and Novo Nordisk not related to this work. JJT reports speaker fees from Novartis and AstraZeneca not related to this work. JCN reports study grant from Novo Nordisk Foundation (NNF16OC0018658) not related to this work. All other authors declare none., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Study sex-differences in efficacy and safety of atrial fibrillation (AF) ablation., Methods and Results: We assessed first AF ablation outcomes on continuous anticoagulation in 633 patients [209 (33%) women and 424 (67%) men] in a pre-specified subgroup analysis of the AXAFA-AFNET 5 trial. We compared the primary outcome (death, stroke or transient ischaemic attack, or major bleeding) and secondary outcomes [change in quality of life (QoL) and cognitive function] 3 months after ablation. Women were older (66 vs. 63 years, P < 0.001), more often symptomatic, had lower QoL and a longer history of AF. No sex differences in ablation procedure were found. Women stayed in hospital longer than men (2.1 ± 2.3 vs. 1.6 ± 1.3 days, P = 0.004). The primary outcome occurred in 19 (9.1%) women and 26 (6.1%) men, P = 0.19. Women experienced more bleeding events requiring medical attention (5.7% vs. 2.1%, P = 0.03), while rates of tamponade (1.0% vs. 1.2%) or intracranial haemorrhage (0.5% vs. 0%) did not differ. Improvement in QoL after ablation was similar between the sexes [12-item Short Form Health Survey (SF-12) physical 5.1% and 5.9%, P = 0.26; and SF-12 mental 3.7% and 1.6%, P = 0.17]. At baseline, mild cognitive impairment according to the Montreal Cognitive Assessment (MoCA) was present in 65 (32%) women and 123 (30%) men and declined to 23% for both sexes at end of follow-up., Conclusion: Women and men experience similar improvement in QoL and MoCA score after AF ablation on continuous anticoagulation. Longer hospital stay, a trend towards more nuisance bleeds, and a lower overall QoL in women were the main differences observed., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objectives: To examine the association between health-related quality of life (HRQoL) and mortality in patients with heart failure (HF)., Background: The potential association of HRQoL and mortality in patients with HF is unclear. We investigated this association in The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators (ICD) in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH)., Methods: In DANISH, a total of 1116 patients with non-ischemic systolic HF on guideline-recommended therapy were randomized to ICD therapy or usual clinical care. HRQoL was assessed at randomization using the disease-specific Minnesota Living with Heart Failure Questionnaire (MLHFQ, 0-105, high score indicating worse HRQoL). Multivariable Cox proportional hazard models were used to compare hazard ratios (HR) for all-cause mortality according to MLHFQ above or below 45, as recommended by a recent meta-analysis, to identify patients with poor HRQoL., Results: HRQoL was completed by 935 (84%) patients at baseline with a median follow-up of 67 months (IQR 47-83). Patients with poor HRQoL (MLHFQ score > 45, median 60 (IQR 53-71),n = 350) had a higher incidence of all-cause mortality than patients with moderate/good HRQoL (MLHFQ ≤45, median 23 (IQR 13-33), n = 585), respectively 26% vs. 18% with an unadjusted HR of 1.57 (95% CI 1.19-2.08, p = .002), and an adjusted HR of 1.39 (95% CI 1.01-1.91, p = .04)., Conclusion: Poor HRQoL was associated with an increased risk of all-cause mortality after adjustment for traditional risk factors., Clinical Trial Registration: https: //clinicaltrials.gov/ct2/show/NCT00542945(DANISH)., Competing Interests: Declaration of competing interest Dr. Køber reports receiving lecture fees from Novartis. Dr. Thune reports receiving lecture fees from Novartis. Dr. Nielsen reports receiving support from the Novo Nordisk Foundation (NNF16OC0018658 and NNF17OC0029148)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Contact force (CF) between radiofrequency (RF) ablation catheter and myocardium and ablation index (AI) correlates with RF lesion depth and width in normal-voltage (>1.5 mV) myocardium (NVM). We investigate the impact of CF on RF lesion depth and width in low (<0.5 mV) (LVM) and intermediate-voltage (0.5-1.5 mV) myocardium (IVM) following myocardial infarction. Correlation between RF lesion depth and width evaluated by native contrast magnetic resonance imaging (ncMRI) and gross anatomical evaluation was investigated., Methods and Results: Twelve weeks after myocardial infarction, 10 pigs underwent electroanatomical mapping and endocardial RF ablations were deployed in NVM, IVM, and LVM myocardium. In vivo ncMRI was performed before the heart was excised and subjected to gross anatomical evaluation. Ninety (82%) RF lesions were evaluated. Radiofrequency lesion depth and width were smaller in IVM and LVM compared with NVM (P < 0.001). Radiofrequency lesion depth and width correlated with CF, AI, and impedance drop in NVM (CF and AI P < 0.001) and IVM (CF and AI depths P < 0.001; CF and AI widths P < 0.05). Native contrast magnetic resonance imaging evaluated RF lesion depth and width correlated with gross anatomical depth and width (NVM and IVM P < 0.001; LVM P < 0.05)., Conclusions: Radiofrequency lesions deployed by similar duration, power and CF are smaller in IVM and LVM than in NVM. Radiofrequency lesion depth and width correlated with CF, AI, and impedance drop in NVM and IVM but not in LVM. Native contrast magnetic resonance imaging may be useful to assess RF lesion depth and width in NVM, IVM, and LVM., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Diabetic nephropathy (DN) is associated with albuminuria and loss of kidney function and is the leading cause of end-stage renal disease. Despite evidence of sex-associated differences in the progression of DN in human patients, male mice are predominantly being used in preclinical DN research and drug development. Here, we compared renal changes in male and female uninephrectomized (UNx) db/db C57BLKS mice using immunohistochemistry and RNA sequencing. Male and female UNx db/db mice showed similar progression of type 2 diabetes, as assessed by obesity, hyperglycemia, and HbA1c. Progression of DN was also similar between sexes as assessed by kidney and glomerular hypertrophy as well as urine albumin-to-creatinine ratio being increased in UNx db/db compared with control mice. In contrast, kidney collagen III and glomerular collagen IV were increased only in female UNx db/db as compared with respective control mice but showed a similar tendency in male UNx db/db mice. Comparison of renal cortex transcriptomes by RNA sequencing revealed 66 genes differentially expressed (p < .01) in male versus female UNx db/db mice, of which 9 genes were located on the sex chromosomes. In conclusion, male and female UNx db/db mice developed similar hallmarks of DN pathology, suggesting no or weak sex differences in the functional and structural changes during DN progression., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Aims: To describe aetiologies and temporal trends in young patients with atrioventricular block (AVB)., Methods and Results: We identified all patients in Denmark, receiving their first pacemaker because of AVB before the age of 50 years between 1996 and 2015. Medical records were reviewed and clinical information and diagnostic work-up results were obtained to evaluate the aetiology. We used Poisson regression testing for temporal trends. One thousand and twenty-seven patients were identified, median age at time of implantation was 38 (interquartile range 25-45) years, 584 (56.9%) were male. The aetiologies were complications to cardiac surgery [n = 157 (15.3%)], congenital AVB [n = 93 (9.0%)], cardioinhibitory reflex [n = 52 (5.0%)], congenital heart disease [n = 43 (4.2%)], complication to radiofrequency ablation [n = 35 (3.4%)], cardiomyopathy [n = 31 (3.0%)], endocarditis [n = 18 (1.7%)], muscular dystrophy [n = 14 (1.4%)], ischaemic heart disease [n = 14 (1.4%)], sarcoidosis [n = 11 (1.1%)], borreliosis [n = 9 (0.9%)], hereditary [n = 6 (0.6%)], side-effect to antiarrhythmics [n = 6 (0.6%)], planned His-ablation [n = 5 (0.5%)], complication to alcohol septal ablation [n = 5 (0.5%)], and other known aetiologies [n = 11 (1.1%)]. The aetiology remained unknown in 517 (50.3%) cases. While the number of patients with unknown aetiology increased during the study period (P < 0.001), we observed no significant change in the number of patients with identified aetiology (P = 0.35)., Conclusion: In a nationwide cohort, the aetiology of AVB was identified in only half the patients younger than 50 years referred for first-time pacemaker implantation. The number of patients with unknown aetiology increased during the study period. These findings indicate need for better insight into aetiologies of AVB and improved diagnostic work-up guidelines., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: The "distressed" (Type D) personality trait has been reported to be over-represented in patients with heart failure (HF) compared to the background population and may provide prognostic information for mortality. We examined the association between Type D personality and outcomes in the DANISH trial (The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality)., Methods: The DANISH trial included a total of 1116 patients with non-ischemic HF on guideline-recommended therapy. Type D personality was assessed with the Type D Scale (DS14) at baseline and investigated through follow-up accordingly. Multivariable Cox proportional hazard models were used to compare hazard ratios (HR) of cardiovascular and all-cause mortality., Results: Type D personality assessment was completed by 873 (78%) patients at baseline and Type D personality was found in 120 (14%) patients. The median follow-up was 67 months (interquartile range [IQR] 48-83). Among patients with versus without Type D personality, 22% versus 19% died from all-cause yielding similar incidence rates of 4.62 (95% CI 3.14-6.87) versus 3.95 (95% CI 3.37-4.66) per 100 person-years. The adjusted risk of all-cause mortality was not significantly different in patients with versus without Type D personality with an adjusted HR of 1.31 (95% CI 0.84-2.03, p = 0.23) with similar results for cardiovascular death (HR 1.46 (95% CI 0.88-2.44, p = 0.15)., Conclusion: Type D personality was not significantly associated with increased risk of all-cause mortality or cardiovascular death in patients with non-ischemic HF.

Objectives: This study sought to evaluate the value of combined electrogram (EGM) information provided by simultaneous mapping using micro- and conventional electrodes in the identification of post-myocardial infarction ventricular tachycardia substrate., Background: Ventricular tachycardias after myocardial infarction are related to scars with complex geometry. Scar delineation and ventricular tachycardia substrate identification relies on bipolar voltages (BV) and EGM characteristics. Early reperfusion therapy results in small, nontransmural scars, the details of which may not be delineated using 3.5 mm tip catheters., Methods: Nine swine with early reperfusion myocardial infarction were mapped using Biosense Webster's QDOT Micro catheter, incorporating 3 microelectrodes at the tip of the standard 3.5 mm electrode. Analysis of EGM during sinus rhythm, right ventricular pacing, and short-coupled right ventricular extrastimuli was performed. The swine were sacrificed and mapping data were projected onto the heart. Transmural biopsies (n = 196) corresponding to mapping points were obtained, allowing a head-to-head comparison of EGM recorded by micro- and conventional electrodes with histology., Results: To identify scar areas using standard electrodes, unique cutoff values of unipolar voltage <5.44 mV, BV <1.27 mV (conventional), and BV <2.84 mV (microelectrode) were identified. Combining the information provided by unipolar voltage and BV mapping, the sensitivity of scar identification was increased to 93%. Micro-EGM were better able to distinguish small near-fields corresponding to a layer of viable subendocardium than conventional EGM were., Conclusions: The combined information provided by multisize electrode mapping increases the sensitivity with which areas of scar are identified. EGM from microelectrodes, with narrower spacing, allow identification of near-fields arising from thin subendocardial layer and layers activated with short delay obscured in EGM from conventional mapping catheter., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with nonischemic systolic heart failure (HF) have increased risk of sudden cardiac death (SCD) and death from progressive pump failure. Whether the risk of SCD changes over time is unknown. We seek here to investigate the relation between duration of HF, mode of death, and effect of implantable cardioverter-defibrillator implantation., Methods and Results: We examined the risk of all-cause death and SCD according to the duration of HF among patients with nonischemic systolic HF enrolled in the DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality). In all, 1116 patients were included. Patients were divided according to quartiles of HF duration (≤8, 9≤18, 19≤65, and ≥66 months). Patients with the longest duration of HF were older, more often men, had more comorbidity, and more often received a cardiac resynchronization therapy device. Doubling of HF duration was an independent predictor of both all-cause mortality (hazard ratio [HR], 1.27; 95% CI, 1.17-1.38; P<0.0001), and SCD (HR, 1.29; 95% CI, 1.11-1.50; P=0.0007). The proportion of deaths caused by SCD was not different between HF quartiles (P=0.91), and the effect of implantable cardioverter-defibrillator implantation on all-cause mortality was not modified by the duration of HF (P=0.59)., Conclusions: Duration of HF predicted both all-cause mortality and risk of SCD independently of other risk indicators. However, the proportion of death caused by SCD did not change with longer duration of HF, and the effect of implantable cardioverter-defibrillator was not modified by the duration of HF., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00542945.

It is important to consider calcium and parathyroid hormone levels in patients with recurrent VT/VF without any obvious cause of arrhythmia. In similar cases to gain rhythm control using isoprenaline and do comprehensive molecular-genetic. Diagnosis and surgery in case of parathyroid adenoma may be needed to obtain definite arrhythmia control., Competing Interests: None declared., (© 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Aims: Implantable cardioverter-defibrillator (ICD) implantation reduce the risk of sudden cardiac death, but not all-cause death in patients with non-ischaemic systolic heart failure (HF). Whether co-existence of diabetes affects ICD treatment effects is unclear., Methods and Results: We examined the effect of ICD implantation on risk of all-cause death, cardiovascular death, and sudden cardiac death (SCD) according to diabetes status at baseline in the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischaemic Systolic Heart Failure on Mortality (DANISH) trial. Outcomes were analysed by use of cumulative incidence curves and Cox regressions models. Of the 1116 patients enrolled, 211 (19%) had diabetes at baseline. Patients with diabetes were more obese, had worse kidney function and more were in New York Heart Association Class III/IV. The risk of device infections and other complications in the ICD group was similar among patients with and without diabetes (6.1% vs. 4.6% P = 0.54). Irrespective of treatment group, diabetes was associated with higher risk of all-cause death, cardiovascular death, and SCD. The treatment effect of ICD in patients with diabetes vs. patients without diabetes was hazard ratio (HR) = 0.92 (0.57-1.50) vs. HR = 0.85 (0.63-1.13); Pinteraction = 0.60 for all-cause mortality, HR = 0.99 (0.58-1.70) vs. HR = 0.70 (0.48-1.01); Pinteraction = 0.25 for cardiovascular death, and HR = 0.81 (0.35-1.88) vs. HR = 0.40 (0.22-0.76); Pinteraction = 0.16 for sudden cardiac death., Conclusion: Among patients with non-ischaemic systolic HF, diabetes was associated with higher incidence of all-cause mortality, primarily driven by cardiovascular mortality including SCD. Treatment effect of ICD therapy was not significantly modified by diabetes which might be due to lack of power., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study aims to identify patients with nonischemic heart failure who are more likely to benefit from implantable cardioverter-defibrillator (ICD) implantation by use of established risk prediction models., Background: It has been debated whether an ICD for primary prevention reduces mortality in patients with nonischemic heart failure., Methods: The Seattle Heart Failure Model (SHFM) predicts all-cause mortality whereas the Seattle Proportional Risk Model (SPRM) predicts the proportion of sudden cardiac death (SCD) versus nonsudden death, with a higher score indicating a greater proportion of SCD. We report the effect of ICD implantation on all-cause mortality and SCD, according to median SPRM and SHFM scores in all 1,116 patients enrolled in the DANISH (Danish study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on mortality) trial., Results: Among patients with an SPRM score above the median (n = 558), ICD implantation reduced all-cause mortality (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.43 to 0.94), whereas patients with lower SPRM scores (n = 558) had no effect (HR: 1.08; 95% CI: 0.78 to 1.49, p for interaction = 0.04). The corresponding numbers for SHFM score above and below the median were HR: 0.84; 95% CI: 0.62 to 1.13 and HR: 0.82; 95% CI: 0.53 to 1.28, respectively (p for interaction = 0.980). In 177 patients with upper SPRM/upper SHFM, ICD implantation reduced all-cause mortality (HR: 0.45; 95% CI: 0.25 to 0.80) when compared to 381 patients with lower SPRM/upper SHFM (HR: 1.09; 95% CI: 0.76 to 1.55) (p for interaction <0.001)., Conclusions: Nonischemic heart failure patients with high predicted relative likelihood of SCD, as estimated by higher SPRM score, seemed to benefit from ICD implantation. (DANISH [Danish ICD Study in Patients With Ditaled Cardiomyopathy]; NCT00542945)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aim: The Danish Study to Assess the Efficacy of Implantable Cardioverter-Defibrillators (ICD) in Patients with Non-ischaemic Systolic Heart Failure (HF) on Mortality (DANISH) found no overall effect on all-cause mortality. The effect of ICD implantation on health-related quality of life (HRQoL) remains to be established as previous trials have demonstrated conflicting results. We investigated the impact of ICD implantation on HRQoL in patients with non-ischaemic systolic HF, a prespecified secondary endpoint in DANISH., Methods and Results: In DANISH, a total of 1116 patients with non-ischaemic systolic HF were randomly assigned (1:1) to ICD implantation or usual clinical care (control). Patients completed disease-specific HRQoL as assessed by Minnesota Living with Heart Failure Questionnaire (MLHFQ; 0-105, high indicating worse). Changes in HRQoL 8 months after randomization were assessed with a mixed-effects model. At randomization, MLHFQ was completed by 935 (84%) patients (n = 472 in the ICD group and n = 463 in the control group) and was reassessed in 274 (58%) and 292 (63%) patients, respectively after 8 months for the primary analysis. Patients in the ICD group vs. the control group had similar improvements in MLHFQ after 8 months [least square mean -7.0 vs. -4.2 (P = 0.13)]. A clinically relevant improvement (decrease ≥5) in the MLHFQ overall score at 8 months was observed in 151 patients in the ICD group and 148 patients in the control group [55% vs. 51%, respectively (P = 0.25)]., Conclusion: Implantable cardioverter-defibrillator implantation in patients with non-ischaemic systolic HF did not significantly alter HRQoL compared with patients randomized to usual clinical care., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Only few studies in selected cohorts have examined whether the CHA 2 DS 2 -VASc score can predict the risk of atrial fibrillation and thromboembolic events in patients without atrial fibrillation., Materials and Methods: Patients with coronary angiography performed between 2004 and 2012 were grouped according to CHA 2 DS 2 -VASc score. We excluded patients with atrial fibrillation, anticoagulant therapy and follow-up <30 days. The endpoints were atrial fibrillation and a composite of ischaemic stroke, transient ischaemic attack and systemic embolism. Event rates per 100 person-years were estimated for each CHA 2 DS 2 -VASc score (0, 1, 2, 3, 4, and >4). Incidence rate ratios were calculated using low-risk patients (CHA 2 DS 2 -VASc score 0 in males or 1 in females) as reference., Results: In total, 78 233 patients were included with group sizes varying between 8299 (CHA 2 DS 2 -VASc >4) and 19 882 (CHA 2 DS 2 -VASc 2). An increasing CHA 2 DS 2 -VASc score was significantly associated with a future diagnosis of atrial fibrillation (P for trend <0.0001) and an incremental risk of ischaemic stroke, transient ischaemic attack, systemic embolism (P for trend <0.0001) and all-cause death (P for trend <0.0001). Patients with a CHA 2 DS 2 -VASc score of 3 had a rate of ischaemic stroke/transient ischaemic attack/systemic embolism of 1.30 per 100 person-years., Conclusions: Among patients undergoing coronary angiography, the CHA 2 DS 2 -VASc score predicted a future diagnosis of atrial fibrillation and the composite risk of ischaemic stroke, transient ischaemic attack or systemic embolism in patients without atrial fibrillation. A CHA 2 DS 2 -VASc score of 3 was associated with a risk that would justify prophylactic oral anticoagulation treatment in a patient with atrial fibrillation., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Objectives: Before cardiac resynchronization therapy (CRT) implantation, cardiac computed tomography (CT) can provide assessment of cardiac venous anatomy and visualize left ventricular (LV) myocardial scar. We hypothesized that localization and burden of transmural myocardial scar verified by cardiac CT are associated with echocardiographic and clinical response to CRT., Methods: We prospectively included 140 CRT recipients undergoing preimplant cardiac CT. We assessed transmural scar, defined as hypoperfusion involving more than one-half of the myocardial wall in each LV segment using a 17-segment model. Echocardiographic nonresponse was defined as less than 5% absolute improvement in LV ejection fraction at 6 months' follow-up. Clinical nonresponse was defined as 1 or more of the following at 6 months' follow-up: death, heart failure hospitalization, or no improvement in New York Heart Association class and less than 10% increase in 6-minute walk-test distance., Results: Higher burden of myocardial scar was associated with echocardiographic nonresponse (adjusted odds ratio, 3.02; 95% confidence interval, 1.03-8.91; P = 0.045). Scar concordant or adjacent to LV pacing site was associated with echocardiographic nonresponse (adjusted odds ratio, 8.2; 95% confidence interval, 1.51-44.27; P = 0.015). No association between scar and clinical nonresponse was demonstrated., Conclusions: Higher scar burden and scar in proximity to the LV pacing site assessed by cardiac CT are associated with echocardiographic nonresponse to CRT. Burden and location of scar were not associated with clinical nonresponse. Further large-scale studies are needed to assess the potential association between myocardial scar detected by cardiac CT and clinical CRT outcome.

Aims: Patients with cancer are insufficiently represented in randomized clinical trials investigating efficacy of implantable cardioverter-defibrillators (ICDs). We aimed to describe outcomes in patients with a pre-existing diagnosis of cancer at time of ICD implantation., Methods and Results: We utilized Danish nationwide registries to identify primary and secondary prevention ICD implantations from 2007 to 2012. Multivariable Cox models were used to assess the risk of appropriate ICD therapy and mortality in patients with and without cancer at time of implantation. During a median follow-up of 2.1 years, 2935 primary prevention ICD and 2730 secondary prevention ICD implantations were identified. Out of these [289 (5.1%)] had pre-existing cancer [primary 140 (4.8%), secondary 149 (5.5%)]. No differential risk for appropriate ICD therapy was found between patients with or without cancer, [primary cancer: 19/140, no cancer: 380/2795, hazard ratio (HR) = 1.07 (0.67-1.69)] and [secondary cancer: 42/149, no cancer: 699/2581, HR = 1.28 (0.93-1.75)]. In primary patients, cancer was not associated with higher risk of 1-year [cancer: 10/140, no cancer: 133/2795, HR = 1.20 (0.84-2.28)] or all-time mortality [cancer: 22/140, no cancer: 339/2795, HR = 1.13 (0.74-1.75)]. In secondary patients, cancer was associated with a higher 1-year [cancer: 19/149, no cancer: 108/2581, HR = 2.62 (1.60-4.29)] and all-time mortality [cancer: 44/149, no cancer: 315/2581, HR = 2.36 (1.71-3.24)]., Conclusion: Implantable cardioverter-defibrillators were implanted in a minority of cancer patients. No difference in risk of appropriate therapy was observed between cancer and non-cancer patients, regardless of implant indication. Cancer was associated with increased mortality in secondary prevention ICD patients, but not in primary prevention ICD patients. In secondary prevention ICD patients, the majority of deaths were attributable to cancer., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Background:  Patients with atrial fibrillation (AF) have an increased risk of ischaemic stroke. The risk can be predicted by the CHA 2 DS 2 -VASc score, in which the vascular component refers to previous myocardial infarction, peripheral artery disease and aortic plaque, whereas coronary artery disease (CAD) is not included., Objectives:  This article explores whether CAD per se or extent provides independent prognostic information of future stroke among patients with AF., Materials and Methods:  Consecutive patients with AF and coronary angiography performed between 2004 and 2012 were included. The endpoint was a composite of ischaemic stroke, transient ischaemic attack and systemic embolism. The risk of ischaemic events was estimated according to the presence and extent of CAD. Incidence rate ratios (IRR) were calculated in reference to patients without CAD and adjusted for parameters included in the CHA 2 DS 2 -VASc score and treatment with anti-platelet agents and/or oral anticoagulants., Results:  Of 96,430 patients undergoing coronary angiography, 12,690 had AF. Among patients with AF, 7,533 (59.4%) had CAD. Mean follow-up was 3 years. While presence of CAD was an independent risk factor for the composite endpoint (adjusted IRR, 1.25; 1.06-1.47), extent of CAD defined as 1-, 2-, 3- or diffuse vessel disease did not add additional independent risk information., Conclusion:  Presence, but not extent, of CAD was an independent risk factor of the composite thromboembolic endpoint beyond the components already included in the CHA 2 DS 2 -VASc score. Consequently, we suggest that significant angiographically proven CAD should be included in the vascular disease criterion in the CHA 2 DS 2 -VASc score., Competing Interests: K.K.W.O. has received speaking honoraria from Bayer A/S. J.C.N. is supported by the Novo Nordisk Foundation (NNF16OC0018658). S.D.K. has received lecture fees from Aspen, AstraZeneca, Bayer, BMS/Pfizer and Boehringer-Ingelheim. G.Y.H.L. is a consultant for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer-Ingelheim, Novartis, Verseon and Daiichi-Sankyo, and speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer-Ingelheim and Daiichi-Sankyo; but no fees are directly received personally. M.M. has received lecture fees and consulting honoraria from Novo Nordisk, Bayer, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, and institutional research grants from Volcano (now Philips), Boston Scientific and Biosensors., (Georg Thieme Verlag KG Stuttgart · New York.)

Aims: To quantify appropriate and inappropriate therapy and complications related to implantable cardioverter-defibrillator (ICD) treatment in young patients receiving an ICD for a hereditary cardiomyopathy or channelopathy., Methods and Results: This was a retrospective study including 117 consecutive patients who had received an ICD at Aarhus University Hospital, Denmark from 1 January 1999 to 31 December 2015. Patients were followed from the date of ICD implantation until migration, death, heart transplantation, or end of follow-up on 1 February 2017. Mean age at implantation was 30.5 ± 12.8 years, and the patients were followed for a mean period of 7.1 ± 4.4 years. The cumulative incidence at 1, 5, and 10 years was 17%, 29%, and 48% for appropriate ICD therapy, 6%, 13%, and 20% for inappropriate ICD therapy, and 7%, 18%, and 33% for device-related complications, respectively. Patients with an ICD implanted for secondary prevention had a higher risk of appropriate therapy compared with patients implanted for primary prevention [adjusted hazard ratio (HR) 5.18, 95% confidence interval (CI) 2.22-12.09; P < 0.01]. There was no difference in the risk of inappropriate therapy (adjusted HR 1.58, 95% CI 0.55-4.56; P = 0.40) or device-related complications (adjusted HR 1.22, 95% CI 0.56-2.68; P = 0.62) between patients with primary and secondary preventive indication., Conclusion: We observed high absolute risk estimates for appropriate ICD therapy in young patients with an ICD indicated by a hereditary cardiomyopathy or channelopathy. Also risks for inappropriate ICD therapy and device-related complications were significant.