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Aims: We analysed baseline characteristics and guideline-directed medical therapy (GDMT) use and decisions in the European Society of Cardiology (ESC) Heart Failure (HF) III Registry., Methods and Results: Between 1 November 2018 and 31 December 2020, 10 162 patients with acute HF (AHF, 39%, age 70 [62-79], 36% women) or outpatient visit for HF (61%, age 66 [58-75], 33% women), with HF with reduced (HFrEF, 57%), mildly reduced (HFmrEF, 17%) or preserved (HFpEF, 26%) ejection fraction were enrolled from 220 centres in 41 European or ESC-affiliated countries. With AHF, 97% were hospitalized, 2.2% received intravenous treatment in the emergency department, and 0.9% received intravenous treatment in an outpatient clinic. AHF was seen by most by a general cardiologist (51%) and outpatient HF most by a HF specialist (48%). A majority had been hospitalized for HF before, but 26% of AHF and 6.1% of outpatient HF had de novo HF. Baseline use, initiation and discontinuation of GDMT varied according to AHF versus outpatient HF, de novo versus pre-existing HF, and by ejection fraction. After the AHF event or outpatient HF visit, use of any renin-angiotensin system inhibitor, angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist and loop diuretics was 89%, 29%, 92%, 78%, and 85% in HFrEF; 89%, 9.7%, 90%, 64%, and 81% in HFmrEF; and 77%, 3.1%, 80%, 48%, and 80% in HFpEF., Conclusion: Use and initiation of GDMT was high in cardiology centres in Europe, compared to previous reports from cohorts and registries including more primary care and general medicine and regions more local or outside of Europe and ESC-affiliated countries., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Restoration of sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA2a) activity through gene transfer improved cardiac function in experimental and pilot studies in humans with heart failure. The AGENT-HF (NCT01966887) trial investigated the impact of adeno-associated virus (AAV1)/SERCA2a on ventricular remodelling using multimodality non-invasive cardiac imaging., Methods and Results: AGENT-HF was a single centre, randomized, double-blind, placebo-controlled trial in adult patients with NYHA class III-IV ischaemic or non-ischaemic heart failure and left ventricular ejection fraction ≤35%. Eligible patients were randomized to receive a single intracoronary infusion of either 1 × 10 13 DNase-resistant particles of AAV1/SERCA2a or placebo. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by cardiac computed tomography at 6 month follow-up. We planned to include 40 patients but the trial was terminated prematurely as the sponsor suspended further enrolment following neutral results of the CUPID-2 outcome trial. At the time of termination, nine patients were randomized with five patients infused with AAV1/SERCA2a and four with placebo. At 6 months, LVESV was increased in both groups compared with baseline: median (interquartile range) in AAV1/SERCA2a vs. placebo: 13 (13;14) mL vs. 3.5 (-36;36) mL, P = 0.74, with a mean difference between groups of 11.4 mL in favour of placebo. No safety issues were noted., Conclusion: AGENT-HF failed to demonstrate any improvement in ventricular remodelling in response to AAV1/SERCA2a at the dose studied. However, because of premature termination, the study was underpowered to demonstrate an effect of AAV1/SERCA2a and these data should be interpreted with caution., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Aims: The transcription factor Islet-1 (ISL1) is a marker of cardiovascular progenitors and is essential for mammalian cardiogenesis. An ISL1 haplotype has recently been associated with congenital heart disease. In this study we evaluated whether ISL1 variants are associated with hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), or with Emery-Dreifuss muscular dystrophy (EDMD)., Methods and Results: The six exon and intron boundaries of ISL1 were screened for genetic variants in a cohort of 454 index cases. Eleven exonic variants were identified in HCM, DCM, ARVC, and/or EDMD. Out of the five novel variants, two are located in the 5'-untranslated region, two are silent (p.Arg171Arg and p.Asn189Asn), and one is a missense (p.Asn252Ser). The latter was identified in the homozygous state in one DCM patient, and in the heterozygous state in 11 relatives, who did not present with DCM but often with cardiovascular features. This variant was found in one HCM patient also carrying a MYH7 mutation and in 3/96 North-African Caucasian control individuals, but was absent in 138 European Caucasian control individuals. We investigated the effect of the ISL1 wild type and p.Asn252Ser mutant on myocyte enhancer factor 2C (Mef2c) promoter activity, an established ISL1 target. Mef2c promoter activity was ∼4-fold higher in the presence of wild-type and ∼6-fold higher in the presence of mutant ISL1 in both HEK and CHO cells., Conclusion: This study describes a new gain-of-function p.Asn252Ser variant in the human ISL1 gene, which could potentially lead to greater activation of downstream targets involved in cardiac development, dilation, and hypertrophy.