Abstract Aims Ventricular arrhythmia (VA) and heart failure (HF) frequently coexist in patients with ischaemic left ventricular (LV) dysfunction. Whether VA and HF events are bidirectionally associated remains unclear. We investigated their bidirectional relationship and associations with mortality. Methods We analysed 1014 patients from the multicentre WICD-MI study. All received a wearable cardioverter-defibrillator after acute myocardial infarction (MI) and subsequently underwent implantable cardioverter-defibrillator (ICD) implantation, with persistent LV ejection fraction ≤35%. Associations between ICD-treated VA, HF-events (HF hospitalization, heart transplantation, or LV assist device implantation), and all-cause mortality were assessed using time-dependent Cox models. Results Over a median follow-up of 2.6 years post-ICD implantation, VA was independently associated with an increased risk of HF events [aHR = 3.50 (1.66–7.38), P = .001], while HF events similarly preceded subsequent VA [aHR = 2.96 (1.59–5.50), P = .0008]. Both were independently associated with all-cause mortality, with a numerically higher aHR for HF events [aHR = 7.96 (4.71–13.47), P < .0001] than for VA [aHR = 4.43 (2.35–8.36), P < .0001]. Sensitivity analyses suggested that the VA–HF association was strongest for shock-treated arrhythmias. In exploratory analyses, VA was strongly associated with subsequent HF events in subcutaneous ICD recipients [aHR = 15.08 (4.62–49.22), P < .0001] but not in transvenous ICD recipients (P for interaction = .0002). Conclusion In ICD recipients with persistent LV dysfunction following MI, VA and HF events are bidirectionally associated and independently associated with mortality. The VA–HF association was strongest for shock-treated arrhythmias. These findings highlight the potential value of integrated HF and VA management.
Abstract Aims To define the impact of diastolic dysfunction (DD) on the response to empagliflozin treatment in patients with heart failure with preserved ejection fraction. Methods and Results Diastolic dysfunction was defined by left atrial volume index ≥34 ml/m2, the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular tissue velocity (E/e) ≥ 13 or left ventricular mass index >115 (males) or >95 (females). We created three categories of increasing DD (0, 1, or ≥2 DD criteria at baseline) to describe the effect of DD on response to empagliflozin therapy and adverse effects. Of 5988 patients in the EMPEROR-Preserved trial, 3766 (63%) had no documented baseline DD, 1619 (27%) had one, and 603 (10%) had two or more measures. Baseline DD was associated with sex, race, ethnicity, and region and was more common with lower heart rate, DBP, body weight, and eGFR. Despite baseline DD not being significantly associated with the primary endpoint of hospitalization for heart failure or cardiovascular death within the placebo group, a progressive treatment effect across the three DD categories was seen (trend test P-value .0014), with estimated hazard ratios of empagliflozin vs placebo of 0.91 (none present), 0.64 (1 present), and 0.49 (≥2). A significant treatment-by-subgroup trend test was also observed for the total number of hospitalizations for heart failure. Both Kansas City Cardiomyopathy Questionnaire Clinical Summary Score improvement at week 52 and safety profile were consistent across DD categories. Conclusion Baseline detection of echocardiographic DD predicted improved clinical response to empagliflozin in a graded fashion, but the reasons cannot be reliably determined from this analysis.
Background and Aims In SELECT, subcutaneous semaglutide (target dose 2.4 mg) weekly in adults with pre-existing cardiovascular disease and body mass index >= 27 kg/m(2) without diabetes significantly reduced major adverse cardiovascular events (MACE) by 20% vs placebo. This analysis explored potential mediators of this cardiovascular benefit. Methods Changes from randomization to 24 months in body weight, waist circumference, plasma high-sensitivity C-reactive protein (hsCRP), glycated haemoglobin (HbA(1c)), lipids, blood pressure, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio were examined individually, and in combination, as potential mediators of MACE risk reduction, using the Vansteelandt repeated regression method (a counterfactual approach). Results Semaglutide significantly (P < .05) improved all potential mediators investigated. Point estimates for % mediation were largest for waist circumference (64.0% [95% confidence interval (CI) 27.5, 179.6]), hsCRP (42.1% [17.9, 110.5]), HbA(1c) (29.0% [-20.7, 120.5]), and body weight (19.5% [-33.0, 110.7]), examined separately, but all had wide CIs. Supplementary analyses suggested unreliability of estimates for body weight and waist circumference, potentially due to differing relationship of body weight and waist change to MACE between treatment arms. Multivariable analysis estimated joint mediation for all potential mediators combined to be 31.4% (95% CI -30.1, 143.6). When variables other than body weight and waist circumference were considered, % mediation was 46.0% (95% CI -6.0, 161.0). Conclusions Mediation analyses could not fully ascribe the effects of semaglutide on MACE to known risk factors in SELECT with any certainty. Further investigation of potential additional biomarkers and mediators of semaglutide's cardiovascular protective effect are of interest. [GRAPHICS] .
Background and Aims A major component of long QT syndrome (LQTS) is LQT2 due to pathogenic variants in KCNH2, which frequently cause trafficking defects. Despite progress in therapeutic management, there is an unmet clinical need for mechanism-targeted therapies. It has been previously shown, using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), that lumacaftor (LUM), currently used for cystic fibrosis, can partially correct hERG trafficking. A single-arm phase 2 study was conducted to determine whether LUM could shorten QTc in LQT2 patients with trafficking defects. Methods Sixteen adult patients with genetically confirmed trafficking-defective KCNH2 variants were enrolled. Participants were admitted to hospital and received LUM for 7 days under continuous telemetry. QTc was quantified on serial electrocardiograms and 12-lead Holter recordings. For mechanistic correlation, hiPSC-CMs were generated from the first five participants with distinct genetic variants and assessed for hERG maturation and trafficking. Results Overall, lumacaftor produced a significant QTc shortening (P < .001). The per-patient change averaged 31 +/- 21 ms. Patients with baseline QTc >= 500 ms exhibited the most substantial effect, with 75% achieving reductions >= 40 ms. No ventricular arrhythmias occurred, and adverse effects were primarily gastrointestinal and self-limited. In hiPSC-CMs, LUM restored hERG trafficking in three out of five variants, mirroring the clinical observations. Conclusions Short-term LUM therapy is safe and yields a significant QTc shortening in LQT2 patients with a trafficking defect. Concordance between cellular and clinical findings reinforces the value of a mechanism-based, variant-informed approach and supports the feasibility of trafficking-correction strategies within a precision-medicine framework for inherited arrhythmia syndromes.
Aims Recent clinical trials have underscored the importance of early initiation of heart failure (HF) guideline-directed medical therapy (GDMT), with growing emphasis on rapid sequencing, particularly after hospitalization for acute HF (AHF). Despite the proven short-term benefit of this approach, few patients receive this therapy at discharge. In patients with AHF, we evaluated whether treatment at discharge with dual sodium-glucose co-transporter-2 inhibitors (SGLT2i)-mineralocorticoid receptor antagonist (MRA) therapy or four-class GDMT was associated with short-term mortality and incremental risk reduction.Methods We analysed two prospective registries of AHF: the China HF-CAP (n = 441 320; main cohort) and the Swedish HF Registry (SwedeHF) (n = 2367; external validation cohort). We assessed the association between discharge prescription of dual therapy SGLT2i and MRA versus neither, and four-class GDMT vs none, with 90-day cardiovascular (CV) and all-cause mortalities, further stratified by baseline serum potassium levels and left ventricular ejection fraction (LVEF) categories.Results In the main cohort, for dual SGLT2i and MRA therapy (n = 71 154) vs neither (n = 81 793) therapy, adjusted odds of 90-day CV and all-cause death were 0.320 [0.283-0.361] and 0.504 [0.472-0.539], respectively. In the external validation cohort, results were directionally consistent. Association between dual SGLT2i and MRA therapy and short-term survival was consistent irrespective of hyperkalaemia and across HF phenotypes. Further, in the main cohort, adjusted odds of 90-day CV death of four-class GDMT (n = 36 301) were 0.122 (0.106-0.14) vs no therapy (n = 18 374).Conclusion After AHF, early initiation of dual SGLT2i and MRA therapy was associated with lower short-term mortality, irrespective of LVEF or potassium levels. Four-class GDMT conferred the lowest risk, emphasizing the importance of timely implementation after AHF.
