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.
Background and Aims A simple diagnostic method able to reliably exclude left main (LM) coronary artery disease (CAD) or LMCAD-equivalent would expand implementation of an initial non-invasive strategy in patients with chronic coronary syndrome (CCS). This study assessed the diagnostic utility of an approach using clinical and ECG stress testing (EST) variables in excluding LMCAD/LMCAD-equivalent in CCS patients.Methods In a multicentre case-control study, CCS patients undergoing invasive coronary angiography (CAG) after a maximal EST were evaluated. Cases were patients with angiographic >= 50% LM stenosis or >= 70% stenosis of both proximal left anterior descending and proximal circumflex arteries, matched with similar patients without them (controls) in a 1:3 ratio. A risk model developed through logistic regression was internally and externally validated.Results Three hundred and thirty-five cases were matched with 797 controls. The model area under the curve (AUC) was .78. Assuming LMCAD prevalence of 5% and a misclassification cost ratio of 1:100 (ratio of cost of performing CAG in a control to cost of not performing CAG in a case), negative predictive value was 98.2%. Thus, CAG could be safely avoided in 41% of patients, missing one LMCAD/LMCAD-equivalent diagnosis for every 58 CAGs safely spared in patients without them.Conclusions Among CCS patients, LMCAD/LMCAD-equivalent can be excluded with high negative predictive value through a model based on clinical and EST parameters, allowing initial non-invasive management of most patients able to exercise. This approach is potentially useful particularly in communities where access to computed tomography coronary angiography is limited.
