Daily Cardiology Research Analysis

IMPORTANCE: The primary analysis of the SELECT randomized clinical trial suggests that semaglutide reduced the rates of cardiovascular (CV) death, myocardial infarction, and stroke in patients with established CV disease (CVD) and overweight or obesity without diabetes. However, the effect of semaglutide on hospitalizations in this population remains unknown. OBJECTIVE: To determine the impact of semaglutide on total hospital admissions and duration of hospital stay. DESIGN, SETTING, AND PARTICIPANTS: The SELECT trial included patients aged 45 years or older with established CVD and a body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 27 or higher without diabetes at 804 clinical settings across North America, South America, Europe, Asia, Africa, and Australia. Patients were randomized from October 2018 to March 2021. This prespecified exploratory analysis was conducted from February 2024 to September 2025. INTERVENTIONS: Once-weekly subcutaneous semaglutide, 2.4 mg, or placebo. MAIN OUTCOMES AND MEASURES: The total number of hospital admissions and days in hospital between the semaglutide and placebo groups. RESULTS: A total of 17 604 patients (median [IQR] age, 61.0 [55.0-68.0] years; 4872 female patients [27.7%]; median [IQR] BMI, 32.1 [29.7-35.7]) were followed up for a median (IQR) period of 41.8 (33.0-47.0) months. There were 11 287 hospital admissions. The number of total hospitalizations was lower in the semaglutide group vs placebo for any indication (18.3 vs 20.4 admissions per 100 patient-years; mean ratio [MR], 0.90; 95% CI, 0.85-0.95; P < .001) and for serious adverse events (15.2 vs 17.1 admissions per 100 patient-years; MR, 0.89; 95% CI, 0.84-0.94; P < .001). The number of days hospitalized for any indication per 100 patient-years was lower in the semaglutide group vs placebo (157.2 vs 176.2 days; rate ratio [RR], 0.89; 95% CI, 0.82-0.98; P = .01), as well as hospitalizations for serious adverse events (137.6 vs 153.9 days; RR, 0.89; 95% CI, 0.81-0.98; P = .02). No heterogeneity was observed for the reduction of hospital admissions with semaglutide in selected subgroups, including BMI, age, and sex. CONCLUSIONS AND RELEVANCE: In this prespecified exploratory analysis of the SELECT randomized clinical trial, the trial cohort had a high rate of hospital admissions. Treatment with once-weekly semaglutide was associated with significant reductions in hospital admissions and overall time spent in hospital, extending its benefits beyond CV risk reduction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03574597.

BACKGROUND AND AIMS: Patients with acute coronary syndromes (ACS) are at high ischaemic risk to which cholesterol, inflammation, and yet-to-be-identified pathways jointly contribute. The junctional protein associated with coronary artery disease (JCAD) drives incident cardiovascular events by acting on coagulation and fibrinolysis. This study aimed to assess whether JCAD serves as a novel marker of or target to address residual risk. METHODS: In the discovery cohort (SPUM-ACS; n = 4787), ACS patients at residual lipid risk [RLR; on-statin LDL cholesterol (LDL-c) ≥70 mg/dL or ≥1.8 mmol/L], residual inflammatory risk [RIR; on-statin high-sensitivity C-reactive protein (hs-CRP) ≥2.0 mg/L], or both (RILR; on-statin LDL-c ≥70 mg/dL and hs-CRP ≥2.0 mg/L) were identified and compared with propensity-score matched controls. Contributions of hs-CRP, LDL-c and JCAD to recurrent major adverse cardiovascular events (MACE) were analysed. In an independent cohort (RISK-PPCI study; n = 496), effects of JCAD on endogenous coagulation and fibrinolysis were gauged, and JCAD-MACE associations were externally validated. RESULTS: At 1 year, patients at RLR, RIR, or RILR were at higher MACE risk as compared to controls [hazard ratio (HR), 1.55, 95% confidence interval (CI) 1.08-2.23; HR 1.80, 95% CI 1.24-2.61; and HR 1.75, 95% CI 1.12-2.75, respectively]. In those at RLR, MACE risk rose with increasing hs-CRP and JCAD, respectively, in uni- (HR per log2 increase, 1.17, 95% CI 1.06-1.30; HR 1.29, 95% CI 1.03-1.62) and multivariable-adjusted models [adjusted (a)HR 1.16, 95% CI 1.03-1.30; aHR 1.27, 95% CI 1.01-1.60]. In those at RIR, MACE risk increased 1.28-fold per log2 increase in JCAD (HR 1.28, 95% CI 1.03-1.59), which prevailed in multivariable-adjusted models (aHR 1.31, 95% CI 1.04-1.65). Similarly, in patients at RILR, MACE risk increased almost linearly with increasing JCAD (HR 1.45, 95% CI 1.09-1.92), independently of potential confounders (aHR 1.47, 95% CI 1.11-1.97). Plasma levels of JCAD correlated positively with proxies of impaired endogenous fibrinolysis, with the JCAD-MACE association being similarly observed in the external validation cohort. CONCLUSIONS: Acute coronary syndrome patients at RLR, RIR, or both are at high ischaemic risk. By modulating coagulation and endogenous fibrinolysis, JCAD represents a promising candidate to address the high residual risk that persists in ACS patients receiving guideline-recommended care. CLINICALTRIALS.GOV IDENTIFIERS: NCT01000701, NCT02562690.

IMPORTANCE: Polygenic background modifies variant penetrance in hypertrophic (HCM) and dilated (DCM) cardiomyopathies, diseases with opposing morphologic characteristics and inversely related genetic pathways. Whether polygenic susceptibility for one disease protects against monogenic risk for the other remains uncertain. OBJECTIVE: To characterize if polygenic background bidirectionally modifies pathogenicity of established rare variants associated with HCM and DCM. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was conducted using data from the Penn Medicine BioBank (PMBB). Volunteers enrolled in PMBB between November 1994 and July 2022 with available electronic health record and genotyping data through September 2024 were included. Analysis was performed in June 2025. EXPOSURES: Normalized polygenic scores (PGSs) for HCM and DCM as well as carrier status of pathogenic variants in established HCM or DCM genes. MAIN OUTCOMES AND MEASURES: HCM and DCM defined using electronic health record diagnosis and procedure codes, as well as echocardiogram measurements obtained from medical records. RESULTS: This study included 49 434 PMBB participants (median (IQR) age, 57 [42-67] years; 24 886 male [50.3%]). An increased HCM PGS was associated with a 1.1% increase in left ventricular ejection fraction (LVEF; 95% CI, 0.9 to 1.3; P = 7.3 × 10-31), a 0.79-mm decrease in left ventricular internal diameter at end-diastole (LVIDd; 95% CI, -0.92 to -0.67; P = 2.3 × 10-36), and a 0.18-mm increase in interventricular septal (IVS) thickness (95% CI, 0.14 to 0.22; P = 9.3 × 10-19). A 1-SD increase in DCM PGS was associated with a 2.0% decrease in LVEF (95% CI, -2.2 to -1.8; P = 3.3 × 10-83) and a 1.0-mm increase in LVIDd (95% CI, 0.93 to 1.1; P = 3.2 × 10-78) and was not significantly associated with IVS (estimate, -1.3 × 10⁻3 mm; 95% CI, -0.04 to 0.03; P = .94). A 1-SD increase in HCM PGS was associated with an increased risk of HCM (odds ratio [OR], 1.8; 95% CI, 1.6-2.0; P = 9.6 × 10-25) and decreased risk of DCM (OR, 0.69; 95% CI, 0.64-0.74; P = 4.3 × 10-22). A 1-SD increase in DCM PGS was associated with an increased risk of DCM (OR, 1.6; 95% CI, 1.5-1.7; P = 1.7 × 10-40) and decreased risk of HCM (OR, 0.69; 95% CI, 0.63-0.76; P = 3.0 × 10-13). Monogenic and polygenic risk terms had significant independent effects when combined in models of disease status and echocardiographic measurements; the inclusion of either an HCM or DCM PGS improved the discrimination (area under the receiving operating characteristic curve) of models of HCM (0.043; 95% credible interval, 0.034-0.053) and DCM (0.045; 95% credible interval, 0.039-0.051) beyond models including age, sex, and monogenic variant status. CONCLUSIONS AND RELEVANCE: The findings in this study indicate that HCM and DCM risk were modified by polygenic background, which exists on an overlapping but opposing spectrum. Consideration of polygenic background may offer clinical value through improving understanding and prediction of these inherited cardiomyopathies.