An intramural course in an anomalous aortic origin of a coronary artery (AAOCA) is a high-risk feature for sudden cardiac death (SCD). One of the proposed mechanisms for this association involves a “flap valve” effect in the intramural segment. The (patho-)histological characteristics of this segment may contribute to risk stratification, however, current data are scarce. The aim of this study was to identify the histological features of the intramural segment and their potential relevance to vascular wall properties and the aortic valve commissure, thereby providing insights into possible functional implications of AAOCA. This prospective multicenter study included consecutive pediatric and adult AAOCA patients who underwent surgical unroofing between 2021 and 2024. The excised arterial vascular wall tissue (i.e. the intramural segment), was immunohistochemically examined for vascular wall components. Two independent observers reviewed the data, correlating findings with preoperative CTA to assess spatial relationships with surrounding aortic and AAOCA tissues. Results were also compared with a post-mortem AAOCA specimen and control tissues. Fifteen patients (mean age 42.9 ± 14.0 years, age range 11–66 years, 60

Cardiomyopathies are important causes of arrhythmias, sudden cardiac death, and heart failure. With accumulating knowledge in clinical, genetic, and molecular phenotyping, the number of distinct disease entities is growing. There is a need for broad, inclusive, high-quality prospective multi-center registries to better analyze these phenotypes, provide accurate risk stratification, and tailor therapies. The Dutch Cardiomyopathy Registry (DCR) will serve as a longitudinal registry for all cardiomyopathy patients, exploiting previously built local databases, allowing adequately powered research studies. The DCR is a multi-center observational registry that unites all Dutch University Medical centers. The registry will have local and central shared databases, which will be hosted and coordinated by the Netherlands Heart Institute. Patients with an established cardiomyopathy diagnosis and carriers of pathogenic or likely-pathogenic cardiomyopathy gene variants will be included. Furthermore, selected family members and individuals who are referred for screening for potential cardiomyopathy are eligible for inclusion. The subjects will receive, per best clinical practice, guideline-recommended diagnostics and treatment. Clinical data will be collected from clinical care at baseline and follow-up, including clinical visits, imaging studies, laboratory assessments, ECG, and additional functional tests. Outcome data consists of clinical performance status, cardiovascular complications and major adverse events, recorded through regular electronic health record files. The DCR will function as a national database, providing relevant information on epidemiology, demographics, natural history, diagnosis, and treatment. This will aid risk prediction and monitoring of new therapies. The DCR can identify patients who are eligible for future studies, including registry-based research.

Importance:Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibition is recommended as second- or third-line lipid-lowering therapy after myocardial infarction (MI), resulting in prolonged periods of inadequate low-density lipoprotein cholesterol (LDL-C) control. Whether in-catheterization laboratory decision of PCSK9 inhibition, started before mechanical reperfusion, could improve LDL-C control and clinical outcomes at 1 year is unknown. Objective:To evaluate evolocumab as first-line therapy vs standard care in patients with high-risk acute MI undergoing percutaneous coronary intervention (PCI). Design, Setting, and Participants:This international, phase 4, prospective randomized, open, blinded end-point adjudication study was conducted at 48 sites in 6 countries. Adults with high-risk ST-elevation MI (STEMI; aged >55 years) or non-ST-elevation MI (NSTEMI) with 1 or more additional high-risk characteristics were enrolled beginning September 29, 2021, through May 22, 2025, with final follow-up on May 22, 2026. Interventions:Patients were randomized 1:1 to receive evolocumab 140 mg subcutaneously every 2 weeks for 1 year (first injection before PCI) in addition to standard care (n = 1087) or standard care alone (n = 1074). Standard care included high-intensity oral lipid-lowering therapy with the optional PCSK9 inhibitor use per guideline indication in the control group. Main Outcomes and Measures:The primary outcome was LDL-C less than 55 mg/dL and at least 50% reduction in LDL-C from baseline at 12 months. The main clinical end point was all-cause death or unplanned cardiovascular hospitalization at 12 months. Results:Among 2161 randomized patients (mean age, 67 years; 1703 males [79%]; 1261 [58%] with STEMI; 900 [42%] with NSTEMI), the primary outcome was achieved in 792 of 970 patients (82%) with evolocumab vs 370 of 934 (40%) with standard care (adjusted odds ratio, 5.54 [95% CI, 4.50-6.82]; P < .001). At 6 weeks, median LDL-C was 16 mg/dL with evolocumab vs 56 mg/dL with standard care. The main clinical end point occurred in 159 of 1087 patients (14.6%) with evolocumab vs 165 of 1074 (15.4%) with standard care (adjusted odds ratio, 0.94 [95% CI, 0.73-1.19]; P = .59). Conclusions and Relevance:In patients with acute MI undergoing PCI, first-line evolocumab combined with high-intensity lipid-lowering therapy produced rapid and sustained LDL-C reduction, with more than 80% of patients reaching the guideline-recommended target at 1 year. However, no clinical benefit was detected during the first year of follow-up, arguing against clinically meaningful acute pleiotropic effects of PCSK9 inhibitors in addition to standard care. Trial Registration:ClinicalTrials.gov Identifier: NCT04951856.

BACKGROUND:Studies comparing treatment strategies based on initiation timing-such as starting PCSK9 inhibitor (PCSK9i) therapy sooner versus later after a myocardial infarction (MI)-are prone to immortal time bias. Clone-censor-weight methods can address these issues and allow the researcher to emulate a trial in which patients are assigned to protocols dictating when PCSK9i is initiated. This study aimed to evaluate the comparability of patients in a clone-censor-weight setup who initiated a PCSK9i within 12 months post-MI versus non-initiators. METHODS:We included adult patients hospitalized for MI in Sweden (2015-2021) and followed them for 3 years. We considered two treatment strategies: initiating PCSK9i within 12 months versus not initiating PCSK9i during the same period. We applied the clone-censor-weight method to address immortal time bias and assessed remaining bias using covariate balance metrics and negative control outcomes. RESULTS:The primary study sample included 38  627 episodes of MI, with 561 (1.5%) initiating PCSK9i treatment within 12 months. These patients were younger, had higher baseline LDL-C levels, and were more frequently treated with ezetimibe during their post-MI follow-up compared to non-initiators. Although clone-censor-weight estimation was free of immortal time bias, it faced challenges in achieving adequate balance of covariates due to the high rates of censoring (relatively small number of people initiating a PCSK9i in the first year) and strong association between covariates and censoring. Truncation of weights provided more stable estimates but at the expense of some covariate imbalances. CONCLUSIONS:The clone-censor-weight method is a promising approach that allows researchers to answer questions about the effect of treatment policies. But practical guidance is needed to address problems that arise from small, highly imbalanced groups, which is common with most newly introduced treatments.

Background:Semaglutide, a glucagon-like peptide-1 receptor agonist, effectively promotes weight loss and improves metabolic parameters in individuals with obesity. However, its use is often accompanied by reductions in lean mass, raising concerns about long-term muscle health. This study explored whether combining semaglutide with exercise could preserve muscle mass and enhance metabolic outcomes. Methods:Ldlr-/-.Leiden mice with diet-induced obesity, insulin resistance, metabolic dysfunction-associated steatohepatitis and atherosclerosis were either left untreated (control) or treated with semaglutide, exercise or the combination for 14 weeks. Histological and transcriptomic analyses were conducted on adipose tissue, muscle, liver and heart to explore underlying mechanisms. Results:Semaglutide significantly reduced fat mass (-31%) but also lean mass (-11%). Combining semaglutide with exercise further reduced fat mass (-45%) and lean mass as well but to a lesser extent (-8%). Semaglutide alone or with exercise improved insulin sensitivity and plasma lipids. The combination improved adipose tissue inflammation, liver steatosis, liver inflammation and atherosclerotic lesion area. Only combination treatment significantly improved grip strength and diameter of gastrocnemius myofibers. Multi-organ histological and transcriptomic analyses revealed organ-specific and synergistic effects of combination therapy, including activation of pathways involved in mitochondrial function, glucose metabolism, and inflammation resolution. Conclusion:Semaglutide improves metabolic, liver, vascular and adipose parameters but reduces lean mass and muscle strength. Combining semaglutide intervention with exercise enhances these benefits with partial preservation of muscle mass and function and activation of distinct molecular pathways not engaged by either monotreatment, thereby underscoring the potential of integrating lifestyle interventions with pharmacological treatment.

Genetic predisposition and alcohol consumption are risk factors for increased blood pressure (BP), but their interactions influencing BP remain understudied. We conducted population-specific and cross-population meta-analyses of genome-wide gene-alcohol (GxAlc) interactions affecting BP in >1.1M individuals from multiple populations. We identified 46 GxAlc interaction loci for BP, including 21 from one-degree-of-freedom interaction tests (PGxAlc<5×10-8; or <0.05/Meff, Meff independent BP associations at P<10-5), and 25 from two-degree-of-freedom tests of main and interaction effects (PGxAlc<0.05/M2df, M2df independent 2df-associations at P2df<5×10-8), including 7 novel and 39 known BP loci. The 12q24 locus highlights the genetic effect of BRAP-rs11066001 on BP, being ~6 times larger in current drinkers than in non-drinkers. Gene prioritization with 46 GxAlc loci identified 15 genes with ≥3 lines of evidence (location, literature, druggability, functional/regulatory annotation, or pathway analyses). Several loci showed sex- and population-specific effects and revealed biological pathways of alcohol's influence on BP, suggesting mechanisms underlying alcohol-induced hypertension.

Cardiac resynchronization therapy (CRT) is well-established in acquired heart failure, but evidence in adults with congenital heart disease (ACHD) remains limited. Current guidelines, extrapolated from non-congenital populations, may not fully address the anatomical and electrophysiological complexities in ACHD. This study aimed to evaluate the safety and efficacy of CRT in ACHD, focusing on changes in QRS duration, systemic ventricular function (SVF), and New York Heart Association (NYHA) class. A retrospective multicenter cohort study was conducted across two tertiary ACHD centers. ACHD patients who underwent CRT implantation between 2014 and 2024 were included. Primary outcomes were QRS duration, SVF, and NYHA class at 3, 6, and 12 months post-implantation, and peri-procedural clinical and device-related outcomes were assessed. Mixed models were used to analyze longitudinal changes, adjusting for de novo vs. upgrade CRT implantation, left bundle branch block (LBBB) vs. non-LBBB QRS morphology, and systemic left vs. right ventricle (sRV) anatomy. 101 patients were included. The mean age was 53 ± 14 year, 41 (40.6

AIMS:The etiology of coronary artery Disease (CAD) appears different for men and women, yet insights into underlying sex-specific biological mechanisms are limited. We integrated genomic and proteomic analyses to investigate sex-specific associations of the plasma-proteome with CAD. METHODS AND RESULTS:In 40,829 UK Biobank participants (free-of-CAD, baseline-365 days thereafter; 55% women; mean age 56.9 ± 8.1 years), we examined associations between 2,922 plasma proteins and incident CAD over a median follow-up of 13.7 years (IQR 13.1-14.4) using multivariable-adjusted Cox proportional hazards models. Sex-specific analyses identified 440 female exclusive and 32 male exclusive proteins associated with incident CAD (FDR-corrected p < 0.05), revealing distinct pathway enrichments, including innate immune response in women and angiogenesis in men. Causality was assessed through combined and sex-stratified two-sample Mendelian randomization (MR) using inverse-variance-weighted analyses with genome wide association summary statistics from 422,108 men (61,969 cases) and 521,695 women (27,128 cases) (UK Biobank, FinnGen freeze 9). Integration of direct sex-protein interaction analyses with sex-combined MR identified 59 proteins with evidence for sex-specific causal effects. Four proteins demonstrated concordant directionality in sex-stratified MR analyses (n = 943,803) and multivariable regression models, namely CDKN2D, MYH9, and SKAP2 (women), and CTSH (men). To assess translational relevance, prioritized targets were further evaluated in secondary major adverse cardiovascular events among carotid endarterectomy patients (MACE; Athero-Express) and acute myocardial infarction (AMI; MISSION!) using plasma proteomics and ELISA. After further top-target identification in the context of MACE and AMI, clinical drug candidates were identified through a machine learning framework, including CTSH (men), and TNFRSF4 (both sexes). CONCLUSIONS:We identified sex-specific associations of proteins and biological pathways with incident CAD. Whereas the majority of proteins had consistent associations in both men and women, our findings suggest a degree of sex-specific pathogenesis with evidence for potential causality, opening new alleys for tailored prevention strategies and clinical cardiovascular risk management.

BACKGROUND AND AIMS:Lipoprotein(a) (Lp(a)) is considered a causal risk factor for atherogenesis. A higher prevalence of certain adverse events, including diabetes mellitus (DM), has been reported for patients with low Lp(a) concentrations. Therapeutics that lower Lp(a) are now in clinical testing. Thus, the association between lower Lp(a) concentration and safety outcomes is of clinical importance. METHODS:The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized 27 564 patients with stable atherosclerotic cardiovascular disease (ASCVD) to evolocumab versus placebo on a background of statin therapy. The relationship between Lp(a) and the risk of prevalent and incident adverse outcomes of interest was examined, adjusting for relevant predictors. RESULTS:Lp(a) was assessed in 25 090 participants at baseline (median 37 nmol/L, interquartile range 13-165). There was no association between Lp(a) concentration and incident risk of haemorrhagic stroke, serious bleeding, neurocognitive events, malignancy, or atrial fibrillation, including those with Lp(a) levels ≤13 nmol/L. There was an inverse association between lower baseline Lp(a) levels and prevalent DM at baseline (adjusted odds ratio 1.03, 95% confidence interval [CI] 1.02-1.04, P < .001; for every 50 nmol/L lower Lp(a)), as well as the incident risk of developing DM during follow-up (adjusted hazard ratio [HR] 1.05, 95% CI 1.02-1.08, P = .002; for every 50 nmol/L lower Lp(a)), with consistent results by treatment arm. Evolocumab did not increase the risk of DM irrespective of baseline Lp(a), even in participants in the top decile of baseline Lp(a) (adjusted HR .72, 95% CI .38-1.35) in whom evolocumab reduced Lp(a) by a median of 71 nmol/L. CONCLUSIONS:In patients with ASCVD, low Lp(a) concentration was not associated with an increased risk of most adverse safety outcomes, but lower Lp(a) was associated with an increased risk of prevalent and incident DM.

Treatment of sarcoma includes high-dose anthracyclines, which can cause cardiotoxicity. This study assesses the correlation of cardiac biomarkers and echocardiographic parameters on asymptomatic cardiotoxicity in sarcoma patients treated with anthracyclines. Consecutive patients diagnosed with sarcoma and treated with anthracyclines were included in this retrospective cohort study using registry data. Echocardiography was performed before start of anthracycline chemotherapy (baseline), after completing treatment (short-term follow-up), and 6-12 months after termination of treatment (long-term follow-up). The primary endpoint was the occurrence of asymptomatic cardiotoxicity at short-term follow-up. We included 44 patients (29.6% female) with a median age of 28.9 [22.2-38.7] years. Baseline left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) decreased significantly from 58.4% ± 5.0% to 54.2% ± 9.3% (p = 0.013) and -19.1% ± 2.2% to -17.2% ± 3.5% at short-term follow-up (p = 0.002), respectively. After Cycle 1, 86.5% of the patients showed NT-proBNP ≥ 125 ng/L compared to 3.9% at baseline (p < 0.001), and after completion of therapy, 65.5% had elevated cardiac Troponin T (cTnT) ≥ 14 ng/L compared to 11.5% at baseline (p = 0.003). Asymptomatic cardiotoxicity was observed in 30 patients (68.2%). Mean follow-up was 2.4 [1.5-2.9] years. cTnT ≥ 14 ng/L after Cycle 4 was associated with cardiotoxicity (HR: 3.75 [1.28-11.0], p = 0.016), and NT-proBNP per 100 units increase after Cycle 1 was associated with an increased risk of mortality (HR: 1.36 [1.004-1.85], p = 0.047). Sarcoma patients treated with high-dose anthracyclines are at increased risk of developing cardiac dysfunction as assessed by LVEF and GLS. cTnT and NT-proBNP levels increase significantly during treatment and can be valuable markers to improve the risk stratification of patients treated with high-dose anthracyclines.