Journal of the American College of Cardiology

Background: Thoracic aortic aneurysms enlarge silently and can cause fatal aortic dissection without timely surgical repair, underscoring the need for improved approaches to identify individuals at high risk. Rare pathogenic variants in established heritable thoracic aortic disease (HTAD) genes explain only a subset of familial and fewer nonfamilial thoracic aortic disease (TAD) cases. Methods: We performed phenotype-stratified, genome-wide, gene-based rare-variant burden analyses of ultrarare damaging missense and predicted loss-of-function variants. Primary analyses focused on aortic dissection, thoracic aortic aneurysm requiring surgical repair, and their combined phenotype. Broader thoracic aortic aneurysm (TAA) was evaluated as a secondary phenotype. Discovery analyses were conducted in the UK Biobank and All of Us, followed by independent replication in the Penn Medicine BioBank, Mass General Brigham Biobank, and Million Veteran Program. Discovery and replication results were subsequently combined in an overall fixed-effect, inverse-variance-weighted meta-analysis across up to five biobanks. Implicated genes were further evaluated in additional clinically ascertained TAD cohorts and using single-cell transcriptomic data from human thoracic aortic tissue. Results: Discovery analyses identified 80 genes reaching study-wide significance across the prespecified TAD phenotypes. These included six established and two putative HTAD genes. Fourteen genes demonstrated independent replication support and reached study-wide significance in the overall meta-analysis across up to five biobanks, which included more than 10,000 cases and 880,000 controls. The eight novel candidate genes among these were FNDC3B, ROCK1, URM1, SLFN11, ENPP1, CLEC16A, CREM, and VCAN. Associations were strongest for dissection and TAA requiring surgical repair. Four novel associations were driven exclusively by missense variants. FNDC3B was observed in a family with HTAD, while additional variants were identified primarily in sporadic dissection or aortic surgery cohorts, suggesting that other genetic or physiologic factors may influence penetrance. The implicated genes showed cell-type-specific expression patterns in human thoracic aortic tissue. Conclusions: These findings expand the genetic architecture of TAD by identifying eight novel candidate genes and demonstrate the utility of phenotype-stratified rare variant burden analyses across large biobanks for gene discovery.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a pan-ethnic disease, at least as common in Black as in White Americans, yet Black patients reach specialist care later, undergo septal reduction less often, and die sooner. Whether the defining trials enrolled representatively is unknown. We sought to measure Black participation in the landmark HCM trials against three expectations of increasing stringency, and to test whether trial site geography or quantitative eligibility thresholds account for the shortfall. METHODS: Of 197 registered interventional HCM trials, 32 met prespecified landmark tiers; demographics were extracted for 16 and 13 reported race. The Black share of Black plus White participants was pooled by random-effects meta-analysis and compared with the US adult population, with each trial?s own site counties, and with a disease-referenced echocardiographic expectation. Site geography and eligibility thresholds were tested using site addresses, census data, and NHANES. RESULTS: Across 13 trials, 70 of 1,780 Black or White participants were Black. The pooled Black share was 3.98% (95% CI 2.68-5.86), against a population expectation of 16.5%, giving a participation-to-prevalence ratio (PPR) of 0.24 (95% CI 0.16-0.36), the lowest of any racial and/or ethnic minority group. The clinical trial site network reached 63.7% of Black and 47.5% of White US adults, with geospatial analysis predicting 26.4% Black enrollment; however, every trial fell below this expectation. Quantitative eligibility thresholds closed only 2.0% of the enrollment gap. CONCLUSIONS: Black participation was about one quarter of the population expectation. Neither site geography nor eligibility thresholds explain it.

Importance Evolocumab reduces major adverse cardiovascular events (MACE) in patients with clinically evident atherosclerotic cardiovascular disease (ASCVD) and in patients at high cardiovascular (CV) risk but without a prior myocardial infarction (MI) or stroke. While evolocumab is shown to be cost-effective in clinically evident ASCVD, emerging CV outcomes evidence and newer guideline recommendations warrant assessment in patients at high CV risk without a prior MI or stroke. Objective To evaluate the cost-effectiveness of evolocumab added to standard therapy compared with standard therapy alone in patients at high CV risk without a prior MI or stroke, as represented by the VESALIUS-CV trial. Design, Setting, and Participants A previously published Markov cohort state-transition model was adapted to simulate VESALIUS-CV patients over a lifetime horizon. Health states included high-risk without a prior MI or ischemic stroke (IS), non-fatal MI, non-fatal IS, post-MI, post-IS, CV death, and non-CV death. Revascularization (RV) was modeled as a procedure with associated costs. The base case considered a US payer perspective and CV risk reduction inputs from evolocumab CV outcomes trials, including VESALIUS-CV, FOURIER, and FOURIER-OLE. Three scenario analyses were evaluated. Scenario 1 retained the US payer perspective and applied CV risk reduction estimates based on the Cholesterol Treatment Trialists' (CTT) Collaboration 2010 meta-analysis. Scenarios 2 and 3 adopted a US societal perspective, using evolocumab CV outcomes trial-based and 2010 CTT Collaboration-based risk reduction estimates, respectively. Main Outcomes and Measures The model outcomes included MACE (defined as MI, IS, or CV death), RV procedures, total costs, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Results In the base case, at the current direct-to-patient price of $3,107 per year, evolocumab added to standard therapy was associated with lifetime reductions of 0.24 MACE and 0.17 RV procedures per person, incremental costs of $24,430, incremental QALYs of 0.34, and an ICER of $71,162 per QALY gained. Evolocumab remained cost-effective across all evaluated scenarios, with ICERs of $42,094, $51,160, and $20,152 per QALY in Scenarios 1, 2, and 3, respectively. Conclusions and Relevance In patients at high CV risk without a prior MI or stroke, evolocumab added to standard therapy was projected to improve CV outcomes and quality-adjusted survival. At the current direct-to-patient price of $3,107 per year, evolocumab was cost-effective in the base-case analysis, with an ICER of $71,162 per QALY gained, and remained cost-effective across scenario analyses, with ICERs ranging from $20,152 to $51,160 per QALY. These estimates were substantially below the $120,000 per QALY threshold defined in the 2025 American Heart Association/American College of Cardiology cost/value methodology statement.

Right ventricular (RV) trabeculation may reflect adaptation to loading conditions and imprinting of early developmental processes, yet its genetic determinants and clinical relevance in adults remain poorly understood. In contrast to the left ventricle, the RV has distinct developmental origins, geometry and loading conditions, suggesting chamber-specific mechanisms of trabecular remodelling. Using deep learning-based image segmentation and fractal dimension analysis, we quantified RV trabecular complexity in diastole and systole in 48,118 UK Biobank participants with genetic data. RV trabecular morphology was associated with systolic function, as well as cardiometabolic and respiratory conditions. Genetic analyses across the allele frequency spectrum identified 52 common loci and 45 genes with a burden of protein-altering variants, implicating sarcomeric function, cytoskeletal organisation, and early cardiac patterning. Although many loci showed shared effects across both ventricles, we also identified RV-specific genetic associations linked to congenital heart disease and respiratory phenotypes. Notably, associations at CFTR suggest a connection between airway-associated mucus regulation and RV remodelling, whereas MYH6 implicates sarcomeric and developmental mechanisms in adult RV patterning. Together, these findings establish RV trabeculation as a trait that captures both shared and chamber-specific mechanisms relevant to cardiovascular health and disease.

Background: A dose finding trial evaluated safety and adherence for pre-cardiac surgery administration of sodium valproate. Integrated multi-omics analyses of myocardium were used to characterise mechanisms underlying the treatment effects. Methods: Adults undergoing cardiac surgery were randomised 1:1:1:1 with concealed allocation to no treatment (Controls), sodium valproate 15mg/kg/day for 1-2 weeks, 15mg/kg/day for 4-6 weeks, or 25mg/kg/day for 4-6 weeks pre-surgery. The primary analysis evaluated adherence and toxicity. Myocardial injury was defined by high sensitivity serum troponin at 24 hours post-surgery. Single-nucleus Assay for Transposase-Accessible Chromatin with sequencing (snATACseq) and single nuclei RNA sequencing (snRNAseq) of myocardial biopsies collected at surgery assessed treatment effects on chromatin accessibility and gene expression. Candidate mechanisms were validated in in vitro. Results: The analysis cohort included 42 participants enrolled between January 2020 and August 2024. Non-compliance (38%) was highest with longer and higher dosing. Sodium valproate 15mg/kg/day for 1-2 weeks had the highest levels of complete treatment adherence (70%), with 20% experiencing moderate/severe drug related adverse effects. An as-treated analyses demonstrated reductions in troponin release in participants receiving Valproate[≤]14 days. Myocardial biopsies from trial participants demonstrated activation of hormetic p53 and Akt-GSK-3{beta} ferroptosis protection pathways. Treatment effects were not attributable to chromatin accessibility. Treatment >14 days resulted in a heart failure phenotype with suppression of ferroptosis protection pathways, endothelial mesenchymal transition, and increased myocardial injury. Conclusions: Sodium valproate 15mg/kg/day for [≤]14 days pre-surgery is well tolerated in adults awaiting cardiac surgery. This treatment was associated with upregulation of ferroptosis protection pathways and reductions in myocardial injury.

Background: Ticagrelor and prasugrel are recommended P2Y12 inhibitors for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), yet uncertainty persists regarding their direct comparative evidence and guideline recommendations differ. Methods: We conducted a multinational retrospective new-user cohort study across 7 claims and electronic health record databases. Adults with ACS undergoing first PCI who initiated ticagrelor or prasugrel were included; patients with prior major ischemic or hemorrhagic events or oral anticoagulant use were excluded. The primary outcome was 1-year major adverse cardiovascular events (MACE: all-cause mortality, acute myocardial infarction, or stroke). Secondary outcomes included net adverse clinical events (NACE) and individual components. Propensity scores were estimated using large-scale L1-regularized logistic regression and applied through stratification. Prespecified diagnostics (covariate balance, empirical equipoise, and systematic error) determined eligibility of each database for inclusion in meta-analysis. Database-specific hazard ratios (HRs) were combined using Bayesian random-effects meta-analysis. Results: Among 7 participating databases, 3 met prespecified diagnostic criteria and were included in the primary meta-analysis, comprising 133,718 patients from one nationwide Korean claims database and two U.S. commercial claims databases (ticagrelor, 109,639; prasugrel, 24,079). For 1-year MACE, the pooled HR for ticagrelor versus prasugrel was 1.28 (95% credible interval [CrI], 0.89-1.88), with substantial between-database heterogeneity. Sensitivity analyses across alternative time-at-risk definitions and propensity score matching were consistent. No statistically credible differences were observed for NACE (HR 1.23, CrI 0.88-1.75), all-cause mortality (HR 1.17, CrI 0.78-1.77), cardiovascular mortality (HR 1.23, CrI 0.81-1.87), ischemic events (HR 1.28, CrI 0.88-1.90), hemorrhagic events (HR 1.01, CrI 0.72-1.39), acute myocardial infarction (HR 1.30, CrI 0.88-1.94), stroke (HR 1.09, CrI 0.73-1.58), or gastrointestinal bleeding (HR 1.04, CrI 0.77-1.41). In a post hoc meta-analysis restricted to the two U.S. databases, the pooled HR for 1-year MACE was 1.49 (95% CrI 1.05-2.10). Conclusions: In this pre-specified multinational observational study, no statistically credible difference in 1-year MACE was observed between ticagrelor and prasugrel in patients with ACS undergoing PCI. However, substantial cross-database heterogeneity warrants further investigation into context-specific comparative effectiveness and safety.

Introduction. Extracorporeal cardiopulmonary resuscitation (ECPR) can support patients who fail to respond to standard resuscitation for out-of-hospital cardiac arrest (OHCA) allowing further time for critical interventions and patient recovery. Although the majority of patients with refractory OHCA have coronary artery disease, the role of emergent percutaneous coronary intervention (PCI) is not clear. We evaluated the effect of PCI on survival to hospital discharge (SHD) in a contemporary cohort of patients with OHCA receiving ECPR. Methods. We performed a retrospective study using data from the Extracorporeal Life Support Organization (ELSO) registry. We included patients ?18 years with OHCA due to a presumed cardiac etiology or an initial shockable rhythm who received ECPR from January 2020 to December 2023. Our primary outcome was SHD. We used inverse probability weighted matching to estimate the average treatment effect of PCI on SHD. We also performed a sensitivity analysis of patients most likely to benefit from PCI (witnessed arrest and no return of spontaneous circulation after five minutes of cardiopulmonary resuscitation. Results. Of 1336 OHCA patients receiving ECPR, 1131 were included in the final analysis after exclusions for age (n=31) and presumed non-cardiac or initial non-shockable rhythm (n=174). The median age was 55 years (IQR 44-62) and most patients were male (n=901, 80%). Twenty-one percent (n=243) received PCI; those patients who received PCI were slightly older (58 [IQR 48-63] vs 53 [IQR 42-62]) and more often male (n=212 [87%] vs n=689 [78%]). In the primary analysis, we found no significant difference in SHD for patients who received PCI compared to those who did not receive PCI (-3.56%, 95% CI -10.31 to 3.19; p-value 0.301). In our sensitivity analysis, we also did not find a significant difference in SHD for patients who received PCI compared to those who did not receive PCI (-4.52%, 95% CI -12.42 to 2.46; p-value 0.246). Conclusion. In our registry-based study of refractory OHCA patients receiving ECPR, emergent PCI was not associated with a significant improvement in SHD.

Background: Cardiac myosin inhibitors (CMIs) directly target sarcomeric hypercontractility and have demonstrated clinical efficacy in obstructive hypertrophic cardiomyopathy (HCM). In symptomatic nonobstructive HCM (nHCM), the phase 3 randomized controlled trials (RCT) differed in whether their primary efficacy endpoints reached statistical significance, although the direction and magnitude of treatment effects were broadly comparable. We therefore conducted a systematic review and meta-analysis to synthesize the randomized evidence on the efficacy and safety of CMIs in symptomatic nHCM. Methods: We systematically searched for randomized placebo-controlled trials evaluating CMIs in adults with symptomatic nHCM according to PRISMA guidance and a prospectively registered protocol (PROSPERO CRD420261466576). Primary efficacy outcomes were changes from baseline in peak oxygen uptake (pVO2) and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), assessed at each trial's primary endpoint. Secondary outcomes included improvement by at least 1 New York Heart Association (NYHA) functional class and change in N-terminal pro-B-type natriuretic peptide (NT-proBNP). The safety outcome was LVEF <50%. Random-effects models were used to pool mean differences (MDs), risk ratios (RRs), and ratios of geometric mean changes. Results: Three RCTs comprising 1,156 participants were included: MAVERICK-HCM, ODYSSEY-HCM, and ACACIA-HCM. Compared with placebo, CMIs were associated with improvements in pVO2 (MD, 0.55 mL/kg/min; 95% CI, 0.22-0.87; I2=0%; P=0.001) and KCCQ-CSS (MD, 2.71 points; 95% CI, 0.87-4.55; I2=0%; P=0.004). Improvement by at least 1 NYHA functional class was more frequent with CMIs (RR, 1.29; 95% CI, 1.03-1.62; I2=24.3%; P=0.024). Across the two phase 3 trials, CMIs reduced NT-proBNP (ratio of geometric mean changes, 0.42; 95% CI, 0.39-0.46; I2=0%; P<0.001), while LVEF <50% occurred more frequently with CMIs (RR, 12.77; 95% CI, 5.98-27.27; I2=0%; P<0.001). Conclusions: In this meta-analysis of randomized trials in symptomatic nHCM, CMIs' pooled estimates favoured CMIs over placebo for improvements in exercise capacity, health status, and NYHA functional class, together with a marked reduction in NT-proBNP. These potential benefits were accompanied by an increased risk of LVEF reduction below 50%.

Background: Bailout cardiac surgery during transcatheter aortic valve replacement (TAVR) is uncommon but remains associated with substantial morbidity and mortality. Although registries have described its incidence and major causes, they often provide limited detail regarding device-related failure mechanisms, attempted transcatheter rescue, and the clinical pathway leading to surgical conversion. We aimed at analyzing post-marketing safety reports from the U.S. Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database to characterize the mechanisms, management strategies, and reported outcomes of bailout surgery during or shortly after TAVR. Methods: We retrospectively analyzed FDA MAUDE reports received from July 1, 2016, through June 30, 2026. Eligible reports described unplanned urgent or emergent open cardiac surgery during or immediately after TAVR. Candidate reports were screened, adjudicated, and deduplicated at the clinical-event level. Events were classified by precipitating complication, transcatheter rescue, operative pathway, and reported outcome. Associations were evaluated using permutation tests, Fisher exact tests with Benjamini?Hochberg correction, adjusted regression models, and sensitivity analyses. Results: After screening 43,239 initial reports, we identified 376 bailout-surgery events, with survival status was documented in 254, including 104 deaths and 150 survivors, corresponding to 40.9% reported mortality. Valve embolization, migration, or malposition was the most frequent complication phenotype (32.4%), whereas ventricular perforation or laceration was associated with the highest mortality (74.1%; OR, 4.86; 95% CI, 1.97?11.99). Mortality differed across complication phenotypes (p<0.001) and operative pathways (p<0.001), but not across transcatheter rescue pathways (p=0.355). Valve explantation with SAVR was associated with lower reported mortality (18.9%; OR, 0.29; 95% CI, 0.12?0.69), whereas unspecified surgery or access/support alone was associated with higher mortality (56.9%; OR, 3.04; 95% CI, 1.80?5.12). Ancillary analyses identified potential platform-specific differences in complication and management patterns, while bailout timing was not independently associated with mortality after adjustment. Conclusions: In this MAUDE analysis, bailout cardiac surgery after TAVR was most commonly precipitated by valve embolization, migration, or malposition, whereas ventricular perforation or laceration was associated with the highest reported mortality. Outcomes differed across complication and operative pathways but not across transcatheter rescue strategies or bailout timing after adjustment. These findings identify clinically relevant post-marketing safety signals but should not be interpreted as incidence estimates, comparative device risks, or causal treatment effects.

Importance Randomised-controlled trials (RCTs) suggest glucagon-like-peptide-1 receptor agonists (GLP-1RAs) reduce the risk of stroke in type 2 diabetes (T2DM); however, the mechanisms remain unclear. If benefits were driven principally by blood pressure (BP) lowering, similar effects on cognitive impairment may be expected. Evaluating data from trials with robust ascertainment and prespecified stroke and/or cognitive outcomes may provide greater clarity. Objective To confirm the effect of GLP-1RAs on stroke risk in RCTs with prespecified, adjudicated stroke endpoints; to explore whether risk reduction is associated with trial-level changes in systolic BP (SBP), glycated haemoglobin (HbA1c), or body weight; to establish whether a parallel cognitive signal exists. Data Sources PubMed, Cochrane, Embase, and CINAHL, from inception to August 2026 (PROSPERO CRD420261305938). Study Selection RCTs comparing GLP-1RAs with placebo/usual care in adults, with ?12 months follow-up, and prespecified stroke and/or cognitive outcomes. Data Extraction and Synthesis Hazard ratios (HRs) for stroke were pooled using inverse-variance random-effect meta-analysis. Univariable meta-regression related logHR for stroke to trial-level between-group differences in SBP, HbA1c and weight, with permutation-based inference and leave-one-out sensitivity analyses. The pooled effect was benchmarked against that predicted from achieved SBP differences. Heterogeneous cognitive outcomes were synthesized narratively. Main Outcomes and Measures Adjudicated stroke events and prespecified cognitive endpoints. Results Among 7 RCTs (n=50,617), GLP-1RA therapy was associated with 17% lower stroke risk (pooled HR 0.83; [95% CI 0.75-0.92]; p<.001). Meta regression showed an association with SBP (? = 0.371; [95% CI 0.013-0.729]; p=.043), but not HbA1c (0.432; [-0.064-0.928]; p=.088) or weight (0.109; [-0.038-0.256]; p=.148). The mean between-group SBP difference (~1.45 mmHg) predicts a stroke reduction of roughly 4%, versus the 17% observed, leaving approximately three quarters of the log-effect unexplained by BP lowering. Four trials (n=4,206) in established neurodegenerative disease showed no cognitive benefit. Conclusions and Relevance GLP-1RA therapy reduces stroke risk by 17% among individuals with T2DM at high cardiovascular risk, a benefit not fully accounted for by conventional cardiometabolic risk factor change. Additional mechanisms warrant evaluation. The absence of cognitive signal suggests the benefit may have cerebrovascular origin, but whether GLP-1RAs prevent vascular cognitive impairment in cardiometabolic populations remains untested.

Objectives: Mitral regurgitation (MR) evolution after transcatheter aortic valve replacement (TAVR) in low-flow aortic stenosis (LFAS) is poorly characterized. We evaluated MR trajectories across LFAS phenotypes, predictors of MR worsening, and associations with clinical outcomes. Methods: We retrospectively studied 614 LFAS patients undergoing TAVR: low-flow high-gradient (LFHG; n=153, 24.9%), classical low-flow low-gradient (cLFLG; n=155, 25.2%), and paradoxical low-flow low-gradient (pLFLG; n=306, 49.8%). MR severity was abstracted from clinical echocardiography reports using a 6-level ordinal scale. MR worsening was defined as a [&ge;]1-grade increase from baseline MR at ~30 days or ~1 year. Multivariable logistic models identified predictors of MR worsening. Kaplan-Meier and Cox models evaluated associations of MR trajectory and LFAS subtype with all-cause death, heart failure hospitalization (HFH), and their composite. Results: Among 614 LFAS patients, 443 had 30-day and 290 had 1-year echocardiographic follow up. At 30 days, MR trajectory differed significantly across LFAS phenotypes, with the highest rate of worsening in cLFLG and the lowest in LFHG. At 1 year, unadjusted MR trajectory distributions did not differ significantly across phenotypes. In adjusted logistic models, cLFLG remained independently associated with MR worsening at both timepoints. MR worsening was associated with worse unadjusted outcomes at 30 days but was not independently associated with the composite endpoint after multivariable adjustment. LFAS phenotype, particularly cLFLG, remained the dominant predictor of adverse clinical outcomes. Conclusions: MR evolution after TAVR is phenotype-specific: cLFLG patients have the highest risk of MR worsening and lowest event-free survival, supporting phenotype-informed post-TAVR surveillance.

Background: Excess epicardial adipose tissue (EAT) is associated with cardiovascular-kidney-metabolic (CKM) dysfunction, but its assessment has traditionally required advanced imaging. We tested whether AI-enhanced echocardiography could enable scalable phenotyping of adverse epicardial adiposity and identify individuals at increased cardiometabolic risk. Methods: We developed PanAdipo, a video-based deep learning model in 1,114,441 videos from 28,797 studies across the Yale-New Haven Health System (YNHHS; 2016-2022), using expert reader annotations of prominent EAT (2.5% of studies). PanAdipo was evaluated in four cohorts: a temporally distinct YNHHS TTE set (n=4,588), an emergency department point-of-care ultrasound cohort across YNHHS (n=10,957), the geographically distinct MIMIC-IV cohort (n=4,549), and the community-based Multi-Ethnic Study of Atherosclerosis (MESA Exam 6, n=2,740). Analyses examined (i) discrimination of prominent EAT; (ii) independence from conventional echocardiographic outputs; (iii) spatial explainability using gradient-weighted class activation mapping; (iv) correspondence with paired cardiac CT-derived body composition phenotypes (n=5,594); and (v) age-, sex-, and BMI-independent associations with cardiometabolic biomarkers and incident metabolic disease. Results: In the held-out health system test set, PanAdipo discriminated prominent EAT with an AUROC of 0.91 (95% CI, 0.88-0.94), exceeding conventional measures of cardiac function and structure. In explainability analyses, the model's attention localized to the epicardial area across views and throughout the cardiac cycle. On paired cardiac CT imaging, the PanAdipo score correlated most strongly with epicardial adiposity (Spearman's rho=0.75; P<0.001) with weaker correlations with other adipose and non-adipose compartments and only modest correlations with BMI across cohorts (rho=0.19-0.40). In MESA, greater PanAdipo scores were independently associated with higher HOMA-IR and triglycerides, associations that persisted among normoglycemic participants. Higher PanAdipo scores were also associated with newly documented metabolic disease, including MASLD/MASH, after adjustment for BMI (HRpooled 1.25 [1.08-1.44] per 1-SD increment in log[PanAdipo]). Conclusions: AI-enabled echocardiography provides a scalable, view-agnostic biomarker that characterizes adverse epicardial adiposity and is associated with cardiometabolic dysfunction, highlighting a novel role for echocardiography in CKM risk stratification.

Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) are indicated for weight reduction and offer cardiometabolic health benefits, yet there is little real-world evidence regarding their association with healthcare resource utilization (HCRU) and costs for Medicare Advantage (MA) beneficiaries with heart failure and obesity. Methods: We used a prevalent new-user study design and the Humana Healthcare Research database to identify MA beneficiaries with heart failure (HF) and obesity receiving standard HF therapy or HF therapy + newly initiating GLP-1 RA between January 1, 2022, and December 31, 2023. We observed adjusted, one-year mean difference in all-cause and heart failure-related HCRU. Results: In our cohort of 4,677 matched pairs (mean age 72 years, male: 41%), one-year, adjusted risk ratio (RR) for HF therapy + GLP-1 RA vs HF therapy was 0.89 (95% CI: 0.84 ? 0.93) for all-cause inpatient utilization, 0.88 (95% CI: 0.82 ? 0.94) for avoidable hospitalizations, and 0.99 (95% CI: 0.95 ? 1.03) for emergency department visits. For individuals receiving HF therapy + GLP-1 RA vs HF therapy, the mean difference was 30.6% (95% CI: 26.7% ?34.7%) for all-cause total costs, 105.9% (95% CI: 99.1% ?112.9%) for pharmacy costs, and ?4.7% (95% CI: ?8.7% to ?0.6%) for medical costs. HF-related HCRU measures were lower among beneficiaries augmenting HF therapy with GLP 1 RA vs individuals receiving HF therapy alone. Conclusions: Among MA beneficiaries with heart failure and obesity, the addition of GLP-1 RA to standard heart failure therapy reduced the likelihood of inpatient admissions or avoidable hospitalizations compared with HF therapy alone.

Aortic stenosis (AS) is a heterogeneous disease of aging characterized by valvular calcification and distinct structural, electrical, and hemodynamic remodeling that are incompletely captured by any single diagnostic measure. Here we show that three AI-derived digital biomarkers resolve AS-related remodeling into complementary structural (cine-CMR Digital AS Severity Index, DASSi), electrical (AI-ECG), and hemodynamic (phase-contrast CMR peak aortic velocity) axes. Among 68,714 UK Biobank participants, all three biomarkers were independently associated with prevalent AS and prospectively predicted aortic valve replacement. Genetic and transcriptomic analyses of the digital phenotypes revealed partially distinct, heritable architectures: peak aortic velocity aligned closely with clinical AS genetics, whereas DASSi and AI-ECG defined a shared myocardial-remodeling axis largely independent of clinical AS susceptibility. These findings support AS as a multidimensional remodeling syndrome and establish a novel digital phenotyping framework for dissecting complex cardiovascular disease into complementary, biologically informative axes.

Background: The optimal P2Y12 inhibitor after percutaneous coronary intervention (PCI) remains debated. A recent frequentist network meta-analysis (NMA) concluded prasugrel provided optimal efficacy-safety balance. We update our previous Bayesian NMA with recent trials and contrast our findings with the frequentist NMA. Methods: We extended our 2023 systematic review by adding two trials published after our search cutoff. The primary efficacy endpoint was a composite of all-cause mortality, a recurrent non-fatal myocardial infarction, or non-fatal stroke (MACE). The primary safety endpoint was study-reported major bleeding events. Bayesian network meta-analysis with a primary binomial complementary log-log model with log(time) offset and random effects was performed. A statistical workflow with prior and posterior predictive checks, convergence diagnostics, model comparisons, sensitivity analyses and probabilities for a range of practical equivalence (ROPE: HR 0.90-1.11) are also reported. Results: 19 RCTs (n = 60,619) were identified. For MACE, prasugrel's probability of a clinical efficacy benefit (hazard ratio (HR) <0.9) was 70% compared to clopidogrel (HR 0.87, 95% credible interval (CrI )0.76-1.03) and 54% compared to ticagrelor. (HR 0.89, 95% CrI 0.73-1.12). For the ticagrelor versus clopidogrel comparison 76% of the posterior probability (HR 0.98, 95%CrI 0.82-1.18) lies in the ROPE. Ticagrelor (HR 1.26, 95%CrI 1.01-1.63) and prasugrel (HR 1.1, 95%CrI 0.88-1.26) showed 86% and 51% probabilities respectively of meaningful bleeding harm (HR > 1.1) versus clopidogrel. Conclusions: Despite 19 RCTs and approximately 60,000 patients, the Bayesian framework revealed clinically important uncertainties and identified probable regions of equivalence among the different P2Y12 inhibitors that were under appreciated with the previous frequentist publication.

Background As transcatheter aortic valve replacement (TAVR) expands to younger patients with longer life expectancy, understanding long-term reintervention and clinically significant valve failure has become increasingly important. Objectives To evaluate temporal trends in TAVR outcomes, characterize the incidence and timing of aortic valve reintervention, compare outcomes after redo-TAVR (TAVR-in-TAVR) versus surgical explantation, and assess freedom from clinically significant valve failure requiring repeat intervention after TAVR versus surgical bioprosthetic aortic valve replacement (SAVR). Methods We performed a retrospective cohort study using the Epic Cosmos. Adults undergoing index TAVR between February 2010 and May 2026 were identified. Primary outcomes included aortic valve reintervention and 30-day major adverse cardiovascular events (MACE). Reintervention incidence was estimated using competing-risk methods with death as the competing event. Propensity-score matching compared redo-TAVR with surgical explantation and TAVR with SAVR. A prespecified 1-year landmark analysis evaluated clinically significant valve failure requiring repeat intervention. Results Among 300,927 patients undergoing TAVR, annual procedural volume increased more than tenfold between 2016 and 2025. Thirty-day MACE decreased from 31.8% before 2017 to 18.6% after 2022 (P<0.001), while mortality declined from 3.0% to 1.4% (P<0.001). During follow-up, 3,315 patients underwent redo-TAVR and 347 underwent surgical explantation. The cumulative incidence of reintervention was 1.1%, 1.2%, 1.5%, and 2.7% at 3, 5, 7, and 10 years, respectively, with significantly lower rates in contemporary procedural eras (Gray test, P<0.001). Compared with surgical explantation, redo-TAVR was associated with lower 30-day mortality, stroke, acute kidney injury, and major bleeding. However, among propensity-matched hospital survivors, surgical explantation was associated with superior long-term survival (hazard ratio: 0.64; 95% CI: 0.44 - 0.93; P=0.018). In the landmark analysis, clinically significant valve failure requiring repeat intervention occurred earlier after TAVR than after SAVR despite a lower overall cumulative incidence of repeat intervention following TAVR. Conclusions Contemporary TAVR is associated with progressively improving procedural outcomes and a low incidence of repeat aortic valve intervention. Redo-TAVR offers lower perioperative risk than surgical explantation, whereas surgical explantation is associated with superior long-term survival among selected patients. Earlier clinically significant valve failure requiring repeat intervention after TAVR underscores the importance of lifetime management strategies as TAVR expands to younger populations.

Background: Adults with congenital heart disease (ACHD) represent a rapidly expanding population with evolving mortality patterns. Despite improved survival, excess mortality persists. Objective: To evaluate the incidence, causes, and predictors of mortality in a contemporary ACHD cohort. Methods: We performed a retrospective cohort study of adults (?18 years) first evaluated at Mayo Clinic from 2002?2023. Baseline clinical, imaging, and electrocardiographic data were analyzed. Vital status was determined using institutional records and the Accurint national mortality database. Kaplan-Meier analysis and Cox proportional hazard models were used to evaluate mortality and identify independent predictors of mortality Results: A total of 7,678 ACHD patients were included, with median age of 36.8 years and median follow-up of 11.4 years. During 78,768 patient-years of follow-up, 1,116 patients died (median age at death 57.2 years), corresponding to an annual mortality rate of 1.4%. The cumulative rate of all-cause mortality at 5, 10, 15, and 20 years was 6.9%, 12.0%, 19.0%, and 26.2%, respectively. When stratified by CHD complexity, the annual death rate in patients with severe CHD (2.4%/year) was twice that of patients with moderate or mild CHD (both 1.2%/year). Older age and ACHD subtypes, specifically, cyanotic heart disease (HR 3.9, 95% CI 2.9?5.3) and Fontan physiology (HR 3.2, 95% CI 2.3?4.4), were strongly associated with increased mortality. Additional independent predictors included male sex, ventricular dysfunction, advanced NYHA class, prior heart failure hospitalization, hypertension, smoking, coronary artery disease, renal dysfunction, and abnormal hemoglobin levels. Cardiovascular causes accounted for 57.7% of deaths with known etiology, predominantly heart failure (48.9%) and sudden cardiac death (21.9%), while non-cardiovascular causes were driven mainly by infection and malignancy. Conclusions: In this large contemporary ACHD cohort, mortality was driven by ventricular dysfunction, heart failure, and systemic end-organ involvement in addition to the underlying congenital anatomy. Both cardiovascular and non-cardiovascular causes contributed significantly to mortality. These findings underscore the need for comprehensive multidisciplinary ACHD care focused on early recognition of cardiac functional decline, management of acquired comorbidities, and end-organ dysfunction.

Background: High intensity statins are foundational after acute coronary syndrome (ACS), yet intensive care unit prescribing occurs while renal reserve, perfusion, and interacting therapies are changing. We tested a renal safety checkpoint integrating kidney status, hemodynamic instability, and drug interaction burden to identify when statin intensity may become nonexchangeable. Methods: We emulated an active-comparator target trial across MIMIC-IV, eICU, and MIMIC-III. Critically ill adults with ACS, acute myocardial infarction, or percutaneous coronary intervention who received high- or moderate-intensity statins within 24 hours were included. The primary outcome was 7-day KDIGO stage 2 or 3 acute kidney injury or incident renal replacement therapy. Eligibility, time zero, treatment assignment, and follow-up were aligned. Database-specific propensity scores, overlap weighting, and standardization addressed confounding and treatment overlap. Safety domains, longitudinal analyses, bootstrap resampling, source omission, and endpoint sensitivities assessed robustness. Results: Among 5,178 patients, 761 developed the primary outcome, including 223 who initiated renal replacement therapy. Standardized risks were 17.40% with high-intensity therapy and 15.01% with moderate-intensity therapy (risk difference, 2.39 percentage points [95% confidence interval (CI), -0.23 to 5.05]; risk ratio, 1.16 [95% CI, 0.99 to 1.39]). Risk separation was greatest with high hemodynamic instability (5.78 percentage points [95% CI, 1.56 to 9.74]) and high drug-interaction burden (6.24 percentage points [95% CI, -0.44 to 12.19]). Renal replacement therapy showed a 1.33-point risk difference (95% CI, 0.18 to 2.67). Conclusions: This study moves statin safety assessment beyond fixed dose label or isolated creatinine measurement. The findings support a clinically actionable monitoring strategy in which early statin intensity is reassessed against evolving perfusion, kidney status, and interaction burden. This approach preserves intensive lipid lowering for physiologically suitable patients while identifying a high risk window in which temporary moderation.

Background: Although prophylactic veno-arterial extracorporeal membrane oxygenation (VA-ECMO) may provide hemodynamic stability during high-risk percutaneous coronary intervention (PCI), it is also associated with potential complications and may not be necessary in most cases. In this context, we proposed a pre-cannulated standby ECMO strategy and designed the ECMO-READY trial to evaluate the comparative effectiveness of pre-cannulated standby versus prophylactic ECMO strategies in patients undergoing high-risk PCI. Methods: The ECMO-READY trial is a prospective, multicenter, open-label, randomized controlled trial conducted in 8 sites in China. A total of 176 patients scheduled to undergo high-risk PCI will be randomly assigned in a 1:1 ratio to either a pre-cannulated standby ECMO strategy or a prophylactic ECMO strategy. The primary outcome is the 30-day incidence of major adverse events, including death, myocardial, infarction, repeat revascularization, stroke, PCI failure, limb ischemia, major bleeding, vascular injury requiring intervention, and need for renal replacement therapy. Secondary outcomes include post-procedural hemoglobin decline, post-procedural platelet count decline, red blood cell transfusion rate, peak post-procedural interleukin-6 level, use of intra-aortic balloon pump, duration of ECMO support, length of hospital stay, hospitalization cost, and each component of the composite primary outcome. Enrollment began in March 2025 and is anticipated to be completed by December 2026. Discussion: The ECMO-READY trial will provide prospective randomized evidence regarding ECMO support strategies in patients undergoing high-risk PCI and may help inform future clinical practice. Trial registration: ClinicalTrials.gov NCT06274411. Registered on February 23, 2024. Keywords Percutaneous coronary intervention, High-risk, Extracorporeal membrane oxygenation, Ready, Standby, prophylactic, Major adverse events

Observational studies suggest an association between COVID-19 and acute myocardial infarction (AMI), however, whether this relationship is causal remains unclear. We conducted a multi-ancestry Mendelian randomization (MR) study across European, East Asian, South Asian, and African populations, evaluating three COVID-19 phenotypes: very severe COVID-19, hospitalized COVID-19, and general infection association with AMI. GWAS summary statistics were obtained from the COVID-19 Host Genetics Initiative Round 7 and UK Biobank/Biobank Japan for AMI. Inverse-variance weighted (IVW) MR was the primary method, with fixed- or random-effects models selected according to heterogeneity test. MR-Egger, weighted median and weighted mode were conducted as sensitivity analyses. In European ancestry, genetic liability to very severe COVID-19 and hospitalized COVID-19 was slightly inversely associated with AMI risk, but without statistical significances across sensitivity analyses. Hospitalized COVID-19 showed a suggestive but non-significant inverse association in South Asian ancestry. No significant associations were identified in East Asian or African ancestries. Our findings did not support a robust causal association between COVID-19 susceptibility or severity and AMI risk across ancestries, suggesting that the observed cardiovascular burden may be driven more by acute pathophysiological mechanisms than shared genetic architecture.