Journal of the American College of Cardiology

Background: Bicuspid aortic valve anatomy increases procedural complexity during transcatheter aortic valve implantation, yet outcome-oriented anatomic risk stratification for intraprocedural events remains limited. Aims: We aimed to develop and externally validate an anatomy-driven score to predict a composite intraprocedural endpoint, assessed at exit from the procedure room, in bicuspid transcatheter aortic valve implantation. Methods: Consecutive patients with bicuspid aortic valve undergoing transcatheter aortic valve implantation were analysed in a development cohort (N=793) and a multicentre external validation cohort (N=134). Candidate preprocedural computed tomography and echocardiographic variables were prespecified by expert consensus and refined using penalized regression with bootstrap stability selection within a domain-constrained framework. A five-indicator score (0 to 10 points) was derived from routine imaging metrics spanning the ascending aorta, aortic root, valve complex, annulus-outflow tract unit, and left ventricle, and tested using multivariable logistic regression. Results: The composite intraprocedural endpoint occurred in 101/793 (12.7%) patients in the development cohort, with stepwise increases across risk strata (7.2%, 13.3%, 30.6%; p<0.001). Each 1-point increase was independently associated with higher risk (odds ratio 1.32; 95% confidence interval 1.18-1.47). A similar gradient was observed in external validation (3.1%, 10.8%, 50.0%; p=0.012; odds ratio 1.55 per point), with a C-statistic of 0.725. Higher risk categories were associated with lower early safety and higher 30-day and 1-year mortality. Conclusions: An anatomy-driven score derived from routine preprocedural imaging demonstrates graded discrimination of intraprocedural risk and may inform procedural planning in bicuspid transcatheter aortic valve implantation.

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 No systematic review has been conducted to pool the existing evidence and quantify cancer prevalence rates in cardiovascular diseases (CVDs). We aimed to estimate pooled cancer prevalence in coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), hypertension, type 2 diabetes mellitus (DM), stroke, peripheral arterial disease (PAD), and valvular heart diseases (VHD). Methods PubMed, Web of Science, and Scopus were searched from 2010 to July 2024. The outcomes were proportions of patients with active, any, previous, blood, solid, and metastatic cancer. The prevalence rates were estimated via one-step generalized linear mixed models. Results Totally, we retrieved 676 studies with enrollment of roughly 180 million participants. The analysis for active cancer included 59 studies with a population of 4,759,695 patients. The pooled prevalence of active cancer was 4.22% (95% confidence interval (CI) 2.18-5.32), 4.43% (95% CI 2.78-6.38), 4.60% (95% CI 1.72-8.13), 4.61% (95% CI, 2.83-6.97), 4.90% (95% CI 3.84-6.37), and 5.55% (95% CI 3.97-7.01) in patients with type 2 DM, chronic HF, any stroke, CAD, VHD, and AF. For any cancer, prevalence rates ranged from 14.10% (95% CI 12.20-15.99) in AF to 7.04% (95% CI 6.05-8.03) in CAD. Conclusion Pooled prevalence rates demonstrate a measurable burden of cancer among patients with a wide range of CVDs, highlighting the need for multidisciplinary management in this population.

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[&le;]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 [&le;]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: Thoracic aortopathy is a disorder with genetic influence usually presenting in adulthood for which family screening is potentially desirable. Family screening is recommended, but the predictors of a positive screen and real-world pickup rates are unknown. Methods: This was a retrospective cohort of 1022 probands (first affected family member identified) with thoracic aortopathy and one or more features suggestive of a genetic etiology, and their presenting family members, assessed in a cardiac clinic (2009?2024). Imaging and genetic testing were employed in family screening. The prespecified outcomes were uptake and pickup rate of family screening, and proband and family member specific characteristics that predicted a positive family screen. Results: Among probands, 43.5% had one or more family member screened, with an average of 3 relatives per successful proband. 27.6% of family members screened positive. A pre-existing family history of aortopathy was the only variable predicting a higher incidence rate for positive family screen (p = 0.0003). Age of presentation < 60 was not predictive. For family members, extravascular features (p < 0.0001), closer relation to the proband (p < 0.02), male sex (p < 0.0001) and older age (p< 0.0001) all predicted a positive screen. Family members were eight times more likely to screen positive through imaging as compared to genetic testing. Probands with a genetic diagnosis of Marfan and Loeys Dietz syndromes accounted for only 4% of the total. Conclusions: Proband-initiated family screening for thoracic aortopathy has a high yield of affected individuals, even among older probands.

Background: Finerenone, a non-steroidal mineralocorticoid receptor antagonist (nsMRA), improves cardiorenal outcomes in chronic kidney disease, type 2 diabetes, and heart failure. However, its clinical efficacy and safety when initiated early after acute myocardial infarction (AMI) remain unknown. Methods: This retrospective cohort study utilized the TriNetX global federated network to identify adult patients with AMI who initiated finerenone within 6 months of the index event. These were compared to a propensity score-matched control group of AMI survivors who did not receive finerenone. Results: After 1:1 propensity score matching, 1,012 patients were included (506 per group; mean age 69 years). The cohort represented a high-risk phenotype with a high prevalence of type 2 diabetes (~84%) and CKD (~80%). Over a 2-year follow-up, finerenone treatment was associated with a lower risk of the composite endpoint of mortality and heart failure (HR 0.644; 95% CI 0.495?0.837; P < 0.001). Notably, finerenone was also associated with a lower risk of progression to ESRD or CKD stage 5 (HR 0.573; 95% CI 0.387?0.851; P = 0.005) and all-cause hospitalization (HR 0.602; 95% CI 0.482?0.751; P < 0.001). There was no significant difference in the risk of adverse events, including hyperkalemia, hyponatremia, and syncope or hypotension between groups. Conclusion: In this real-world study of high-risk post-AMI patients, early initiation of finerenone was associated with lower risks of composite cardiovascular events, all-cause mortality, and renal disease progression, without a significant increase in adverse events. These findings warrant validation in prospective randomized controlled trials.

Background: Non-monogenic arteriopathies are often classified as distinct entities according to the arterial territory involved, yet they share clinical features and may co-occur in the same individual. This pattern suggests shared susceptibility across anatomically distinct arteriopathies, potentially driven by common biological and genetic mechanisms. Methods: We investigated the shared genetic architecture of five arteriopathies (cervical artery dissection (CeAD), intracranial aneurysm (IA), spontaneous coronary artery dissection (SCAD), aortic aneurysm and dissection (AAD), and fibromuscular dysplasia (FMD)) using LD score regression, Association analysis based on SubSETs (ASSET), pairwise Multi-Trait Analysis of Genome-wide association summary statistics (MTAG), pleiotropy mapping and Mendelian randomization (MR) to identify shared loci and prioritise candidate causal genes. Results: LD score regression identified significant positive genetic correlations between CeAD-SCAD (rg = 0.64), IA-AAD (rg = 0.33), IA-SCAD (rg = 0.37), CeAD-AAD (rg = 0.56) and SCAD-AAD (rg = 0.20). ASSET identified 37 shared independent loci, and in MTAG analyses, one novel locus was identified for CeAD and SCAD (SLC39A8) and one for IA (FGF5). 13 loci showed strong cross-trait colocalization, including PHACTR1, LRP1, and CDKN2B-AS1. Using the Genotype-Phenotype Map, we found that arteriopathy-associated variants colocalized with blood pressure- and migraine-related traits, while many showed effect directions opposite to those observed for coronary artery disease. Proteome-wide MR identified 67 circulating proteins associated with at least one trait, including ECM1 and SHISA5 for CeAD and FGF5 for IA, with 17 supported by colocalization. Transcriptome-wide MR identified 204 colocalized tissue?specific signals, of which, 14 were shared across multiple traits. Enrichment analyses implicated pathways related to vascular development, smooth muscle cell function, extracellular matrix organization, and TGF-? signaling. Conclusions: These findings support shared genetic architecture across anatomically distinct arteriopathies, implicating pathways involved in vascular structure and prioritising therapeutic targets for future mechanistic investigation.

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods: We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results: Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti-volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions: The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting.

Aims This multicenter study aims to compare outcomes of total aortic arch replacement (TAR) using the frozen elephant trunk (FET) technique in patients with and without heritable thoracic aortic disease (HTAD) and to assess whether HTAD influences postprocedural adverse aortic events (AAEs). Methods From 06/2007 to 05/2024, aortic databases from 13 European centers were screened for HTAD patients undergoing TAR with FET. All consecutive dissection and aneurysm non-HTAD patients from the four core centers served as comparator. The primary outcome was AAE, a composite of diameter progression, distal stent graft induced new entry (dSINE), malperfusion, rupture and pseudoaneurysm at 5 years after FET implantation. Results Of 2739 FET patients, 196 (7.2%) were diagnosed with HTAD. The control group consisted of 867 non-HTAD FET patients. Marfan syndrome was the most common condition (72%), followed by Loeys-Dietz syndrome (11%), vascular Ehlers-Danlos syndrome (5.6%) and Turner syndrome (2.0%). Seventeen (8.8%) patients were diagnosed with ns-HTAD. At 5 years 46 (24%) AAEs occurred in the HTAD group, 169 (20%) in the non-HTAD group (p=0.2). Diameter progression was the most common event (10% vs. 12%; p=0.6), followed by dSINE (5.8% vs. 4.5%; p=0.5), malperfusion (4.2% vs. 3.3%; p=0.5), rupture (2.1% vs. 0.7%; p=0.09) and pseudoaneurysm (0.5% vs. 0.2%; p=0.5). Conclusions The FET technique appears safe and effective for acute and chronic aortic disease in HTAD patients, with outcomes comparable to non-HTAD cases and no increase in graft-related complications, challenging traditional concerns about stent graft use in genetically mediated aortic disease.

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.

Importance: Cardiac conduction disorders have traditionally been regarded as a secondary manifestation of underlying structural heart diseases. However, isolated conduction disorders may precede the onset of heart failure (HF) suggesting shared mechanisms. Objective: To evaluate the prevalence and clinical significance of pathogenic/likely pathogenic (P/LP) rare variants in cardiomyopathy genes among individuals with conduction disorders. Design, Setting, and Participants: Biobank analysis of 192,834 participants with whole genome sequence data from Vanderbilt's BioVU and 353,092 participants from the All of Us Research Program (AoU). Participants with primary conduction disorder (left bundle branch block [LBBB], right bundle branch block [RBBB], high-grade atrioventricular block [AVB]) were identified after excluding secondary causes. Exposures: P/LP variants in cardiomyopathy genes. Main Outcomes and Measures: Primary outcome was P/LP carrier status by age and HF status. Secondary outcomes included incident HF and composite ventricular arrhythmias/sudden cardiac death/mortality (VA/SCD/mortality). Results: Among 16,959 participants with conduction disorders in BioVU and 13,442 in AoU, 432 (2.6%) and 206 (1.5%) were P/LP carriers, respectively. Conduction disorder was independently associated with carrier status (BioVU p<0.001; AoU p=0.005). Carrier probability varied by age at conduction disorder onset and HF status. Among participants with HF at age 30 years, predicted carrier probability for LBBB was 7.5% in BioVU and 20.2% in AoU; for high-grade AVB, 7.7% and 8.5%, respectively, compared with 3.7% and 2.9% among those with HF without conduction disorder. P/LP carrier status among participants with conduction disorders was associated with increased risk of incident HF (BioVU p<0.001; AoU p<0.001) and ventricular arrhythmia/sudden death/mortality (BioVU p<0.001; AoU p<0.001). Carriers also demonstrated increased susceptibility to conduction disorder following HF diagnosis, including more than two-fold higher risk of third-degree AVB (BioVU aOR 2.48, 95% CI 1.85-3.32; AoU aOR 2.26, 95% CI 1.35-3.80). Conclusions: Adults with primary conduction disorders have an increased prevalence of P/LP variants in cardiomyopathy genes, which is most pronounced with diagnoses at early ages of adulthood. Furthermore, there is evidence of an interaction between P/LP carrier status and conduction disorder to increase HF risk and composite cardiovascular outcomes, underscoring the potential role of genetic evaluation in patients with primary conduction disorders to inform long-term outcomes.

Background: Aspirin-free P2Y12-inhibitor monotherapy after percutaneous coronary intervention (PCI) is an alternative to dual antiplatelet therapy (DAPT), but the evidence rests largely on full-dose ticagrelor in acute coronary syndrome and on designs retaining a DAPT run-in; East-Asian patients may not require the same antithrombotic intensity. We compared standard DAPT, DAPT with half-dose ticagrelor, and aspirin-free half-dose ticagrelor monotherapy initiated on the day of PCI in chronic coronary syndrome (CCS). Methods: Sixty-one East-Asian patients with CCS scheduled for elective PCI were randomized 1:1:1 to Control (aspirin plus clopidogrel), Experimental A (aspirin plus ticagrelor 45 mg twice daily), or Experimental B (ticagrelor 45 mg monotherapy, aspirin discontinued at day 2). DAPT arms continued for six months; Experimental B continued indefinitely. P2Y12 reaction units (PRU) were measured at baseline and at a median of 17 days. Results: PRU reduction was three-fold greater in both ticagrelor arms than in Control ({Delta}PRU -188 and -181 versus -60.5; P<0.001), with no difference between ticagrelor arms (P=0.772). At 12 months, major adverse cardiovascular events (MACE) and clinically relevant bleeding each occurred in 1 of 17 Experimental B patients (5.9%) and in neither other arm. One Experimental A patient crossed over for ticagrelor-induced dyspnea; no stent thrombosis or cardiac death occurred. Conclusions: In East-Asian patients with CCS, half-dose ticagrelor produced markedly greater platelet inhibition than standard DAPT, with an identical effect whether given with or without aspirin. It merits evaluation in an adequately powered randomized trial. Clinical Trial Registration. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT07622056

Background. Septal reduction therapy (SRT) is recommended in drug-refractory, symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We evaluated whether aficamten, a novel cardiac myosin inhibitor, can reliably transition guideline-eligible SRT candidates to ineligibility, and the associated safety profile of aficamten in this group. Methods. We analyzed participants with oHCM enrolled in FOREST-HCM (NCT04848506), the long-term open-label extension study of aficamten, from 28 May 2021 to 9 May 2025. Results. Three hundred and fifteen patients were included, of whom 104 met 2024 ACC/AHA guideline criteria for SRT eligibility at baseline. The SRT-eligible cohort was predominantly female (57%), with mean resting and Valsalva left ventricular outflow tract (LVOT) gradients of 63 {+/-} 39 and 109 {+/-} 42 mmHg, and all were in New York Heart Association (NYHA) class III. All baseline SRT-eligible patients became SRT-ineligible with aficamten therapy during study follow-up over a median of 42 days (IQR: 17, 49), except for one participant who withdrew from the study to pursue SRT (total of 3 participants withdrew). After dose titration, 3/104 (2.9%) remained guideline-eligible; by week 72 no patients met eligibility criteria. At maintenance, resting and Valsalva LVOT gradients improved by a least-squares mean of ?41 mmHg ([95% CI ?44 to ?37]; P<0.0001) and ?56 mmHg ([95% CI ?62 to ?51]; P<0.0001), respectively. Relative to baseline, NT-proBNP improved by 77% (95% CI 74 ? 80%), high-sensitivity cardiac troponin I decreased by 38% (95% CI 30 ? 46%), KCCQ-CSS improved by a mean of 20.2 (SD 19.3) points, and 95.2% of SRT-eligible patients had improved by ?1 NYHA class. Overall, the safety profile was favorable, with 2 occurrences of left ventricular ejection fraction (LVEF) < 50% over 193.7 patient-years of follow-up (1 event per 100 patient-years), managed by down-titration. There were no baseline SRT-eligible patients who died or developed LVEF <40%. Conclusions. Aficamten resolved guideline eligibility for SRT in nearly all baseline-eligible patients, with rapid and durable improvements in hemodynamics, symptoms, biomarkers and health status sustained for up to 3.5 years. Instances of LVEF <50% were rare and without clinical sequelae. These data support aficamten as a safe and effective alternative to SRT in oHCM.

Background: Clinical outcomes of switching versus continuing direct oral anticoagulant (DOAC) among atrial fibrillation (AF) patients who experienced an ischemic stroke despite receiving DOAC therapy are uncertain. Methods: We included patients with AF who were hospitalized for ischemic stroke (index stroke) between January 1, 2016, and June 30, 2022, while receiving DOAC therapy and who resumed DOAC within 90 days after discharge in the Merative MarketScan Commercial and Medicare databases. Patients were classified as DOAC-switched or DOAC-continued according to whether the DOAC agent changed or remained the same after the index stroke; secondary analyses considered individual DOACs. The primary outcome was recurrent ischemic stroke; secondary outcomes included major bleeding and a composite outcome (bleeding or ischemic stroke). Propensity score-based overlap weighting and weighted Cox models were used to estimate adjusted hazard ratios (aHRs). Results: A total of 1175 patients were eligible for the study, of whom 970 (82.6%) continued and 205 (17.4%) switched DOAC therapy. Comparing DOAC-switched to DOAC-continued was not significantly associated with recurrent ischemic stroke (aHR, 1.20; 95% CI, 0.63-2.30), major bleeding (aHR, 0.60; 95% CI, 0.21-1.72), or the composite outcome (aHR, 0.98; 95% CI, 0.56-1.70). However, among patients who received apixaban before stroke, switching to rivaroxaban was associated with a higher risk of recurrent ischemic stroke (aHR, 2.70; 95% CI, 1.05-6.95). Conclusions: Overall, switching DOAC therapy after ischemic stroke was not associated with improved clinical outcomes. Switching from apixaban to rivaroxaban, however, could increase risk of recurrent ischemic stroke.

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.

Background: Gaps in care (GIC) among patients with congenital heart disease (CHD) are associated with adverse outcomes, yet the specific social and healthcare-related factors contributing to GIC and the clinical consequences of delayed re-engagement in care remain poorly characterized. Large electronic medical record datasets often cannot distinguish true GIC from clinically appropriate care patterns or capture the patient-level factors contributing to GIC. Methods: We conducted a retrospective cohort study, combining large data with manual chart review, of 1,746 patients of all ages with surgically repaired CHD between 2003 and 2020 at a tertiary care center serving four states. GIC was defined as more than 3 years and 3 months between cardiology visits and exceeding the physician recommended follow-up interval. Results: Of the cohort, 916 patients (52%) met criteria for potential GIC. Following a structured manual chart review, a substantial subset was reclassified as having appropriate care, leaving 275 patients (15.7%) with true GIC. After multivariable adjustment, older age and simple anatomic CHD complexity were independently associated with GIC. Among patients with GIC, 17.8% had a documented contributor, most commonly insurance instability or social factors. Of those 41.5% returned to care (RTC), and many were asymptomatic but had significant disease progression. Thirteen percent of patients who RTC required cardiac intervention, including semi-urgent or urgent procedures, and 26.7% of those requiring intervention experienced significant morbidity or mortality, including stroke, infective endocarditis, urgent transplant referral, or death. These outcomes occurred across all levels of CHD complexity, including patients with simple CHD. Conclusions: GIC remain prevalent in patients with surgically repaired CHD and are associated with significant morbidity and mortality across the full spectrum of anatomic complexity. They are most often driven by insurance instability and social vulnerability rather than clinical factors, and many adverse outcomes may be preventable with consistent longitudinal care. These findings support a shift toward proactive care models that integrate standardized follow-up pathways, systematic assessment of patient-level needs, and emerging analytic tools to identify at-risk patients before GIC occur.

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 Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease. Sociodemographic factors may influence time to treatment initiation and resulting clinical outcomes, yet these relationships are poorly characterized. OBJECTIVE Assess the effects of sex and race on tafamidis initiation and subsequent outcomes and their interaction with factors such as ATTR-CM type and social deprivation measures. METHODS A retrospective cohort analysis was conducted using the US Komodo Healthcare Map (01/2016-06/2024) among patients with amyloidosis, identified by ICD-10-CM diagnosis codes. Cumulative incidence of treatment initiation and survival probabilities for cardiovascular-related hospitalization (CVH) or death were estimated by Kaplan-Meier, stratified by sex and race. Cox proportional hazards models were fitted for both endpoints to estimate hazard ratios, adjusting for demographics and clinical characteristics. RESULTS Of 11,311 patients identified, White and Black patients (n=9,223) were included in subsequent analyses. Within 12 months of diagnosis, White women had the lowest cumulative incidence of tafamidis initiation (11.4%), followed by Black women (22.0%), Black men (26.7%), and White men (31.0%). Event-free survival at 12 months was lowest in Black women (42.9%), followed by Black men (46.8%), White women (48.6%), and White men (54.4%). Median (95% CI) time to CVH or death was shortest for Black women (8.0 months [6.8-10.0]) followed by Black men (9.9 months [8.8-12.0]), White women (11.0 months [9.6-13.0]), and White men (15.0 months [14.0-16.0]). CONCLUSIONS In this large, real-world cohort of US patients with ATTR-CM, sex and race contributed to disparities in tafamidis initiation and survival, underscoring compounded disparities in both access and outcomes.