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.

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.

Background: Tirzepatide and semaglutide improve functional status and heart failure (HF) events in patients with obesity and HF with preserved ejection fraction. Tirzepatide has been associated with greater control of cardiometabolic risk factors in patients with obesity compared to semaglutide. Whether tirzepatide is associated with lower risk of new-onset HF than semaglutide in patients with obesity is underexplored. Methods: A retrospective cohort study was conducted using data pooled from the TriNetX platform. Patients with obesity who initiated therapy with tirzepatide or semaglutide during the period Jun 4, 2021 to Aug 13, 2026 were identified and 1:1 propensity-score matched to produce two study cohorts. The one-year incidence of new-onset HF was calculated and compared between the two cohorts. Secondary outcomes included new-onset systolic HF, new-onset diastolic heart failure, new-onset atrial fibrillation or flutter, all-cause mortality, and hospital encounters. Cox proportional hazards models were fitted to calculate hazard ratios (HR) along with 95% confidence intervals (CI). Results: Two well-matched cohorts (N=424,269 in each) were formed. The incidence of new-onset HF was lower in the tirzepatide group (1.0% vs. 1.3%; absolute risk difference -0.3%, 95% CI -0.35 to -0.26; HR 0.9, 95% CI 0.86[boxh]0.93). The tirzepatide group were also at lower risk of all-cause mortality (HR, 95% CI: 0.8, 0.77[boxh]0.91) and new-onset systolic HF (0.8, 0.79[boxh]0.92). All other secondary outcomes occurred at similar rates in both study groups. Conclusion: Among patients with obesity, tirzepatide therapy was associated with lower risk of new-onset HF compared to semaglutide although the effect sizes were modest.

Background Several disease-modifying agents for transthyretin amyloid cardiomyopathy (ATTR-CM) have been investigated, but differences in trial design and background stabilizer use complicate interpretation of their efficacy. This meta-analysis assessed their efficacy overall and by background stabilizer use. Methods PubMed, Embase, and the Cochrane Library were searched through September 2026 for phase III randomized, placebo-controlled trials of disease-modifying therapy in ATTR-CM. Primary endpoints were all-cause mortality, 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), pooled with a random-effects model. Treatment effects were compared between the monotherapy and baseline stabilizer strata using a mixed-effects model. Results Five trials (ATTR-ACT, APOLLO-B, ATTRibute-CM, HELIOS-B, CARDIO-TTRansform; N=3497) were included. Disease-modifying therapy reduced all-cause mortality (risk ratio, 0.76; 95% confidence interval [CI], 0.66-0.87; I2=0%) and improved 6MWD (pooled standardized mean difference [SMD], 0.43; 95% CI, 0.20-0.67), KCCQ-OS score (SMD, 0.37; 95% CI, 0.19-0.55), and NT-proBNP (SMD, -0.53; 95% CI, -0.89 to -0.18). The mortality benefit was similar whether therapy was given alone or added to a background stabilizer (pooled risk ratio, 0.77 vs. 0.71; P for interaction = 0.59), but treatment effects on 6MWD (pooled SMD, 0.49 vs. 0.14), KCCQ-OS score (0.44 vs. 0.07), and NT-proBNP (-0.65 vs. -0.13) were smaller among patients receiving a background stabilizer (P for interaction = 0.012, <0.001, and 0.029, respectively). Conclusion Disease-modifying treatments reduced all-cause mortality and favored functional capacity, health status, and NT-proBNP outcomes in patients with ATTR-CM. Exploratory subgroup analyses showed smaller treatment effects on 6MWD, KCCQ-OS score, and NT-proBNP among patients receiving a background stabilizer, with no statistically significant difference in the mortality effect according to baseline stabilizer use.

Background and Aims: Calcific aortic valve disease (CAVD) is a common valvular heart condition and has no effective medical therapy. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the acquisition of somatic mutations in hematopoietic stem cells which provides a selection advantage, has been associated with incident aortic stenosis (AS), particularly when driven by TET2 mutations. Methods: We evaluated the association of CHIP and gene-specific CHIP subtypes with AS in the UK Biobank (UKB) and with aortic valve hemodynamics in the Atherosclerosis Risk in Communities (ARIC) study to prioritize gene driver mutations for mechanistic study. We then generated human ASXL1-mutant THP-1 derived macrophage like cells and evaluated the ability of THP-1 conditioned media to promote a calcific response in human valvular interstitial cells (VICs). We additionally performed mass spectrometry proteomics to characterize the ASXL1-mutant THP-1 macrophage secretome. Therapeutically relevant inflammatory pathways were inhibited with anakinra (interleukin [IL]-1) or tocilizumab (IL-6). Results: Among 449,109 individuals in the UKB with whole exome sequencing, large CHIP clones and non-DNMT3A CHIP subtypes (e.g., TET2, ASXL1, and JAK2 CHIP) were independently associated with risk of incident AS. Among 1,963 individuals in ARIC with CHIP sequencing and echocardiographic data, only ASXL1 CHIP was associated with worse aortic valve hemodynamics. In vitro, ASXL1-mutant human THP-1-derived macrophage-like cells had increased AIM2 inflammasome activation. THP-1 media promoted VIC calcification, which was accelerated in ASXL1 mutant macrophages. Proteomic profiling identified inflammatory proteins linked to valvular calcification. Accelerated VIC calcification was reduced by IL-1 inhibition by anakinra or IL-6 inhibition by tocilizumab. Conclusions: Integrating human cohort data with experimental evidence using ASXL1-mutant human macrophage-like cells and human valve cells, these findings identify ASXL1-mutant CHIP as a distinct inflammatory subtype associated with valvular calcification and support IL-1 and IL-6 signaling as candidate therapeutic pathways for future investigation in CAVD.

Background Real-world data regarding mavacamten use in underserved and racially diverse populations remain limited, particularly for long-term therapy implementation. Structural barriers such as financial instability, fragmented healthcare access, and challenges adhering to REMS-related monitoring requirements may affect longitudinal therapy implementation. Methods We performed a retrospective observational study of consecutive patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) evaluated for mavacamten therapy at a tertiary HCM center in Bronx, NY, between 6/2022-10/2025. Patients were followed for up to 48 weeks after treatment initiation. Clinical characteristics, treatment interruptions, adverse events, echocardiographic and functional outcomes, and implementation barriers were assessed descriptively. Results Seventy-two patients with symptomatic oHCM were evaluated for mavacamten; sixty-seven initiated treatment. Mean age was 66.9{+/-}15.3 years, 72% were female, and 61% identified as Black or Hispanic. Median resting left ventricular outflow tract (LVOT) gradient decreased from 51mmHg (IQR30-88) at baseline to 7mmHg (IQR5-10) at 48 weeks. Median Valsalva LVOT gradient decreased from 74mmHg (IQR50-104) to 20mmHg (IQR10-29). At final follow-up, 80% of patients improved by [&ge;]1 NYHA functional class. LVEF declined below 50% in five patients and recovered in all cases. Approximately one-quarter experienced treatment interruption or discontinuation, nearly half related to insurance instability, non-adherence, and REMS-related monitoring barriers. Conclusions Mavacamten demonstrated efficacy and safety outcomes comparable to those reported in clinical trials and prior registries in this predominantly underserved minority urban cohort. However, structural and healthcare-access barriers substantially affected long-term treatment implementation. These findings highlight the need to address healthcare-system barriers to ensure equitable implementation of contemporary HCM therapies.

Arrhythmogenic cardiomyopathy (ACM) is an inherited disease characterized by fibrofatty remodeling and sudden cardiac death linked to desmosomal dysfunction. Yet, 40% of cases remain genetically unexplained, and non-desmosomal mutations offer insight into ACM pathophysiology. Myoferlin (MYOF), a calcium (Ca2+)-binding protein in cardiomyocytes, is linked to cardiomyopathy, but its mechanism remains unknown. Whole-exome sequencing identified a heterozygous MYOF missense variant (p.G1654S) in an ACM family; we subsequently found three unrelated p.G1654S cases. We hypothesized that MYOF deficiency promotes Ca2+ handling deficits and arrhythmogenesis in ACM. In patient iPSC-derived cardiomyocytes, MYOF p.G1654S protein dimerized with wild-type protein and underwent accelerated lysosomal degradation, showed disrupted Ca2+ handling, and displayed increased arrhythmia burden, all rescued by genomic correction. MYOF interacted with CaV1.2, and verapamil pharmacologically rescued arrhythmias. Heterozygous Myof knockout mice showed systolic dysfunction and fibrosis. These findings establish MYOF as a causative ACM gene and therapeutic target that mediates arrhythmogenesis by disrupting MYOF-CaV1.2.

Background: Glucagon-like peptide-1 receptor agonists (GLP1-RA) improve cardiovascular outcomes in patients with type 2 diabetes (T2D) and obesity, and more recently they have been shown to be beneficial in patients with obesity and heart failure with preserved ejection fraction. Their role in patients with heart failure and reduced ejection fraction (HFrEF) and T2D remains underexplored. Methods: A retrospective cohort study was conducted using data pooled from the TriNetX platform. Patients with T2D and HFrEF who were initiated on GLP1-RA therapy during the period May-13-2026 to Jun-6-2026 were identified. One:one propensity-score matching with controls was performed. Time-to-event analysis was conducted to compare the one-year incidences of all-cause mortality and a primary composite outcome of acute myocardial infarction, ischemic stroke and acute heart failure, between the two matched-cohorts. Secondary outcomes included individual components of the primary composite outcome and any inhospital encounter. Results: Two well-matched cohorts with 38,879 patients in each were formed. Patients treated with GLP1-RAs had a lower incidence of all-cause mortality (4.2% vs. 12%; absolute risk difference [ARD] -7.8, 95% CI -8.17 to -7.41; HR 0.4, 95% CI 0.34[boxh]0.38) and the primary composite outcome (32.5% vs. 48.3%; ARD -15.8, 95% CI -16.47 to -15.11; HR 0.6, 95% CI 0.57[boxh]0.60) compared to the control group. The GLP1-RA group were also at lower risk of all secondary outcomes compared to the control group. Conclusion: In a real-world study, GLP1-RA therapy was associated with lower risk of all-cause mortality and cardiovascular outcomes in patients with T2D and HFrEF.

Background. Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events in almost any organ. While myocarditis has received the most attention, data on pericardial disease with ICI use are limited. We examined pericardial adverse event reporting with nine ICIs using the FDA Adverse Event Reporting System (FAERS). Methods. We combined legacy AERS and current FAERS quarterly files from January 2011 to June 2026 into 18,629,240 unique cases, deduplicated by case number, and removed cases the FDA had listed as deleted. ICI exposure was identified from generic names, brand names, development code names and the active-ingredient field. Pericardial events were defined by seven MedDRA preferred terms. We estimated reporting odds ratios (ROR), proportional reporting ratios (PRR), Bayesian information components (IC) and empirical Bayes geometric means (EBGM). We also examined myocarditis co-reporting, time trends, a comparison with other antineoplastic agents, a MedDRA query-based outcome, and 14 alternative definitions. Results. The analysis included 18,514,045 cases: 277,434 involved an ICI, 34,792 carried a pericardial term, and 1,680 had both. Pericardial events were reported disproportionately with ICIs (ROR 3.35 (95% CI 3.19 to 3.52); PRR 3.34; IC025 1.62). Eight of nine agents had a ROR above 1 (3.32 to 5.63). Among the most frequently reported terms, estimates were highest for cardiac tamponade (5.59 (95% CI 4.98 to 6.28)), followed by pericardial effusion (3.83 (95% CI 3.60 to 4.07)) and pericarditis (2.09 (95% CI 1.89 to 2.31)). After removing cases that also reported myocarditis, the ROR was 3.13 (95% CI 2.98 to 3.30). Most sensitivity analyses gave similar estimates (ROR 3.13 to 3.47); defining exposure by generic drug names alone, which identified only 44% of exposed cases, gave 3.99. Compared with cases naming other L01 antineoplastic agents, the ROR was 1.13 (95% CI 1.08 to 1.19): 1.28 (95% CI 1.20 to 1.36) for ICI-only cases and 0.96 (95% CI 0.89 to 1.04) when another antineoplastic was also named. The ICI-specific reporting odds ratio fell each quarter (odds ratio 0.977 per quarter, 95% CI 0.973 to 0.980). Conclusions. In FAERS, pericardial events were reported more often with ICIs than with other drugs across most agents and terms; however, incidence and causation cannot be determined. The excess over other antineoplastic agents was small, and reporting disproportionality declined over time. These findings support clinical awareness of pericardial disease in patients receiving ICIs and warrant study in data that can measure incidence.

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of the more than 64 million heart failure cases globally, yet its pathophysiology is incompletely understood, its molecular determinants are poorly defined, and disease-specific therapies remain limited. Comprehensive characterization of the cardiac motion abnormalities central to HFpEF has not been feasible at the population level. Methods: We developed a deep learning framework integrating image segmentation with optical flow motion analysis and applied it to standard cine cardiac magnetic resonance images from 83,569 UK Biobank participants, deriving 32 myocardial and inner cavity velocity phenotypes spanning the cardiac cycle, including mid-diastolic velocities not previously quantified at population scale. We examined the prognostic relevance, genetic architecture, and candidate causal mediators of the optical flow velocity phenotypes. Results: In a pragmatically defined HFpEF subcohort, mid-diastolic and late-diastolic optical flow velocities were reduced relative to healthy reference participants, while higher systolic left ventricular myocardial velocity was associated with lower all-cause mortality (HR 0.61 per SD; 95% CI 0.45-0.82). Genome-wide association analyses identified 12 risk loci associated with optical flow velocity phenotypes. Phospholamban (PLN), the canonical regulator of sarcoplasmic reticulum calcium reuptake, demonstrated the broadest pleiotropy across all cardiac phases. SOX5, a transcription factor involved in extracellular matrix development, showed significant genome-wide association exclusively with mid-diastolic velocities. Mendelian randomization implicated RABGAP1L as a candidate causal mediator of early diastolic velocity (IVW {beta} = -0.255 per NPX for early diastolic right ventricular inner circumferential velocity; p = 5.49 x 10^-22), nominating a calcium-handling pathway in diastolic dysfunction. Conclusion: Genetic and causal-inference evidence implicates intracellular calcium handling and extracellular matrix remodeling as candidate mechanisms underlying diastolic dysfunction. Together, this work establishes deep-learning-enabled cardiac motion phenotyping as a scalable approach to interrogate the molecular basis of HFpEF and nominates candidate targets for therapeutic development.

Objective: Rare STAB2 loss-of-function variants emerged in population studies as being associated with elevated venous thromboembolism (VTE) risk. STAB2 encodes the cell-surface scavenger receptor stabilin-2, and reduced stabilin-2 function might increase VTE risk via elevated plasma levels of its ligands, including von Willebrand factor (VWF) and coagulation factor VIII (FVIII). Approach and Results: A 13-year-old patient with dependency on parenteral nutrition had experienced episodes of central venous catheter-related thrombosis, including the complete thrombotic occlusion of the deep pelvic veins, and pulmonary embolism. Exome sequencing for increased VTE risk identified a homozygous STAB2 splice-site variant and its effect on splicing was characterized in fibroblast-derived RNA and in a minigene splicing system. Plasma VWF, FVIII, and fibrinogen and serum hyaluronic acid (HA) levels were determined. Immunohistochemistry was performed on liver biopsy tissue. The STAB2 splice-site variant caused aberrant STAB2 mRNA splicing. The patient's healthy mother and one healthy sibling were also homozygous for the STAB2 splice-site variant but had no history of VTE. Plasma FVIII levels and VWF activity were elevated in all three, and VWF antigen was elevated in two homozygous individuals. Strikingly, approximately 1000-fold elevated HA levels were observed in all three homozygous individuals. Stabilin-2 immunohistochemistry on a liver biopsy from the proband's mother revealed no detectable signal, whereas control human liver showed strong labelling of liver sinusoidal endothelial cells. The STAB2 splice-site variant thus results in loss of detectable stabilin-2 protein. Conclusion: To current knowledge, this is the first family-based report of stabilin-2 deficiency with markedly elevated circulating HA, VWF, and FVIII levels in humans. These findings support impaired stabilin-2-dependent ligand clearance as a thrombosis susceptibility state with incomplete penetrance. The data are consistent with a significant role for stabilin-2 in circulating HA clearance in humans, but do not establish elevated HA itself as a cause of VTE.

Preoperative anaemia is common in adults undergoing cardiac surgery and may identify patients at increased perioperative risk. This systematic review and meta-analysis synthesised contemporary observational evidence in accordance with PRISMA 2020. Five databases were searched for peer-reviewed English language studies published from 2017 to July 2026. Random effects meta-analyses used restricted maximum likelihood estimation with Hartung-Knapp confidence intervals; crude exact count estimates were synthesised primarily and adjusted estimates separately. Fourteen observational cohort studies involving 74,571 adults, including 17,349 (23.3%) with anaemia, were included. Preoperative anaemia was associated with red cell transfusion (OR, 3.66; 95% CI, 2.14-6.24), acute kidney injury or renal failure (OR, 2.43; 95% CI, 1.84-3.21), early mortality (OR, 2.11; 95% CI, 1.40-3.17), and postoperative infection (OR, 1.49; 95% CI, 1.21-1.82), but not postoperative stroke (OR, 1.16; 95% CI, 0.43-3.17). Certainty was low for renal outcomes and very low for the other outcomes. Preoperative anaemia is an important perioperative risk marker, particularly for transfusion and renal complications, although causality cannot be established.

BackgroundThe progression of abdominal aortic aneurysm (AAA) is closely associated with the phenotypic switch of vascular smooth muscle cells (VSMC). While members of the Serine/Arginine-rich splicing factor (SRs) superfamily are increasingly acknowledged for their pivotal role in modulating cell phenotype, the specific contribution of these factors to AAA development has remained underexplored. MethodsThrough integrated analyses the whole transcriptome of human and murine AAA tissues derived from clinical samples and animal models, we identified serine-arginine repeat matrix 4 (SRRM4) as a candidate gene regulating AAA formation. To investigate the role of SRRM4 in AAA formation, we used global and VSMC-specific SRRM4-knockout mice to construct AAA mouse models in two different ways. The impact of SRRM4 on AAA was further investigated in in vivo and in vitro models ResultsElevated levels of SRRM4 mRNA and protein were observed in VSMC from both human and murine AAA tissues. Targeted silencing of SRRM4 in VSMC (but not in endothelial or myeloid cells) significantly attenuated AAA formation in both AngII- and CaCl2-induced mouse models. Our results identify the RE1 silencing transcription factor (REST) as a critical target gene of SRRM4 in AAA, a master regulator of cellular phenotypic stability. We show that SRRM4 modulates VSMC phenotype through alternative splicing of the REST gene, resulting in a non-functional REST4 isoform. Furthermore, our study shows that REST directly represses STAT1, a mechanism by which SRRM4 influences VSMC phenotypic transition. Regarding clinical significance, inhibition of both STAT1 expression and function was shown to be beneficial in preventing AAA formation and slowing disease progression in mouse models. ConclusionsThis investigation uncovers a previously unrecognized role of SRRM4-mediated splicing of the REST gene in the progression of AAA and identifies a novel REST/STAT1 axis critical in the phenotypic modulation of VSMC. The findings of this study may provide insights for the development of innovative therapeutic strategies for AAA. What is New?O_LIOur study demonstrates that the RNA splicing factor SRRM4 (serine/arginine repetitive matrix 4) expression is increased in human and murine abdominal aortic aneurysm (AAA) tissues and unveils a previously undescribed role of SRRM4 in regulating AAA development. C_LIO_LISRRM4 promotes AAA development and progression through inducing splicing of REST (RE1 silencing transcription factor) gene and upregulating STAT1 (signal transducer and activator of transcription 1) expression, which result in extracellular matrix degradation, inflammation, and VSMC phenotypic switching. C_LIO_LIOur study provides proof-of-concept evidence indicating the therapeutic value of STAT1 inhibition in AAA prevention and treatment. C_LI What Are the Clinical Implications?O_LIOur study defining a novel mechanism underlying the SRRM4/REST/STAT1 axis is crucial for developing new therapeutic strategies for AAA. C_LIO_LIBased on these findings, we have initiated a prospective study (REST4-AAA; ClinicalTrials.gov Identifier: NCT07056491) to evaluate REST4 expression levels in serum of AAA patients and explore its potential as a serum biomarker for AAA prediction C_LIO_LIOur findings indicate that fludarabine, a clinically available agent reported to selectively suppress STAT1, effectively attenuates AAA progression in mice, suggesting its potential for repurposing as a therapeutic strategy for AAA. C_LI

Brugada syndrome (BrS) is an inherited arrhythmia disorder with limited drug therapy, quinidine being the principal agent. Loss-of-function variants in SCN5A reduce the cardiac sodium current (INa), but the arrhythmogenic imbalance also depends on the transient outward potassium current (Ito). Here we generated human induced pluripotent stem cell-derived cardioids with right-ventricular identity from a patient carrying an SCN5A frameshift variant (p.A665Gfs*16) and characterised them by patch-clamp and optical mapping. BrS cardioids showed 60% lower peak INa, more than doubled Ito, 38% slower conduction and 76% longer spontaneous cycle length. We then tested AR-788, a benzylaminothiazole-benzimidazole carboxamide of the ARumenamide class. In wild-type (WT) cardiomyocytes AR-788 inhibited Ito concentration-dependently (12%, 30% and 42% at 5, 10 and 20 uM; extrapolated IC50 25.4 uM), and at 10 uM it returned BrS Ito to the level of untreated WT cells (21.71 vs 21.48 pA/pF, p = 0.9716) without reducing INa. It also reduced the rapid delayed-rectifier current (IKr) tail current by 40%, a liability requiring formal proarrhythmia profiling. These data identify AR-788 as an Ito-suppressing member of the ARumenamide class and provide proof of concept that a small molecule can correct the potassium-current excess in a human BrS model.

Background: Myocardial infarction (MI) and heart failure (HF) impose a physical and emotional toll that has not been measured nationally with a standard instrument. Methods: We pooled the 2019 to 2024 Medical Expenditure Panel Survey into 4 mutually exclusive groups of adults aged 18 and older: MI without HF, HF without MI, both conditions, and neither condition. Quality of life was assessed with the Veterans RAND 12-item component summaries, T scores (mean 50, SD 10) on which higher is better and 3 points is minimally important. Survey-weighted linear regression adjusted for demographics, socioeconomic factors, and comorbidity. Results: Among 79,853 adults representing 253.8 million US adults, 4.2% (3,340) had MI alone, 0.6% (480) HF alone, and 0.3% (236) both. Unadjusted physical scores ranged from 33.2 with HF alone to 39.1 with MI alone, versus 50.5 with neither. Adjusted physical scores were lower by 3.84 points (95% CI, 3.20-4.47) with MI alone, 8.32 (95% CI, 7.04-9.61) with HF alone, and 7.74 (95% CI, 5.73-9.76) with both, each beyond the minimally important threshold. Adjusted mental scores were lower by 1.35 points with MI alone, 1.20 with HF alone, and 1.69 with both, all below that threshold. Adults with both conditions did not differ from those with HF alone (0.58 points; 95% CI, -1.76 to 2.92). Emergency visits, inpatient discharges, and expenditure were higher in every cardiac group and highest with both conditions, where annual expenditure reached $37,198 versus $7,845 with neither. Conclusions: Physical quality of life fell steadily across the cardiac groups, with HF rather than prior MI accounting for most of it. The difference in mental quality of life did not persist after adjustment. Utilization and spending were highest with both conditions.

BackgroundMacitentan is a dual endothelin receptor antagonist used in pulmonary arterial hypertension (PAH) and has also been studied in other forms of pulmonary hypertension (PH). Evidence across PH phenotypes has been heterogeneous. This study aims to evaluate the efficacy and safety of macitentan compared with concurrent control therapies across PH phenotypes and to explore whether treatment effects differ according to PH classification. MethodsPubMed, Embase, and the Cochrane database were searched from inception through June 2026. Randomized and non-randomized comparative studies of patients with PH receiving macitentan were eligible. Prespecified efficacy outcomes were 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), and cardiac index; prespecified safety outcomes included mortality and adverse events. Random-effects meta-analyses were performed using mean differences (MDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes. ResultsFourteen studies met the eligibility criteria. Macitentan was associated with a greater reduction in PVR (MD, -134.50 dyn.s.cm; 95% CI, -226.10 to -42.86) and an increase in cardiac index (MD, 0.44 L/min/m; 95% CI, 0.22 to 0.67). No statistically significant difference was observed for 6MWD (MD, 5.04 m; 95% CI, -15.06 to 25.14) or mPAP (MD, -2.70 mmHg; 95% CI, -6.46 to 1.05). In pooled safety analyses, mortality was lower and risks of anemia, peripheral edema, and discontinuation due to adverse events were higher with macitentan. Heterogeneity and the small number of studies within several phenotype-specific analyses limited the precision of subgroup findings. ConclusionsMacitentan-containing therapy was associated with favorable changes in selected hemodynamic outcomes but not with a statistically significant improvement in 6MWD or mPAP. The safety findings were characterized by higher risks of anemia, peripheral edema, and treatment discontinuation. These results should be interpreted in the context of differences in PH phenotype, dose, comparator, study design, and outcome measurement.

Background: The systemic immune-inflammation index (SII) is a routinely available blood-derived marker with potential prognostic relevance after coronary artery bypass grafting (CABG). We evaluated associations between preoperative SII and postoperative outcomes. Methods: PubMed, Embase, Scopus and Web of Science were searched to 1 October 2026, with supplementary searches through 14 October 2026. Peer-reviewed observational studies evaluating preoperative SII in adults undergoing CABG were eligible. Methodological quality was assessed using the Newcastle-Ottawa Scale. Compatible categorical associations and exploratory adjusted continuous mortality effects were pooled separately using restricted maximum-likelihood random-effects models; other findings were summarized descriptively. Results: Thirty-one reports were included, with an aggregate sample of 30,976 and possible cohort overlap; five contributed to meta-analysis. Two off-pump cohorts comprising 1,378 patients and 180 atrial-fibrillation events yielded an imprecise crude association with postoperative atrial fibrillation (OR 1.60, 95%CI 0.53-4.82; I2=68%). An exploratory crude synthesis indicated greater intra-aortic balloon pump use with higher SII (OR 2.45, 95%CI 1.16-5.18; I2=51%). Two cohorts with differing follow-up yielded an exploratory adjusted mortality HR of 1.11 (95% Wald CI 1.05-1.18) per study-specific SD increase in log-SII. In one 624-patient cohort, high SII was associated with postoperative acute kidney injury after adjustment (OR 3.35, 95% CI 2.25-4.97).Apparent atrial-fibrillation discrimination varied (AUC 0.587-0.946). Conclusions: Preoperative SII showed associations with selected adverse outcomes after CABG, supporting further evaluation as an accessible prognostic marker. Its incremental value beyond established clinical risk models requires validation. Keywords: Systemic immune-inflammation index; Coronary artery bypass grafting; Atrial fibrillation; Prognosis; Systematic review

The biomechanical properties of the human aorta play a key role in cardiovascular function and disease, yet their population-wide trends and variations remain largely unknown. To fill this crucial gap, we quantified variations in aortic size, stiffness and stresses across 57,434 individuals from the UK Biobank using two-dimensional cine MR imaging and a combined deep-learning, probabilistic and biomechanical modelling framework. Aortic diameter and distensibility (inverse of stiffness) were calculated for the ascending and descending aorta, and their conditional distributions were characterised as a function of age, sex, body size and blood pressure. These observations were integrated with ex-vivo tissue mechanics to infer stress distributions across the aortic wall and the associated uncertainty. Our analysis revealed several new relationships. Larger aortas were found to be stiffer, and greater body size (height and/or weight) was associated with larger aortas with no change in stiffness. Aortic distensibility was negatively associated with systolic, but not diastolic, blood pressure. Apparent sex differences in aortic size were substantially reduced after accounting for body size. Importantly, the maximum stress was found to depend not only on aortic size, as previously thought, but also on distensibility, with lower distensibility associated with higher stresses. The results provide first-of-their-kind population-scale reference distributions for human aortic stiffness, which will improve the personalisation of computational models and digital twins. The correlation between stress and distensibility strongly supports progressing beyond the current diameter-based criteria (based on the law of Laplace) and for the inclusion of stiffness in the clinical risk assessment of aortic diseases. Overall, this study forms the foundation for personalised quantitative medicine and biomechanically informed risk stratification of aortic aneurysms and dissections.

Background: Localized or segmental overgrowth is a rare condition that may co-occur with vascular malformations. These diseases generally are caused by somatic mutations in the PI3K/AKT/mTOR pathway. Most lesions are progressive and may cause symptoms including pain, functional impairment, and disfigurement. Treatment options are limited, especially for the overgrowth component. Objective: To evaluate the efficacy and safety of the mTOR inhibitor sirolimus in patients with overgrowth with or without a vascular malformation over a 6-months treatment period. Methods: We conducted a single-arm, open-label, phase II study including 18 patients (12 pediatric, six adult) with overgrowth, all of whom initiated oral sirolimus. 16/18 (88.9%) participants received oral sirolimus for 6 months, with dosing adjusted to achieve target blood trough levels of 3-8 ng/mL. Primary outcome was radiological response at six months assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary outcome parameters were evaluated at three, six and nine months and included size and visual appearance of the overgrowth, quality of life (QoL), pain intensity, performance status, and safety. Results: No patient achieved complete or partial radiological response. 17 of 18 patients (94.4%) maintained stable disease at month six; one was not evaluable. QoL measured with WHOQOL-BREF improved modestly in patients aged >= 18 years (n=5, mean difference to baseline +9.3 (95%-CI: -0.9 to 19.5) in physical and +9.2 (95%-CI: 0.7 to 17.7) in psychological domains at month 6). In pediatric participants, no relevant improvement in KINDL total scores was observed over the study period. No significant changes occurred in pain scores. Performance status measured by the Lansky/Karnofsky scales showed minor improvement (mean +3.5 points (95%-CI: 1.0 to 6.1)). All patients experienced at least one adverse event, but no serious adverse events or CTCAE v5.0 grade [&ge;]3 toxicities occurred. Sirolimus was well tolerated. Six patients decided to resume sirolimus after study completion. Conclusions: Sirolimus induced minor lesion shrinkage in a subset of patients, although this did not meet the predefined radiological RECIST endpoint. However, sirolimus can lead to functional improvement in some adults, which may indicate that the primary radiological outcome did not capture patient-perceived benefit.