Circulation: Genomic and Precision Medicine

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: Metabolic perturbations associated with cardiovascular disease (CVD) risk factors prior to clinical disease manifestation may inform novel preventative measures. Here we characterize metabolome-wide associations with various cardiometabolic risk factors in an asymptomatic population to develop a mechanistic metabolic framework of preemergent metabolic shifts. Methods: Plasma was collected from a clinically healthy cross-sectional cohort (n = 361; Clinical Trials.gov ID: NCT02367287). Cohort mass spectrometry-based metabolomics (biocrates MxP(R) Quant 500 kits) were complemented with expanded lipidomic coverage for a sex/age-matched subset with LDLc difference > 60 mg/dL (n = 38). LDLc-focused partial least square regressions and discriminate analyses were performed, after false discovery rate corrections. Results: As LDLc levels increased, plasma sphingolipids and cholesteryl esters, and transulfuration products were higher, while ether-linked phosphatidylcholines serine, glycine, alanine, methionine were lower. The subset analysis further highlighted elevations in triglycerides and deoxyceramides with elevated LDLc. When adjusted for alanine concentrations, deoxyceramide concentrations increased as serine declined (p = 0.0012), and the deoxyceramide:ceramide ratios were higher in the high LDLc group (p = 0.039). Lower serine levels were also accompanied by parallel changes in glycine (p= 0.0004), and anti-parallel changes in transsulfuration pathway metabolites particularly when adjusted for ceramide levels. Notably, the alanine:serine ratio was more strongly associated with fasting triglycerides (r = 0.38; p <0.0001) than LDLc. Conclusions: Serine depletion by increased demands of sphingolipid, and possibly transsulfuration pathway, metabolism is associated with elevations in cytotoxic deoxyceramides and reductions in glycine and methionine availability for one-carbon metabolism. These changes were strongly associated with fasting triglycerides and insulin resistance, a key marker of residual CVD risk.

BACKGROUND: The chromosome 9p21.3 locus is among the strongest genetic risk loci for cardiovascular disease (CVD), yet the regulatory mechanisms underlying this association remain poorly understood. Previous vascular disease studies focused predominantly on the role of this locus in smooth muscle cell (SMC) dysfunction, whereas its potential role in endothelial cells (ECs) remains less well characterized. Here, we sought to identify candidate regulatory variants at 9p21.3, their distal target genes, and effector transcripts that contribute to CVD-related phenotypes in ECs. METHODS: Promoter capture Hi-C was used to map chromatin interactions at 9p21.3 in primary human ascending aortic SMCs (n=6), supplementing the previously obtained ECs (n=16) dataset. To support the regulatory relevance of these interactions, expression quantitative trait locus analysis was performed in 136 vascular biopsies. Variant effects were prioritized in silico using AlphaGenome. The regulatory activity of the prioritized region was validated using CRISPR activation. RESULTS: Chromatin interaction mapping identified a complex regulatory architecture at the 9p21.3 locus involving 19 putative regulatory elements and 15 genes across ECs and SMCs. MIR31HG showed the most recurrent distal promoter connectivity with the 9p21.3 region. Consistent with the chromatin interaction map, expression of MIR31HG transcripts was associated with genetic variation at the 9p21.3 locus. In ECs, the lncRNA MIR31HG, but not miR-31, was responsive to hemodynamic flow. Depletion of MIR31HG in ECs was associated with endothelial activation. Epigenetic tracks and deep learning predictions highlighted an active enhancer element at 9p21.3, which was subsequently validated by CRISPR activation and increased MIR31HG expression, confirming its capacity to regulate MIR31HG over a large genomic distance of approximately 538 kb. CONCLUSIONS: Altogether, these data implicate lncRNA MIR31HG as a likely effector of the 9p21.3 CVD locus, linking the cis-regulatory element and heritable genetic variation in the respective region to endothelial activation through long-range enhancer regulation.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation, and pathogenic variants in LMNA are a well-established cause of inherited DCM. The LMNA gene encodes nuclear lamins A/C, which maintain nuclear integrity, regulate gene expression and mediate mechanotransduction. Here, we investigated the pathogenic consequences of the NM_170707.4(LMNA):c.274C>T NP_733821.1:p.(Leu92Phe) variant, previously associated with lipodystrophy features, using patient-derived induced pluripotent stem cells, differentiated into cardiomyocytes and show implication of LMNA in sarcomere remodeling and mitochondria efficiency. We generated iPSC lines from two DCM patients carrying LMNA p.Leu92Phe variant in heterozygous form and a healthy parental control. Cardiomyocytes differentiation efficiency was preserved, however, LMNAp.Leu92Phe iPSC-CMs exhibited laminopathies associated phenotypes, such as nuclear shape abnormalities and lamin A/C aggregation. Moreover, in vitro study revealed that LMNA p.Leu92Phe iPSC-CMs alter sarcomere reformation and decrease mitochondrial respiration after cardiomyocyte remodeling, which is associated with a worsening nuclear shape phenotype. Functional analyses highlight defects in calcium handling, thereby explaining arrhythmia and dilated cardiomyopathy features in patients. Our results show that the LMNA p.Leu92Phe variant compromises nuclear lamina integrity and disrupts functional cardiomyocyte properties, particularly during sarcomere remodeling, highlighting the long-term impact of this specific variant in LMNA-associated DCM.

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.

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.

Standard polygenic risk scores capture overall genetic liability to coronary artery disease (CAD) but do not reveal the biological processes contributing to risk in an individual. Here, we applied data-driven latent factor decomposition to 526 genome-wide significant CAD-associated variants, using their associations with 78 CAD-related phenotypic traits. We identified eight genetic components corresponding to cholesterol-enriched lipoproteins, triglyceride-rich lipoproteins, lipoprotein(a), metabolically unhealthy normal weight, obesity, endothelial dysfunction, coagulation and cardiac remodeling. Process-specific polygenic risk scores (pPRSs) captured biological profiles beyond those reflected by conventional risk factors. In UK Biobank (n = 458,905), the Swedish CArdioPulmonary bioImage Study (n = 24,904) and Mass General Brigham Biobank (n = 53,848), pPRSs were consistently associated with clinical and subclinical CAD and showed distinct biomarker, proteomic and comorbidity profiles. These findings establish a framework for biologically resolved genetic CAD risk and may inform process-specific approaches to precision prevention.

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: Coronary perivascular fat attenuation index score (FAI-Score) on coronary computed tomography angiography (CCTA) quantifies vascular inflammation and predicts cardiac mortality in symptomatic cohorts. However, its prevalence, anatomical distribution, and clinical correlates in asymptomatic primary prevention populations remain uncharacterized. Methods: In an IRB-approved prospective study across two clinical sites, 84 consecutive asymptomatic adults (mean age 53.7 {+/-} 8.6 years; 63.1% men) with no prior coronary artery disease underwent screening CCTA and comprehensive clinical, metabolic, and biomarker profiling. AI-standardized FAI-Score was quantified across three epicardial vessels (LAD, LCx, RCA). High and very high perivascular inflammation were pre-specified as any vessel [&ge;]75th and [&ge;]90th percentiles, respectively. Luminal stenosis and plaque were graded using CAD-RADS 2.0. Results: Elevated FAI-Score ([&ge;]75th percentile) was present in 42.9% of participants (36/84; 95% CI 32.8% - 53.5%), with 17.9% (15/84; 95% CI 11.1% - 27.4%) exhibiting very high inflammation ([&ge;]90th percentile). Multi-vessel inflammation was identified in 17.9% (15/84), with the RCA most frequently involved ([&ge;]90th percentile in 13.1%). Standard circulating biomarkers, including ApoB, non-HDL-C, HbA1c, and PREVENT-ASCVD 10-year risk showed no association with binary inflammation. Systemic hs-CRP (median 0.8 mg/L) exhibited an inverse correlation with maximum vessel FAI-Score (Spearman {rho}=-0.27, p=0.014). Men demonstrated higher rates of elevated FAI-Score than women (52.8% vs. 25.8%, p=0.016; [&ge;]90th percentile: 26.4% vs. 3.2%, p=0.007). Strikingly, 46.2% (30/65) of participants with normal luminal anatomy (CAD-RADS 0) and 47.2% (25/53) with zero plaque burden harbored elevated FAI-Score; all 15 individuals with very high FAI-Score had CAD-RADS 0 (Fisher's exact p=0.018). Body mass index was the sole secondary correlate surviving false discovery rate correction (AUC = 0.71, p=0.001, all-test FDR q=0.028). Regularized multivariable models showed modest out-of-sample discrimination for FAI-Score elevation (cross-validated AUC = 0.71). Conclusions: Coronary perivascular inflammation is common among asymptomatic adults and frequently uncouples from structural plaque and luminal stenosis. Routine circulating biomarkers and clinical risk calculators fail to identify inflamed vessels, highlighting FAI-Score as an independent dimension of primary cardiovascular risk assessment.

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: 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.

Despite the widespread use of L-type calcium channel blockers (CCBs), recent observational and murine functional work has suggested a potential adverse effect of this medication class on the aorta. Here, we apply a Mendelian randomization (MR) framework to assess the potential causal role of CACNA1C - the principal target of L-type CCBs in the human aorta - on thoracic aortic aneurysm and dissection (TAA/D). Genetic instrumental variables were derived from aortic expression quantitative trait locus data, and combined with large-scale genome-wide association data of TAA/D and ascending aortic diameter. Mirroring the on-target vascular effects of L-type CCBs, higher genetically predicted CACNA1C expression was linked to higher blood pressure, and to higher risks of hypertension and coronary artery disease. In contrast, higher predicted aortic expression of CACNA1C was linked to lower risk of TAA/D ({beta}=-0.18, P=0.005) and to a smaller ascending aortic diameter in the general population ({beta}=-0.08, P=0.005). While we caution against overinterpretation of our MR results in isolation, the convergence with observational and functional data calls for dedicated clinical trials to assess the safety of CCBs in the context of aortic disease.

BackgroundClonal hematopoiesis of indeterminate potential (CHIP) is associated with ageing and atherosclerotic coronary artery disease (CAD), but evidence has largely come from peripheral blood. Whether somatic mutational profiles differ between arterial tissue and blood, and whether hematopoietic clones are represented in arterial tissue, remain poorly understood. MethodsWe performed deep whole-exome sequencing on 302 blood granulocytes and 263 arterial tissues from patients undergoing coronary artery bypass graft surgery, including 221 matched blood-tissue pairs, with mean sequencing depths of 130.5X and 120.8X, respectively. Somatic variants were identified using Mutect2. Associations with age and CAD complexity, assessed using SYNTAX score, were evaluated using multivariable regression. Primary analyses focused on variants with variant allele fractions of 10-25%. ResultsCHIP was detected in 24/302 (7.9%) blood granulocytes, predominantly involving DNMT3A, TET2, and ASXL1. In contrast, somatic mutations in CHIP-associated genes in arterial tissues showed a distinct profile dominated by CALR, SETDB1, and PDSS2. Somatic mutation carrier status increased with age in blood ({beta} = 0.07, p = 0.02) and arterial tissues ({beta} = 0.06, p = 0.04). Blood CHIP was associated with lower SYNTAX score ({beta} = -1.05, p = 2.66 x 10-3), partly driven by DNMT3A carriers ({beta} = -1.06, p = 0.04), whereas arterial CALR mutations were associated with higher SYNTAX score ({beta} = 1.14, p = 0.03). Among 221 matched pairs, only four identical variants, involving CHEK2, DNMT3A, GNB1, and SRSF1, were detected in both compartments. Genome-wide analyses showed compartment specificity, with bile acid metabolism enriched among arterial tissue-specific mutations (PAdj = 0.038). ConclusionBlood and arterial tissues in CAD harbour distinct somatic mutational landscapes with limited cross-compartment sharing. These findings suggest that cardiovascular somatic mutations may reflect both hematopoietic and arterial tissue-associated processes and motivate cell-resolved and spatial studies to define their origins and roles in cardiovascular ageing.

Standard cardiac biomarkers such as ejection fraction, ventricular volumes, and strain compress complex three-dimensional heart dynamics into a small set of predefined measurements, leaving clinically important heterogeneity unrecognised. Here we propose a personalised normative cardiac framework in which each individual is compared to a digital twin representing expected healthy cardiac function given their age, sex, and body habitus. We show that structured patterns of deviation from these normative twins, discovered through systematic exploration of a generative cardiac dynamics space, constitute novel dynamic phenotypes that are not captured by conventional biomarkers. Applied independently to two UK Biobank cardiac cohorts with distinct shape representation, a 128-dimensional four-chamber statistical shape descriptor (HeartSSM, n = 52,365) and a 64-dimensional deep generative latent space from a conditional variational mesh autoencoder (MeshHeart cVAE, n = up to 39,376), we identify reproducible, continuous deviation-from-normative-twin scores (three discrete deviation phenotypes in the HeartSSM cohort) that improve cardiovascular risk stratification beyond ejection fraction, ventricular volumes, myocardial mass, and strain. The strongest effect was seen for incident atrial fibrillation among individuals with preserved ejection fraction (at least 50%): incremental C-index delta C = +0.068 (5-fold cross-validated delta C = +0.063; likelihood-ratio P = 3.3 x 10^-8), with a separate, smaller effect for incident stroke in the same preserved-EF subgroup in the independent MeshHeart cVAE representation (which showed no signal for atrial fibrillation) (delta C = +0.024, P = 2.6 x 10^-4). Both effects were checked against placebo controls in which the deviation scores were replaced by Gaussian noise. To test whether the normative twin generalises beyond UK Biobank's specific scanning and processing pipeline, we applied the MeshHeart cVAE normative twin, unmodified, to an independent external cohort of healthy volunteers imaged at a different hospital (GenScan/Hammersmith, n = 315): deviation scores in this cohort were of comparable magnitude to the UK Biobank healthy reference (ratio of means = 1.09; Mann-Whitney P = 1.4 x 10^-5), indicating that the normative twin captures cross-site-transferable structure rather than a scanner- or pipeline-specific artefact. Our findings suggest that cardiac phenotyping can move beyond predefined measurements toward data-driven dynamic phenotypes that better capture the heterogeneity underlying cardiovascular disease risk, even among individuals whose ejection fraction appears normal.

Background Non-communicable diseases (NCDs) impose substantial population burden. Their polygenic architecture informs early risk stratification through polygenic risk scores (PRS). Previous studies reported elevated-PRS burden comparable to some modifiable risk factors (MRFs), yet evidence remains confined to European populations. We quantified the PRS-attributable NCD burden in Taiwan. Methods Linking Taiwan Biobank and National Health Insurance Research Database (N = 140K), we analyzed 42 high-burden NCDs. Elevated genetic risk (PRSe; top 10%) was assessed using Cox models. We estimated population attributable fractions (PAFs) and disability-adjusted life years (DALYs) using Taiwan-specific estimates from Global Burden of Disease 2023, and examined associations between an integrated PRS (iPRS) and healthcare utilization. Findings Strongest PRSe associations occurred for atrial fibrillation (AFib; HR = 3.56 [95% CI: 3.23-3.92]) and gout (2.41 [2.33-2.49]), yielding PAFs of 20% and 12%, respectively, while population-level attributable DALYs were largest for type 2 diabetes (T2D), intracranial hemorrhage (ICH), and lung cancer. At the individual level, PRS_e corresponded to 1.50 [1.42-1.57] healthy life-years lost for T2D and 0.57 [0.40-0.76] for ICH, approaching 2.4 years for the top 1% PRS. Polygenic attributable burden was overall greater in men. For several diseases, PRS_e-associated PAF and DALYs exceeded those of individual MRFs (e.g., smoking, alcohol use). Top-decile iPRS was linked to 23.9% (15.0-33.6%) more hospital days, 19.1% (13.2-25.3%) more inpatient visits, and 9.6% (6.9-12.4%) more outpatient visits. Interpretation Polygenic risk accounts for a measurable--and for several diseases, MRF-comparable--share of NCD burden in Taiwan, providing a quantitative foundation for integrating genetic liability into preventive care and health planning.

Background: Loss- and gain-of-function variants in SCN5A, encoding the cardiac sodium channel Nav1.5, are major causes of inherited cardiac channelopathies. Their pathophysiology has almost exclusively been attributed to altered cardiomyocyte excitability and cardiac conduction. However, growing evidence indicates that autonomic dysfunction contributes to these disorders, raising the possibility that Nav1.5 dysfunction may also affect the intrinsic cardiac nervous system. Objectives: We investigated whether Nav1.5 is functionally expressed in murine intrinsic cardiac neurons and evaluated its contribution to neuronal excitability. Methods: Scn5a expression was investigated by digital PCR and immunocytochemistry in isolated murine intracardiac neurons. Whole-cell patch-clamp recordings were used to characterize sodium currents and action potential properties in wild-type and Scn5a+/- mice. Results: Scn5a transcripts and Nav1.5 protein were detected in intrinsic cardiac neurons. Voltage-clamp recordings identified a tetrodotoxin-resistant sodium current accounting for approximately 8% of the total sodium current and displaying pharmacological and biophysical properties consistent with Nav1.5. Activation and inactivation analyses indicated that Nav1.5 is the predominant sodium conductance available at most polarized membrane potentials. Accordingly, Scn5a haploinsufficiency selectively altered action potential threshold, maximal upstroke velocity, overshoot and duration in neurons resting below -60 mV, whereas more depolarized neurons were essentially unaffected. No structural or neurochemical remodeling of intrinsic cardiac ganglia was detected. Conclusion: Nav1.5 is a functional determinant of intrinsic cardiac neuronal excitability. These findings identify the intrinsic cardiac nervous system as a new cellular target of SCN5A dysfunction and suggest that inherited cardiac sodium channelopathies could involve alterations in both myocardial and intrinsic neuronal electrophysiology.

Background: Hypertension prevalence rises sharply in females after menopause, exceeding that of age-matched males in later life, conferring greater relative cardiovascular disease risk in females than in males. However, the underlying mechanisms remain poorly understood. Method: We studied multi-tissue RNA-sequencing data from 193 CVD-free participants aged >55 years in the GTEx database and extended the findings to 1,605 age-matched Framingham Heart Study participants. Results: We identified a dominant female hypertension co-expression signature in blood, expressed at lower levels in females with uncontrolled high blood pressure than in males (sex-by-hypertension interaction) in both cohorts. Genes contributing to this signature were enriched for post-transcriptional modification and insulin signalling and regulated by ETS family transcription factors (TFs). Ten ETS TFs showed the same female-specific hypertension association and together explained the signature?s expression. Moreover, in females, but not males, lower blood signature scores were associated with a pro-inflammatory transcriptome in the artery and kidneys. Conclusions: Collectively, we identified the ETS-transcriptomic axis as a potential mechanism explaining sex differences in human hypertension.

Objectives: To investigate whether genetic predisposition to hypertensive disorders of pregnancy (HDP), measured using polygenic risk scores (PRS), is associated with subsequent cardiovascular disease (CVD) outcomes in analyses stratified by HDP history. Study design and main outcome measures: This population-based cohort included 1,284 women from the 1994-95 Busselton Health Study with genotype data, pregnancy history, cardiovascular risk factors, and linked hospitalisation and death records to 2022. Four HDP-related PRS were assessed: two for preeclampsia, one for gestational hypertension, and one for broad HDP phenotype. Outcomes were incident first CVD events classified into categories. Fine-Gray competing-risk models adjusted for age, cardiovascular risk factors, and genetic principal components estimated subdistribution hazard ratios (sHR) per standard deviation increase in PRS. Results: Of 1,284 women, 309 reported a history of HDP and 651 experienced an incident CVD event during follow-up. In analyses stratified by HDP history, the largest estimates were observed for first cerebrovascular disease, although event numbers were small. The PGS003586 preeclampsia PRS showed the largest estimate (sHR 3.41, 95% confidence interval (CI) 1.54-7.58, p = 0.003), while PGS004593, another preeclampsia-related score, was also positively associated with cerebrovascular disease (sHR 1.86, 95% CI 1.05-3.30, p = 0.035). The gestational hypertension and broad HDP scores also showed positive estimates, but CI included 1.0, indicating inconclusive evidence. Conclusions: Among women with a history of HDP, preeclampsia-related PRS showed preliminary evidence of an association with incident cerebrovascular disease. Given the small number of events, findings should be interpreted cautiously and validated in larger, multi-ancestry cohorts.

We investigated the genetic basis of a previously unclassified congenital vascular anomaly in a patient with multifocal cutaneous vascular tumors. Through genomic analysis, we identified a novel heterozygous de novo germline variant in GA-binding protein-alpha (GABPA), an ETS family transcription factor. Histopathologic evaluation demonstrated capillary-venous lesions lacking glucose transporter 1 expression, distinguishing this entity from common infantile hemangioma. Notably, the tumor vasculature exhibited a prominent alpha-SMA-positive perivascular cell layer, with nuclear localized GABPA detected in endothelial and perivascular cells. The GABPA c.509T>G (p.L170R) variant is absent from large population databases, including gnomAD, DeCAF, and RGC-MCPS databases, indicating it is extremely rare. The affected leucine residue is highly conserved across species and located within the Pointed (PNT) domain, a critical region mediating GABPA protein-protein interactions. AlphaMissense predicts this substitution to be highly damaging. Structure-based analysis using an AlphaFold-predicted approach, combined with in silico mutagenesis and molecular interaction analyses, revealed that the L170R substitution introduces new electrostatic interactions while disrupting native hydrophobic contacts within the PNT domain. Functional assessment in zebrafish demonstrated that mosaic stromal expression of GABPA-L170R caused abnormal vascular architecture compared with GABPA-wild-type controls, establishing a direct link between this variant and disrupted vascular development. Collectively, the genetic rarity, evolutionary conservation, predicted structural perturbation, and disruptive effects on vascular development establish GABPA-L170R as likely disease-causing variant. These findings define a new molecular mechanism underlying congenital vascular tumor formation and expand the role for ETS-family transcriptional regulation in human vascular anomalies.

Rationale: Atrial fibrillation (AF) is sustained by electrical triggers and atrial substrate, but whether AF itself generates circulating factors that acutely reinforce arrhythmogenesis is unknown. Objective: To determine whether rhythm-dependent serum bioactivity directly destabilizes atrial electrophysiology and to identify associated cellular mechanisms and circulating mediators. Methods and Results: Cardiac samples were obtained from patients with persistent atrial fibrillation (AF) during AF and after restoration of sinus rhythm (SR) using electrical cardioversion. In isolated Langendorff-perfused mouse hearts, AF serum increased the duration, frequency, and cumulative burden of spontaneous atrial depolarizations compared with paired control perfusate. In human induced pluripotent stem cell derived atrial cardiomyocytes, AF patient serum decreased Ca2-transient amplitudes without significant effect on kinetics or Ca2 spark activity. Moreover, AF serum reduced peak sodium current without materially altering voltage-dependent gating or paced action-potential properties. Data-independent acquisition proteomics identified rhythm-associated changes in extracellular-matrix, proteolytic, inflammatory, and signaling proteins, including MMP9, Ccathepsin G, and 14-3-3 family members. Targeted pathway perturbation differentially modified serum-induced Ca2 phenotypes, indicating context-dependent, multifactorial bioactivity. Serum-induced Ca2 responses were not associated with indices of atrial disease severity, including low-voltage substrate burden and left atrial pressure. Conclusions: Persistent AF is accompanied by rhythm-dependent circulating bioactivity that acutely promotes atrial electrical instability and Ca2-dependent trigger formation. These findings extend the concept that AF begets AF beyond tissue-intrinsic remodeling and identify a potentially reversible serum-mediated feed-forward mechanism linking rhythm status and circulating proteomic signals in an atrial substrate severity independent fashion. Keywords: atrial fibrillation; serum; atrial cardiomyopathy; calcium signaling; circulating factors; proteomics