Circulation

BackgroundLong COVID postural orthostatic tachycardia syndrome (LCPOTS) is characterized by persistent orthostatic tachycardia and multiple constitutional symptoms, many of which suggest persistent inflammation. We sought to define mechanisms responsible for ongoing immune activation in LCPOTs and to determine if this is related to autonomic dysregulation. MethodsWe performed a case-control study of 25 patients with LCPOTS and 15 controls who recovered from COVID-19 without persistent autonomic sequelae. Peripheral blood mononuclear cells were analyzed by flow cytometry to quantify circulating CD3CD14 T cell-monocyte doublets, cytokine production, memory phenotype, mitochondrial ROS, and isolevuglandin (IsoLG)-adduct formation. Forster resonance energy transfer was used to assess T-cell receptor-HLA interactions within doublets. Single-cell RNA sequencing (scRNA-seq) was performed on a subset of participants, and autonomic phenotyping included orthostatic heart rate responses, heart rate variability, baroreflex sensitivity, and blood volume measurements. ResultsLCPOTS was linked to impaired cardiovagal function and greater autonomic symptom burden. It was also associated with roughly a threefold rise in circulating CD3CD14 doublets and enhanced T cell-monocyte interactions. These complexes demonstrated signs of genuine immune synapse formation and were enriched with effector-memory and TEMRA T-cell types. T cells in doublets produced higher levels of IFN-{gamma} and IL-17A, and the proportion of cytokine-producing doublets correlated with the severity of orthostatic tachycardia and total COMPASS-31 score. Monocytes from LCPOTS showed increased mitochondrial content, superoxide generation, and IsoLG-adduct accumulation, along with decreased expression of antioxidant genes, including those related to NFE2L2. ConclusionsOur findings suggest that ongoing immune activation contributes to LCPOTS pathogenesis. We propose that impaired cardiovagal regulation stimulates monocyte ROS production, promotes neoantigen formation, and T cell activation. This persistent immune response, together with disrupted mitochondrial function, likely contributes to the diverse symptoms linked to LCPOTS. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LILong COVID postural orthostatic tachycardia syndrome is associated with persistent orthostatic tachycardia and disabling orthostatic intolerance symptoms after SARS-CoV-2 infection. C_LIO_LIImmune dysregulation and oxidative stress have been implicated in long COVID, but the cellular mechanisms linking inflammation to autonomic dysfunction are not well defined. C_LIO_LICirculating T cell: monocyte doublets are a recently recognized marker of ongoing immune activation. C_LI What New Information Does This Article Contribute?O_LIPatients with LCPOTS exhibit a marked increase in circulating CD3CD14 T cell-monocyte doublets. C_LIO_LIDoublet-associated T cells are enriched for inflammatory effector-memory/TEMRA phenotypes and produce IFN-{gamma} and IL-17A in proportion to orthostatic tachycardia and autonomic symptoms severity. C_LIO_LIImpaired cardiovagal activity, monocyte mitochondrial ROS, IsoLG-adduct formation, and suppression of antioxidant pathways identify a mechanistic axis linking oxidative injury to persistent immune activation in LCPOTS. C_LI Summary of Novelty and SignificanceThis study identifies a mechanistic link between impaired cardiovagal function, mitochondrial oxidative stress, and persistent immune activation in LCPOTS. We show that circulating CD3CD14 T cell-monocyte doublets are expanded in LCPOTS and form true immune synapses, as demonstrated by T-cell receptor-HLA proximity. These are enriched in inflammatory effector-memory/TEMRA T cells and are associated with increased IFN-{gamma} and IL-17A production that correlate with orthostatic tachycardia severity and symptom burden. We further identified increased mitochondrial ROS, accumulation of IsoLG adducts, and reduced antioxidant gene expression in monocytes, suggesting that oxidation-induced neoantigen formation sustains pathogenic T-cell engagement. Together, these findings move LCPOTS beyond a descriptive post-viral syndrome and define a biologically plausible immune mechanism with diagnostic and therapeutic implications. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/26352776v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@12f15b0org.highwire.dtl.DTLVardef@38e9e9org.highwire.dtl.DTLVardef@84c229org.highwire.dtl.DTLVardef@1e72cae_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundCalcific aortic valve stenosis (AVS) is the most prevalent valvular heart disease in Western adults, yet no disease-modifying therapy exists. High shear stress (HSS) generated by progressive valvular obstruction drives endothelial injury and immune-mediated inflammation, but the contribution of circulating T cells to AVS pathogenesis remains poorly defined. ObjectivesWe tested whether chronic HSS corresponds with epigenomic reprogramming of peripheral T cells proportionate with hemodynamic severity to yield a clinically informative proxy of disease. MethodsA prospective cohort of 70 participants was recruited for peripheral blood sampling, including 34 with severe symptomatic AVS (aortic valve area <1.0 cm2, mean gradient [&ge;]40 mmHg) scheduled for transcatheter aortic valve implantation and 36 age- and sex-matched controls. Peripheral T cells were isolated and profiled by genome-wide CpG methylation (Illumina MethylationEPIC) and RNA-sequencing. To test whether HSS directly activates inflammatory signaling, Jurkat T cells were exposed to 20 dyn/cm2 HSS via parallel-plate microfluidic chamber and concomitant CD3/CD28 stimulation, followed by assessment of NFAT nuclear translocation and NFAT target gene expression. ResultsUnsupervised clustering of the 5,000 most-variable CpG loci resolved an epigenomic axis segregating AVS from control T cells (PC1, 15.8% variance explained; P = 3.9x10-6). Multivariable-adjusted analysis identified 3,950 differentially methylated positions (1,889 hyper-, 2,061 hypo-methylated), enriched in promoter-associated CpG islands implicating aortic valve morphogenesis (P = 6.0 x 10-10) and cell-cell adhesion pathways (P = 9.5 x 10-5). Multi-omics factor analysis isolated a latent factor that independently associated with AVS (adjusted P = 1.8x10-3; AUC = 0.79), enriched for chemokine receptor binding and TNF-family signaling, and correlated with canonical HSS-responsive transcripts, consistent with a T cell-mediated shear stress activation. An 18-CpG elastic-net methylation risk score discriminated AVS from controls (AUC = 0.89) and independently predicted hemodynamic severity ({beta} = 7.05 mmHg/SD, 95% CI 2.31-11.79). HSS augmented NFAT nuclear translocation in CD3/CD28-activated Jurkat T cells and induced NFAT-responsive inflammatory transcripts. ConclusionsSevere AVS is associated with promoter-enriched epigenomic remodeling of circulating T cells that converges on hemodynamic stress-dependent inflammatory programs. An 18-CpG methylation risk score outperforms clinical covariates and tracks hemodynamic severity, establishing peripheral T cell DNA methylation as a molecular corollary of AVS.

Importance Dilated cardiomyopathy (DCM) is a major cause of heart failure that disproportionately affects individuals of African genetic ancestry (AFR), among whom familial clustering of disease is also more pronounced relative to those of European ancestry (EUR). However, established monogenic DCM genes, identified primarily in EUR populations, explain a smaller proportion of DCM cases in AFR populations. A recent study identified a common AFR-specific nonsense variant in CD36 that accounts for a substantial burden of DCM in AFR. How the risk and population impact of this variant compare with those of established genetic causes of DCM is unknown. Objective To compare the contribution of a CD36 nonsense variant to DCM risk with that of truncating variants in TTN and pathogenic or likely pathogenic (P/LP) variants in other established DCM genes. Design, Setting, and Participants Multicohort genetic association study including AFR and EUR participants with exome or genome sequence and DCM case status from four datasets: All of Us, Million Veteran Program, Penn Medicine Biobank, and the DCM Precision Medicine Study. Exposure Carrier status for TTN truncating variants, P/LP variants in 11 high confidence DCM genes, and the CD36 nonsense variant (Y325*; 0, 1, or 2 copies). Main Outcomes and Measures Odds of DCM; prevalence of risk-variant carriers among DCM cases; and population attributable fraction (PAF) for DCM. Results Among 82,623 AFR individuals across four studies, the mean age was 53.4 years and 1,625 had DCM. CD36 Y325* risk-allele homozygotes had 4.8-fold (95% CI, 3.1-7.3) increased odds of DCM, and CD36 Y325* heterozygotes had 1.4-fold (95% CI, 1.2-1.7) increased odds. TTN truncating variants also conferred elevated risk of DCM in AFR participants (OR, 8.46; 95% CI, 5.3-12.3). Among AFR DCM cases, 2.5% were CD36 homozygotes, second only to TTN truncating variants (4.3%) and exceeding all other high-confidence DCM genes combined (1.5%). In population-level analyses incorporating both heterozygous and homozygous CD36 Y325* carriers, the population-attributable fraction for CD36 (9.0%) surpassed that of TTN truncating variants (3.6%). Conclusions and Relevance An ancestry-specific CD36 variant contributes more to DCM burden in AFR ancestry than established DCM genes, including TTN truncating variants, typically considered the most common genetic cause of DCM. These findings reshape the known genetic architecture of DCM in individuals of African ancestry and highlight the importance of representation in genomic research.

Background: Treatment response in heart failure with reduced ejection fraction (HFrEF) is assessed predominantly through left ventricular (LV) functional recovery, while longitudinal changes in left atrial (LA) hemodynamic burden remain underexplored. The LA stiffness index (LASI), derived from E/e' and LA reservoir strain, integrates LV filling pressure and LA compliance. Objectives: We investigated longitudinal trajectories of LASI and their prognostic implications in HFrEF treated with angiotensin receptor-neprilysin inhibitor (ARNI)-based therapy. Methods: From the multicenter STRATS-HF-ARNI registry, 1,039 patients with HFrEF who underwent serial echocardiography at baseline and one-year follow-up were classified into four LASI trajectory patterns dichotomized at the cohort median (1.22): persistently compliant (Group A, 46.8%), reverse remodeling (B, 28.5%), progressive stiffening (C, 3.2%), and persistently stiff (D, 21.6%). Results: On multivariable Cox regression, Group D was independently associated with elevated risks of all-cause mortality (adjusted hazard ratio [aHR] 2.68, 95% CI 1.57-4.59), cardiovascular mortality (aHR 4.36, 1.97-9.64), and HF hospitalization (aHR 3.83, 2.22-6.60), whereas Group B showed outcomes comparable to Group A. One-year LASI progression independently predicted all three outcomes. LASI elevation at one year predicted adverse outcomes even among patients with recovered LV function, and LASI trajectory classification provided incremental prognostic discrimination beyond conventional diastolic and strain parameters. Among sinus-rhythm patients (n=786), Group C exhibited the highest risk of new-onset atrial fibrillation. Conclusions: In HFrEF treated with ARNI-based therapy, LASI trajectories identify distinct prognostic phenotypes. Persistent LA stiffness confers adverse outcomes independent of LV recovery, and serial LASI assessment may enhance risk stratification beyond LV-centric metrics.

Background: Lipoprotein(a) (Lp[a]) is a genetically determined causal and independent cardiovascular risk factor and Lp(a) targeted therapies are being developed. However, evidence on the safety of substantial Lp(a) lowering during pregnancy is limited. We evaluated the impact of Lp(a) lowering on adverse pregnancy and perinatal outcomes (APPOs) using human genetic evidence. Material and Methods: We applied a drug-target Mendelian randomization (MR) approach using genetic variants associated with Lp(a) in the UK Biobank at the LPA locus to proxy pharmacological Lp(a) lowering. Summary-level APPO data were obtained from the MR-PREG collaboration, comprising up to 714,899 women across multiple studies. Twenty APPOs were included. Sensitivity analyses included adjustment for fetal genotype, alternative Lp(a) datasets, leave-one-study-out analyses, and exploration of Lp(a) genetic scores and individuals homozygous for LPA loss-of-function variants in the UK Biobank. Results: Across 20 APPOs, MR estimates showed no strong evidence of causal effects, with no associations surviving false discovery rate P-value correction. Most estimates were close to null, including gestational hypertension, gestational diabetes, preeclampsia, miscarriage and neonatal intensive care unit admission. Some associations were slightly larger in magnitude but with wide confidence intervals: gestational age (mean difference 0.04 weeks, 95% CI 0.02-0.06 per 210nmol/L reduction in Lp[a]) and congenital malformation (OR 0.82, 95% CI: 0.72-0.94) in the protective direction of effect, and higher odds of stillbirth (OR 1.09, 95% CI: 1.00-1.19) and low Apgar at 1 minute (OR 1.11, 95% CI: 0.99-1.24). Sensitivity analyses consistently supported the primary findings, with no evidence of increased maternal nor offspring risk in analyses adjusting for maternal-fetal genotype, across alternative exposure datasets, or in leave-one-study-out tests. Individual-level analyses of Lp(a) genetic score and LPA loss-of-function variants showed no associations, although power was limited. Conclusion: These findings suggest that substantial lowering of Lp(a) is unlikely to increase APPO risk, although modest effects, particularly for rare outcomes, cannot be excluded.

Donor derived cell free DNA (ddcfDNA) is increasingly used for post transplantation non invasive surveillance; however, its clinical interpretation remains inconsistent, with widely ranging thresholds and is typically applied as a single binary cutoff in literature. The optimal decision framework for rule out and rule in decisions, and whether a single threshold remains clinically meaningful, are currently uncertain. We performed a Bayesian hierarchical summary receiver operating characteristic (HSROC) meta analysis of 14 studies (1,763 patients) evaluating ddcfDNA against endomyocardial biopsy. To account for serial testing within individuals, we applied a cluster corrected design effect, reducing 6,103 observations to 2,518 effective tests. Threshold dependent sensitivity and specificity were modelled continuously. We compared a conventional single threshold approach (Youden index) with a data driven adaptive framework defining rule out and rule in thresholds. Clinical utility was evaluated using decision curve analysis across a range of rejection prevalences (10% to 30%), incorporating repeat testing strategies. The pooled area under the HSROC curve was 0.78 (95% CrI, 0.67 to 0.84). The Youden optimal threshold (0.20%) yielded balanced sensitivity (0.77) and specificity (0.77) but failed to support clinical objectives of diagnosis. An adaptive framework identified a rule out threshold of 0.16% (sensitivity 0.80) and a rule in threshold of 0.48% (specificity 0.90), defining a indeterminate / grey zone. Across all prevalence scenarios, ddcfDNA guided strategies provided positive net benefit compared with biopsy all and biopsy none approaches. A repeat if borderline strategy consistently achieved the highest net benefit, particularly in low and intermediate risk settings, by reducing false positive biopsies without materially compromising detection. A single threshold interpretation is not clinically adequate for post heart transplant surveillance. Our tri state, prevalence aware framework integrating rule out, indeterminate, and rule in zones with selective repeat testing, more accurately reflects biomarker behavior and improves clinical decision making. These findings support a shift away from binary thresholds toward dynamic, context dependent use of ddcfDNA in transplant surveillance.

Effective hypertension management depends on sustained engagement with primary care, and there is a need to understand the magnitude and determinants of follow-up loss in real-world primary care. We analyzed electronic health record (EHR) data from 26,541 patients with hypertension across primary care practices participating in the EvidenceNOW quality-improvement initiative. We characterized retention in care, longitudinal blood pressure (BP) control, and predictors of loss to follow-up using descriptive statistics, cumulative retention curves, and multivariable Cox proportional-hazards regression. At baseline, mean systolic and diastolic BP were 140.0 {+/-} 20.6 and 84.7 {+/-} 13.0 mmHg, respectively; only 10.7% (95% CI 10.4-11.1) of patients had controlled BP and 18.1% never returned for any follow-up visit. Among the 21,729 patients who had [&ge;]1 follow-up encounter, retention declined steeply over time--from 59.9% at 6 months to 16.3% at 36 months. Patients identifying as Black/African American (adjusted hazard ratio [aHR] 1.44; 95% CI 1.33-1.56), Hispanic/Latino (aHR 1.43; 1.35-1.52), or Other race/ethnicity (aHR 1.50; 1.41-1.59) had significantly higher hazards of being lost to follow-up than White patients, whereas older age, female sex, comorbid diabetes, heart failure, chronic kidney disease, stroke, and baseline BP control were each independently protective. Among patients retained for at least 12 months, BP control rose to 63.7% and remained near 64-66% through 36 months. These findings reveal a substantial and inequitable longitudinal care-engagement gap that is likely a principal driver of suboptimal hypertension control in the United States and identify actionable demographic and clinical targets for primary-care retention interventions.

Background: Andersen-Tawil syndrome type 1 (ATS1) is caused by loss-of-function mutations in KCNJ2, which encodes the inward rectifier K+ channel Kir2.1, a key determinant of IK1. Impaired Kir2.1 destabilizes membrane excitability and predisposes to ventricular arrhythmias. Most ATS1 variants disrupt channel regulation by phosphatidylinositol 4,5-bisphosphate (PIP2), but whether specific mutations confer differential arrhythmic risk remains unclear. Objective: To determine whether ATS1 variants disrupting Kir2.1-PIP2 interactions define distinct arrhythmic risk profiles and establish a mechanistically informed framework for risk stratification. Methods: We performed a pooled patient-level analysis of 225 ATS1 patients carrying KCNJ2 variants impairing Kir2.1-PIP2 interaction. Inclusion of 22 clinical and electrocardiographic variables were used to identify mutation-specific risk profiles and predictors for arrhythmia risk. The approach was validated in a multicenter cohort of 20 ATS1 patients. Functional validation was performed using patient-derived iPSC-CMs, cardiac-targeted mouse models, and structural in silico analyses. Results: ATS1 variants segregated into three discrete clusters corresponding to high-, intermediate-, and low-risk arrhythmic phenotypes, establishing a mutation-dependent hierarchy of arrhythmic risk. Regression analyses identified six variables independently associated with severe arrhythmic outcomes. Patient-derived iPSC-CM demonstrated graded impairment of electrical propagation and arrhythmia susceptibility, with a hierarchy in conduction velocity, CV:Control > R82W > R218W > G215D). Cardiac-targeted ATS1 mouse models reproduced the clinical risk stratification. Structural modeling showed that high-risk variants localize near the channel pore and disrupt Kir2.1-PIP2 interactions through mutation-specific mechanisms. Conclusions: ATS1 caused by Kir2.1-PIP2-disrupting variants is not a uniform disorder but comprises biologically distinct subgroups with predictable differences in arrhythmic severity. Integrating genetics, functional phenotyping, and structural modeling provides a mechanistically grounded framework for ATS1 risk stratification and precision therapy development.

Background: People with ischemic heart disease (IHD) remain at high risk of recurrent major cardiovascular events despite contemporary therapy. Over two decades, a translational research program has evaluated pressure pain sensitivity (PPS) as a non-invasive marker of central autonomic dysfunction and a mutual risk phenotype in IHD and type 2 diabetes. A PPS-guided non-pharmacological intervention has been shown to substantially reduce five-year all-cause mortality in IHD. Methods: In a randomized controlled trial, 213 adults with stable IHD and elevated PPS, suggesting ANSD, were allocated to PPS-guided intervention (n=106) or control (n=107). The active group received three months of structured education (daily PPS self-measurement, cutaneous sensory nerve stimulation, supportive mental and physical exercises, telemedical feedback) followed by self-directed continuation. Controls received a booklet on general stress-management. The primary endpoint for this prespecified secondary analysis was a composite of eight major cardiovascular events. Results: Over 5 years, at least one major adverse cardiovascular event occurred in 19.8% of the PPS-guided group versus 43.8% of controls (odds ratio 0.32, 95% CI 0.17-0.62, P=0.0003). Incidence rates were directionally in favor of active intervention across all event categories (P=0.004). Conclusions: A brief PPS-guided non-pharmacological intervention, followed by self-directed continuation, was associated with a marked long-term reduction in major adverse cardiovascular events, complementing previously reported large reductions in all-cause mortality in the same cohort. Within the context of a multi-decade PPS research program, these findings support PPS-guided care as a low-resource autonomic intervention ready for pragmatic scale-up testing as an adjunct to cardiometabolic care.

Objective To evaluate the associations between maternal history of psychiatric disorders and the risk cardiovascular disease (CVD) in offspring. Design Population based cohort study. Setting Nationwide health registers in Sweden. Participants All 4 171 005 liveborn singletons in Sweden from 1973 to 2014. Follow-up started at birth and ended until the first diagnosis of CVD, death, emigration, or December 31st, 2023, whichever occurred first. Exposures for observational studies Maternal psychiatric disorders diagnosed before delivery (n=208,680, 5.0%). Main outcome measures The primary outcome was the first diagnosis of CVD in offspring, identified through hospital registers. Additional outcomes included specific CVD subtypes. To address potential familial confounding, a cousin comparison was performed, comparing the risk of CVD in offspring born to mothers who were biological sisters. Mediation analyses examined the roles of congenital heart disease, small for gestational age, and preterm birth. Results During up to 51 years of follow-up, 307 596 (7.4%) offspring had a diagnosis of CVD. Maternal history of psychiatric disorders was associated with a higher risk of overall CVD both in the full cohort (hazard ratio 1.19, 95% confidence interval 1.17 to 1.21) and the cousin-comparison cohort (n=1 577 113; 1.08, 1.03 to 1.13). In disease-specific analyses, a prominent association with heart failure was robustly observed in both the full cohort (1.59, 1.37 to 1.85) and the cousin comparison cohort (1.51, 1.06 to 2.17). Mediation analyses indicated that congenital heart disease mediated 9.5% of the association between maternal psychiatric disorders and offspring CVD risk. Preterm birth and small for gestational age contributed minimally (<3%) to the observed associations. Conclusions Maternal history of psychiatric disorders was associated with an increased risk of CVD up to early middle-age in offspring. Congenital heart disease partly mediated this association.

Acute coronary syndrome (ACS) remains a major contributor to cardiovascular mortality despite advances in emergency cardiovascular intervention and coronary revascularization strategies. This retrospective cohort study evaluated the association between early hemodynamic instability and major adverse cardiovascular events (MACE) among 1,248 ACS patients admitted between January 2023 and December 2025. Patients were categorized into stable and unstable groups based on early emergency department hemodynamic assessment including blood pressure, lactate level, Killip classification, vasopressor requirement, and cardiac output estimation. The primary outcome consisted of 30-day MACE including cardiovascular mortality, recurrent myocardial infarction, cardiogenic shock, ventricular arrhythmia, and urgent revascularization. A total of 372 patients (29.8%) demonstrated early hemodynamic instability and experienced significantly higher rates of cardiogenic shock, ventricular arrhythmia, mechanical ventilation, ICU admission, and 30-day mortality compared with stable patients. Multivariable regression analysis identified serum lactate >4 mmol/L (adjusted OR 3.42; 95% CI 2.10-5.11), systolic blood pressure <90 mmHg (adjusted OR 2.96; 95% CI 1.88-4.47), and left ventricular ejection fraction <35% (adjusted OR 2.71; 95% CI 1.77-4.09) as independent predictors of MACE. Early hemodynamic instability was strongly associated with poor short-term cardiovascular outcomes, suggesting that integrated emergency hemodynamic profiling may improve early risk stratification and facilitate timely cardiovascular intervention.

BackgroundPreeclampsia (PE) is a complex hypertensive disorder of pregnancy characterized by endothelial dysfunction, immune dysregulation, and systemic vascular injury. Multiple genome-wide association studies (GWAS) have revealed genetic signals shared with hypertension and blood pressure traits, potentially obscuring biological mechanisms that are more specific to PE pathogenesis. Furthermore, the functional consequences of most PE-associated variants remain poorly understood. In addition, GWAS relies on short-read sequencing and array-based analyses, limiting the ability to identify insertions, deletions, and other structural variants that may contribute to disease-associated regulatory mechanisms. In this study, we investigated the regulatory architecture of PE-specific genetic variants and evaluated their potential linkage disequilibrium (LD) with structural variants. MethodsWe integrated GWAS, transcriptomic, and long-read sequencing data to investigate the regulatory architecture of PE-specific genetic variants. Summary statistics for PE, hypertension, systolic and diastolic blood pressure were obtained from the GWAS Catalog, and variants uniquely associated with PE (P [&le;] 1x10-4) were prioritized. Cis-expression quantitative trait locus (cis-eQTL) analyses were performed in whole-blood RNA-sequencing data from 180 African American women. Significant associations were replicated in biologically relevant tissues from the GTEx Project, including vascular, renal, and immune-related tissues. Long-read sequencing-derived structural variants (SVs) were subsequently evaluated for LD with replicated eQTL loci. ResultsA total of 10,843 PE-specific variants, present in whole-genome sequencing data of the 180 women, were evaluated. Cis-eQTL analyses identified 480 significant eQTL-gene associations involving 277 unique variants and 192 genes (FDR [&le;] 0.05). Replication analyses supported 69 eQTL-gene associations across five GTEx tissues, involving 35 variants and 14 genes. Replicated signals were enriched in vascular tissues, particularly artery tibial and artery aorta. Several prioritized genes converged on immune and vascular pathways, including MICA, HLA-DPB1, SEMA4D, JUP, ZFP57, and TMEM204. Integration of GWAS and eQTL effects demonstrated consistent regulatory shifts associated with PE-risk alleles, including downregulation of immune-related loci and upregulation of select vascular-associated genes. Long-read sequencing analyses identified 66 high-LD (r2 [&ge;] 0.80) SNP-SV-gene associations, including 12 replicated eQTL variants, 8 candidate SVs, and 3 replicated genes, suggesting that structurally complex genomic regions may contribute to the observed regulatory signals. ConclusionsThe tissues enriched in the regulatory signal highlight the importance of systemic endothelial biology in PE susceptibility. The findings of this study support a model in which PE-specific genetic susceptibility converges predominantly on interconnected immune and vascular regulatory mechanisms. The integration of eQTL analyses with long-read structural variant discovery provides additional insight into the complex genomic architecture underlying PE and highlights candidate regulatory loci that may not be adequately captured through conventional GWAS approaches alone. The study also emphasizes the importance of conducting functional genomic analyses in diverse populations to improve understanding of disease biology and advance precision medicine efforts. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/728031v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1caf4a5org.highwire.dtl.DTLVardef@1839b4eorg.highwire.dtl.DTLVardef@14922c3org.highwire.dtl.DTLVardef@894040_HPS_FORMAT_FIGEXP M_FIG C_FIG Regulatory Genomics of Preeclampsia-Specific Risk Variants Highlights Immune and Endothelial Mechanisms. GWAS summary statistics for preeclampsia, hypertension, SBP, and DBP were integrated to identify 10,843 preeclampsia-specific variants that were subsequently evaluated in cis-eQTL analyses using whole-blood RNA-sequencing data from 180 African American women (left). Cis-eQTL analyses identified 480 significant associations involving 277 variants and 192 genes (FDR [&le;] 0.05), of which 69 eQTL-gene associations involving 35 variants and 14 genes replicated across five GTEx tissues, with strongest enrichment observed in vascular tissues, particularly artery tibial and artery aorta (center). Prioritized genes, including MICA, HLA-DPB1, SEMA4D, JUP, ZFP57, and TMEM204, converged on interconnected immune and endothelial pathways associated with systemic vascular dysfunction, impaired placentation, and inflammatory dysregulation in preeclampsia. Integration of long-read sequencing data further identified 66 high-LD SNP-SV-gene associations involving 12 replicated eQTL variants, 8 candidate structural variants, and 3 replicated genes, suggesting that structurally complex genomic regions may contribute to regulatory mechanisms not fully captured through conventional GWAS approaches alone. eQTL indicates expression quantitative trait locus; FDR, false discovery rate; GTEx, Genotype-Tissue Expression project; SBP, systolic blood pressure; DBP, diastolic blood pressure; LD, linkage disequilibrium; SV, structural variant.

Familial longevity, quantified using the Longevity Relatives Count (LRC) score indicating the proportion of ancestral long-lived family members, associates with a pronounced 13 years delayed onset of cardiometabolic disease (CMD). Understanding the molecular basis of familial longevity therefore provides critical insights into mechanisms of cardiometabolic resilience. However, the combined metabolomics and proteomics profile associated with the delayed CMD onset observed in such long-lived family members is not understood yet. Hence, we integrated plasma metabolomics and proteomics in 495 participants from the Leiden Longevity Study to identify molecular signatures associated with (a contrast in) the LRC score. Metabolomics profiling captured 429 features, including amino acid derivatives, nucleosides, and lipid mediators, while proteomics quantified 374 proteins related to cardiovascular, metabolic, and inflammatory pathways. Three within-family analysis approaches were examined and overlapping findings were interpreted. We identified ten metabolites and nine proteins that are associated with increased familial longevity, exemplified by a high LRC score. High LRC scoring individuals exhibited lower levels of amino acid derivatives (prolylhydroxyproline, 5-hydroxy-tryptophan, asymmetric dimethylarginine), nucleosides (2-methylguanosine, 7-methylguanosine, pseudouridine), N-acetylneuraminic acid and quinolinic acid, indicating optimized extracellular matrix integrity, vascular function, and reduced neuroinflammatory activity. Lipid mediators, including elevated 6-keto-PGF1a and reduced 9-HOTrE/alpha-linolenic acid ratio, reflected preserved endothelial homeostasis and attenuated inflammatory signaling. At the proteome level, strong ancestral familial longevity is associated with immune regulators (RETN, NPPB, IGSF8), extracellular matrix components (EFEMP1, EPHB4), and adhesion/signaling molecules (LRP11, ICAM3, KIT, ADGRG2), highlighting coordinated regulation of inflammation, tissue remodeling, and regenerative capacity. Multi-omics pathway analyses indicated convergence on amino acid and nucleotide metabolism, lipid signaling, extracellular matrix remodeling, and receptor-mediated communication. Collectively, these multi-omics systemic signatures define a molecular framework of ancestral familial longevity characterized by reduced inflammation, preserved tissue integrity, and enhanced metabolic and regenerative processes. Our findings provide mechanistic insight into the biology of familial longevity and potentially cardiometabolic resilience.

Catheter ablation is an established rhythm-control strategy for atrial fibrillation, but outcomes in persistent atrial fibrillation (PsAF) remain heterogeneous across evolving strategies and energy modalities. An updated synthesis is needed to define current effectiveness and adverse-event profiles in the modern ablation era. We conducted a systematic review and meta-analysis of prospective clinical trials of catheter ablation for PsAF published from 2010 through December 2025. We included randomized and nonrandomized prospective interventional studies reporting effectiveness and adverse events, and pooled outcomes using random-effects models. Prespecified subgroup analyses evaluated ablation strategy (pulmonary vein isolation [PVI] vs PVI with adjunctive lesion sets [PVI+]), ablation modality (radiofrequency [RF], cryoballoon [CRYO], and pulsed field [PF]), and endpoint definition (recurrence-only vs composite measures). Thirty-two studies (9,194 patients) met inclusion criteria; 28 (7,948 patients) contributed to effectiveness analyses. The pooled 12-month arrhythmia-free proportion was 0.65 (95% CI, 0.61-0.68), with substantial heterogeneity. Effectiveness was numerically higher with PVI+ than PVI-only (0.66 [0.60-0.72] vs 0.63 [0.59-0.67]), similar for PF (0.65 [0.57-0.72]) and RF (0.65 [0.61-0.69]), and slightly lower for CRYO (0.64 [0.54-0.74]). Recurrence-only endpoints yielded higher effectiveness than composite endpoints (0.67 [0.63-0.71] vs 0.60 [0.55-0.64]). Safety analyses included 32 studies (9,002 patients). Adverse events were low but heterogeneous (0%-14.56%); pooled vascular access and pericardial complication incidences were each 1%, while thromboembolic events, accessory organ injury, and mortality were rare (pooled 0%). PF ablation showed numerically lower overall complication incidences than RF and CRYO. In contemporary trials, catheter ablation for PsAF shows moderate effectiveness and low overall adverse-event risk. Adjunctive strategies and PF ablation are promising, but no approach is consistently superior. These findings support tailored, patient-specific ablation selection in PsAF.

Type 1 diabetes (T1D) is associated with early-onset and increased risk of coronary artery disease (CAD), particularly myocardial infarction (MI), that is not fully explained by traditional cardiovascular risk factors. Hematopoietic aging, marked by clonal hematopoiesis of indeterminate potential (CHIP) and leukocyte telomere length (LTL) attrition, has been linked to CAD risk in the general population. We investigated whether T1D is associated with increased prevalence and earlier onset of CHIP and accelerated LTL attrition, and whether these processes contribute to CAD risk. We analyzed 416,565 UK Biobank participants (1,342 T1D cases) with harmonized CHIP calls and qPCR-derived LTL measurements. T1D was defined using ICD-10 codes, diagnosis before age 40 years, and insulin initiation within one year. CHIP was defined as variant allele fraction >=2%, with higher thresholds evaluated in sensitivity analyses. Multivariable regression compared CHIP prevalence, age-specific CHIP probability, and LTL between T1D and controls. Associations of CHIP and LTL with prevalent and incident (median follow-up approximately 13.5 years) MI and CAD were evaluated within T1D. Mendelian randomization, conjFDR, and integrated single-cell genomic analyses assessed genetic relationships. CHIP prevalence was higher in T1D than in controls (4.40% vs 3.00%; absolute risk difference 1.39%, 95% CI 0.29 to 2.49; p=3.7x10-3), with higher adjusted odds (OR 1.71, 95% CI 1.31 to 2.23; p=6.9x10-5). Age modeling indicated an approximately 7-year earlier shift in CHIP risk in T1D (3% prevalence at age 52.2 vs 59.0 years). Mean LTL did not differ significantly between T1D and controls (beta -0.040 SD; p=0.13); however, T1D disease duration was associated with shorter LTL independent of covariates (beta -0.0082 SD per year; p=0.002). Within T1D, shorter LTL was associated with higher risk of both prevalent and incident MI (OR 0.77, 95% CI 0.65 to 0.91; p=0.003; HR 0.63, 95% CI 0.44 to 0.91; p=0.012). CHIP was not significantly associated with MI or CAD in this cohort. Genetic analyses supported a bidirectional relationship between T1D and LTL, but not CHIP, and identified 47 T1D-LTL loci enriched for hematopoietic stem and progenitor cell pathways. In conclusion, T1D is associated with accelerated hematopoietic aging, reflected by earlier and more prevalent CHIP and disease duration-dependent LTL attrition. LTL attrition, but not CHIP, was associated with MI risk, implicating telomere dynamics as a contributor to excess cardiovascular risk in T1D.

Background: Cardiovascular-kidney-metabolic (CKM) syndrome is a leading driver of cardiovascular morbidity and mortality. Whole-body molecular imaging is well-positioned to phenotype such syndromes, yet no imaging biomarker quantifies cumulative CKM burden. Bone scintigraphy with 99mTc-labeled bisphosphonates is widely performed and expanding with transthyretin amyloidosis assessment, under which Perugini grade 0 (absent cardiac uptake) is considered clinically benign. Objective: We hypothesized that the soft tissue-to-bone ratio (STBR) on these scans captures CKM burden and is an independent prognostic biomarker. Methods: We retrospectively analyzed 8,769 consecutive patients without cardiac uptake on 99mTc-DPD whole-body planar scintigraphy. The primary endpoint was all-cause mortality. Secondary endpoints were major adverse cardiovascular events (MACE) and heart failure hospitalization. Cox models were adjusted for ten established cardiovascular risk factors. Imaging-phenotype association (IPA) analysis mapped STBR to 1,210 clinical traits. STBR distribution across CKM stages was assessed in four prespecified analyses, including a non-cancer subgroup. Results: During a median follow-up of 5.1 years (IQR 2.5-8.2), 2,418 deaths occurred. Patients with prespecified STBR >0.5 (n=772, 8.8%) had significantly higher mortality (adjHR 1.73, 95% CI 1.54-1.94, p<0.0001) with an adjHR of up to 3.42 at higher thresholds (95% CI 2.05-5.42, p<0.0001). Hazard increased monotonically with STBR. STBR >0.5 was independently associated with MACE (adjHR 1.51, 95% CI 1.11-2.05, p=0.008) and heart failure hospitalization (adjHR 1.31, 95% CI 1.02-1.67, p=0.03). The association was robust across all prespecified subgroups and sensitivity analyses, including continuous STBR and patients without renal insufficiency. IPA analysis identified significant associations with type 2 diabetes, chronic kidney disease, chronic ischaemic heart disease, heart failure, atrial fibrillation, liver disease, amyloidosis, and hypertension among binary traits, as well as with CRP, NT-proBNP, BUN, cholesterol (inverse), and hemoglobin (inverse) among continuous parameters. STBR increased monotonically across CKM stages in all sensitivity analyses (all p<0.0001). Conclusions: STBR derived from routine 99mTc-DPD bone scintigraphy in patients without cardiac uptake is an independent prognostic imaging biomarker associated with cumulative cardiovascular-kidney-metabolic burden. As an opportunistic measure from scans already acquired at scale, STBR could refine CKM risk stratification at no additional cost, radiation, or acquisition time.

BK channels, coded by the Kcnma1 gene, integrate voltage and intracellular Ca2+ signals and are recognized for their roles in smooth muscle and neuronal excitability. However, their contribution to baseline cardiac physiology remains poorly defined. Here we uncover a fundamental function for BK channels in maintaining normal cardiac performance, independent of pathological stress. Using non-invasive echocardiography, transcriptional profiling, and mechanistic analyses, we demonstrate that Kcnma1 deletion disrupts ventricular function, and remodels metabolic and stress-response pathways. Transcriptomic profiling revealed selective downregulation of mitochondrial uncoupling proteins (UCPs) and suppression of the PGC-1/FOXO3a axis, without broad loss of oxidative phosphorylation components. Enhancing UCP expression restored cardiac performance, indicating that mitochondrial uncoupling and redox control constitute key downstream effectors of BK signaling. Together, these results identify a physiological role for BK channels in maintaining myocardial function and define a mitochondrial BK-UCP axis, critical for cardiac homeostasis.

Hypertension represents the most prevalent chronic cardiovascular condition, typically culminating in pathological cardiac remodeling characterized by hypertrophy and extensive fibrosis. Although the cellular phenotypes associated with these changes are well-documented, the precise mechanisms by which hypertensive stress is sensed and transduced into a fibrotic program remain poorly defined. To elucidate these mechanisms, we investigated the role of Lysyl oxidase (LOX), an extracellular matrix (ECM)-modifying enzyme that is upregulated during hypertensive stress and associated with cardiovascular diseases. By employing cell-type specific Cre-Lox technology to conditionally delete Lysyl oxidase in either smooth muscle cells (SMCs) or fibroblasts, the primary ECM-secreting cell populations, we demonstrate that fibroblast-specific Lox deletion had no significant impact on the progression of cardiac fibrosis. Conversely, SMC-specific Lox deletion selectively inhibited the fibrotic response without affecting other remodeling parameters, such as cardiac hypertrophy. Notably, in the SMC-specific Lox knockout hearts, fibrosis was restricted to the perivascular niche and failed to propagate into the cardiac interstitium. We find that this transition is a mechanical, ECM-dependent process initiated by SMCs. Our results identify SMCs, rather than fibroblasts, as the primary sensors and initiators of the hypertensive fibrotic response. These findings demonstrate that fibrosis can be uncoupled from other hypertensive manifestations and identify SMC-mediated ECM modification as a potential therapeutic target for treating hypertensive heart disease.

Cardiovascular diseases (CVDs) are highly heritable, but pathogenesis at the organ and physiological level is still poorly defined. Polygenic risk scores (PRSs), which estimate individual genetic susceptibility to a disease, may allow for the identification of associated abnormal organ structures. Ultimately, identifying where cardiovascular polygenic risk manifests can guide early interventions, shape mechanistic hypotheses, and motivate prevention trials for cardiac remodelling. This study investigated the association between PRSs for five common CVDs [heart failure (HF), coronary artery disease (CAD), atrial fibrillation (AF), abdominal aortic aneurysm (AAA) and ischaemic stroke (IS)] and 28 imaging-derived phenotypes (IDPs) from cardiac magnetic resonance imaging of ~62,000 participants in UK Biobank. To investigate the cardiac features associated with elevated polygenic risk of CVDs, we tested CVD PRSs against cardiac IDPs and identified 97 significant associations (FDR [&le;] 0.05). We further identified 32 significant putative mediators between CVD PRSs and incident disease events, revealing that across CVDs, polygenic risk manifested as distinct patterns in cardiac structures. HF implicated all cardiac chambers, including left ventricular and left atrial dysfunction alongside enlarged aorta. AF was characterised by biatrial enlargement and reduced ejection fractions, most prominently in the left atrium but also involving left ventricular wall thickness. IS exhibited left ventricular hypertrophy and left atrial dysfunction, while CAD predominantly involved left ventricular hypertrophy. AAA was primarily characterised by enlarged descending aorta. Overall, cardiac IDPs mediated a substantial proportion of polygenic risk for CVDs, in particular for HF. Taken together, our results show that cardiac structure and function lie on the pathway between polygenic risk and cardiovascular events.

Background: Traditional heart rate (HR) adjusted QT correction (QTc) formulae often fail to eliminate the inverse HR-QT interval relationship, particularly in pediatric patients. In this study, we optimized our previously published adaptive QTc (QTcAd) formula by including additional demographic variables and broadening the pediatric age range. We tested the hypothesis that QTcAd improves congenital long QT syndrome (congenital LQTS) detection performance and reduces erroneous classifications across pediatric cohorts. Methods: We retrospectively analyzed 8,306 ECGs from 4,556 cardiovascular disease (CVD)-free pediatric patients. For neonatal patients (1-30 days old), we derived daily QTcAd parameter values. For older patients, we developed regression models to estimate QTcAd parameters (mean Heart Rate (HR) = -15.9ln(days) + 219; |m| = 0.0001(days) + 1, where |m|=absolute HR-QT regression slope). To support LQTS screening, we constructed dynamic QTcAd thresholds by estimating age-specific reference limits. Diagnostic performance was tested in a clinically confirmed LQTS cohort (n=137), and further evaluated in the Pediatric Heart Network (PHN; n=2,394) and Emergency Department (ED; n=2,002) cohorts. Results: Using the confirmed LQTS cohort as the event population and the CVD-free cohort as the non-event population, QTcAd demonstrated higher sensitivity than QTcB (92% vs 46.7%). QTcAd maintained high specificity (96.9% vs 98.9%), which resulted in a higher Youden index (0.889 vs 0.456). In the PHN healthy cohort, both QTc formulae classified the majority of individuals as normal (QTcAd 95%; QTcB 98.2%) indicating few false-positives. In the ED cohort, QTcAd reduced borderline/prolonged QTc classifications requiring follow-up, yielding 270 fewer repeat-testing triggers than QTcB. We developed a publicly accessible calculator to compute QTcAd and classify congenital LQTS risk. Conclusion: We developed and validated an enhanced QTcAd formula for pediatric patients. QTcAd-based-age-adjusted dynamic thresholding improved performance for congenital LQTS screening, while maintaining high specificity. This reduces false-positive LQTS classifications and repeat ECGs, thereby decreasing unnecessary downstream clinical evaluation.