Circulation

Background: Despite optimal lipid-lowering and antithrombotic therapy, substantial residual cardiovascular risk persists in established atherosclerotic cardiovascular disease (ASCVD), partly driven by chronic vascular inflammation. Methods: Systematic review and meta-analysis of RCTs comparing colchicine to placebo or no treatment in adults with established ASCVD. Searches on March 21, 2026 (PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP). PROSPERO CRD420261346516. Primary outcome: 4-point MACE (CV death, MI, stroke, urgent revascularization). DerSimonian-Laird random-effects with HKSJ adjustment. Exploratory trial-level meta-regression: time-to-initiation (TTI) and cumulative dose as continuous moderators. Results: DL pooled HR for 4-point MACE: 0.68 (95% CI 0.51-0.89; p=0.0060). HKSJ-adjusted HR: 0.68 (95% CI 0.27-1.70; p=0.3018). Substantial heterogeneity (I2=81.4%; 95% prediction interval 0.29-1.57, crossing 1.0). Exploratory meta-regression: TTI (beta=-0.00187/day, p=0.003) and cumulative dose (beta=-0.00163/mg-day, p=0.0003; k=5, explicitly underpowered). Non-CV mortality: HR 1.07 (0.76-1.50; p=0.694). GI discontinuation: pooled RR 1.95 (1.09-3.48; p=0.024). GRADE certainty: Moderate (4-point MACE). Conclusions: Low-dose colchicine is associated with reduced 4-point MACE in ASCVD (DL HR 0.68; HKSJ HR 0.68). The substantial heterogeneity and wide prediction interval indicate that effect size varies substantially across clinical settings. The divergence between CLEAR SYNERGY (acute; HR 0.99) and sub-acute/chronic trials (HR 0.33-0.77) drives heterogeneity. Meta-regression suggests TTI and cumulative exposure may be key moderators but is underpowered. The non-CV mortality signal is not confirmed. This analysis informs precision anti-inflammatory prescribing in ASCVD.

BACKGROUND Point-of-care (POC) high-sensitivity cardiac troponin (hs-cTn) testing has the potential to expedite decision-making and reduce emergency department (ED) length of stay for patients presenting with possible myocardial infarction (MI) by ensuring that results are consistently available when looked for by clinicians. We assessed the real-life effectiveness and safety of implementing POC hs-cTn testing in the ED. METHODS We conducted a pragmatic, stepped-wedge cluster randomized trial. The control arm was usual care with an accelerated diagnostic pathway utilizing a single-sample rule-out step with a central laboratory hs-cTn assay. The intervention arm used the same pathway with a POC hs-cTnI. The primary effectiveness outcome was ED length of stay assessed using a generalized linear mixed model, and the safety outcome was 30-day MI or cardiac death. RESULTS Six sites participated with 59,980 ED presentations (44,747 individuals, 61{+/-}19 years, 49.5% female) from February 2023 to January 2025, in which 31,392 presentations were during the intervention arm. After adjustment for co-variates associated with length of stay, the intervention reduced length of stay by 13% (95% confidence intervals [CI], 9 to 16%. P<0.001), corresponding to a reduction of 47 minutes (95%CI, 33 to 61 minutes) from a mean length of stay in the control arm of 376 minutes. The 30-day MI or cardiac death rate was similar in the control and intervention arms (0.39% and 0.39% respectively, P=0.54). CONCLUSIONS Implementation of whole-blood hs-cTnI testing at the POC into an accelerated diagnostic pathway was safe and reduced length of stay in the ED compared with laboratory testing.

BackgroundPathogenic desmin (DES) variants have been implicated in early-onset atrial disease, yet the mechanisms by which desmin dysfunction alters atrial structure and function remain unclear. Desmin anchors the cytoskeleton to the nuclear envelope (NE) through the linker of nucleoskeleton and cytoskeleton (LINC) complex, suggesting that defects in this network may drive atrial cardiomyopathy. MethodsHuman desmin wild-type (WT) and the pathogenic variants p.S13F, p.N342D, and p.R454W were stably expressed in HL-1 atrial cardiomyocytes. Desmin organization, nuclear morphology, LINC-complex integrity (nesprin-3, lamin A/C), and DNA leakage, assessed by cyclic GMP-AMP synthase (cGAS), were analyzed by confocal microscopy. Action potential duration (APD) and calcium transients (CaT) were measured optically. Human myocardium samples from DES variant carriers were analyzed for validation. Data-independent acquisition (DIA) mass spectrometry profiled atrial proteomes from desmin-network (DN) and titin variant carriers and controls. The heat-shock proteins (HSPs) inducer geranylgeranylacetone (GGA) was evaluated for rescue effects. Resultsp.N342D caused severe filament-assembly defects with prominent perinuclear aggregates, whereas p.S13F showed mixed phenotypes with frequent perinuclear aggregates, and p.R454W largely preserved filamentous networks. p.N342D and p.S13F induced nuclear deformation with disrupted nesprin-3 and lamin A/C distribution. In p.N342D and p.S13F, desmin aggregates drove focal lamin A/C accumulation, nuclear envelope (NE) rupture, DNA leakage, and increased cGAS activation. DES variants significantly shortened APD20/90 and reduced CaT amplitude, indicating pro-arrhythmic electrical remodeling. Atrial proteomics revealed a DN-specific signature enriched for cytoskeletal, NE, intermediate filament, and chaperone pathways, consistent with the structural injury observed in vitro. GGA prevented desmin aggregation and nuclear morphology changes, and mitigated APD shortening in p.N342D-expressing cardiomyocytes. Human myocardium from DES variant carriers showed concordant desmin aggregation and polarized lamin A/C distribution. ConclusionsDES variants induce a desmin-dependent atrial cardiomyopathy characterized by cytoskeletal disorganization, disruption of LINC-complex, NE rupture with DNA leakage, and pro-arrhythmic electrophysiological remodeling. These findings provide mechanistic insight into how DN variants promote atrial disease. HSPs induction by GGA partially restores structural and functional integrity, identifying a potential therapeutic approach for desmin-related atrial cardiomyopathy. Clinical perspectiveWhat is new? O_LIPathogenic DES variants induce a previously unrecognized atrial cardiomyopathy characterized by desmin aggregation, and desmin-network (DN) collapse, disruption of the linker of nucleoskeleton and cytoskeleton (LINC) complex, and nuclear envelope rupture with DNA leakage. C_LIO_LIVariants that lead to desmin aggregation (e.g., p.N342D) cause focal lamin A/C polarization, cyclic GMP-AMP synthase (cGAS) activation, and structural injury at the nuclear envelope. C_LIO_LIDES variants produce pro-arrhythmic electrical remodeling, including action potential duration shortening and impaired Ca{superscript 2} handling in HL-1 atrial cardiomyocytes. C_LIO_LIAtrial proteomics from DN variant carriers reveals enrichment of pathways related to cytoskeletal, nuclear envelope, intermediate filament, and chaperone, supporting a desmin-dependent remodeling program. C_LIO_LIThe heat-shock protein inducer geranylgeranylacetone (GGA) prevents desmin aggregation, restores nuclear morphology, and mitigates electrical and Ca{superscript 2} handling remodeling. C_LI What are the clinical implications? O_LIThese findings establish DN dysfunction as a distinct cause of atrial cardiomyopathy, providing a mechanistic basis for the association between pathogenic DES variants and atrial arrhythmias, including atrial fibrillation. C_LIO_LINuclear envelope rupture and cytosolic DNA leakage represent new mechanistic evidence which links cytoskeletal injury and atrial arrhythmogenesis. C_LIO_LIIdentifying structural vulnerability in DES variant carriers fosters awareness of genetic counseling for atrial disease, enabling early detection and risk stratification. C_LIO_LIThe protective effects of GGA suggest that restoring proteostasis may be a therapeutic strategy for desmin-related atrial cardiomyopathy and potentially other genetic atrial diseases. C_LI Novelty and significance statementO_ST_ABSNoveltyC_ST_ABSThis study identifies a desmin-dependent atrial cardiomyopathy driven by cytoskeletal aggregation, LINC-complex disruption, and nuclear envelope rupture with DNA leakage. We show that pathogenic DES variants are associated with pro-arrhythmic molecular remodeling and that human atrial proteomics confirm nuclear envelope and cytoskeletal injury as core features. Importantly, the heat-shock protein-inducer GGA rescues structural, molecular, and electrophysiological defects, revealing a modifiable pathway in desmin-mediated atrial disease. SignificanceThese findings provide the first integrated mechanistic explanation linking DN variants to atrial cardiomyopathy. By uncovering nuclear envelope rupture and cGAS activation as key drivers of atrial cardiomyopathy, this work expands the molecular framework for inherited atrial disease and highlights proteostasis enhancement as a potential therapeutic strategy for patients carrying DES and related cytoskeletal variants. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/26348559v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1fb0bfborg.highwire.dtl.DTLVardef@cfc00borg.highwire.dtl.DTLVardef@1493578org.highwire.dtl.DTLVardef@1556b61_HPS_FORMAT_FIGEXP M_FIG C_FIG

BACKGROUNDExcessive trabeculations and myocardial crypts are recurrent features across cardiomyopathies, yet their developmental origins and clinical significance remain poorly defined. To reveal the link between cardiac morphogenesis and disease, we generated humanized mouse models carrying patient-derived MYBPC3 frameshift mutations associated with overlapping hypertrophic cardiomyopathy (HCM) and left ventricular non-compaction (LVNC). METHODSWe applied CRISPR-Cas9 to introduce distinct MYBPC3 frameshift alleles into the mouse genome and performed comprehensive phenotypic and transcriptomic profiling from fetal life through adulthood. RESULTSAdult homozygous Mybpc3 frameshift mutant mice like humans displayed hallmark HCM; however, without LVNC. Fetal and neonatal mutant hearts exhibited markedly enlarged ventricular trabeculae and crypts that progressed postnatally into the observed adult hypertrophy. Transcriptomic analysis revealed stage-specific dysregulation of oxidative metabolism, nonsense-mediated decay (NMD), and cell cycle pathways, peaking at postnatal days 1 and 7, indicating that these stages represent critical time points in disease onset. The persistent NMD signature, also observed in phenotype-negative heterozygotes, suggests a compensatory stress response. Enlarged trabeculae exhibited 2-fold increased trabecular cardiomyocyte proliferation, reversing the normal compact-trabecular proliferative gradient and leading to impaired ventricular compaction in neonates. Hey2CreERT2 lineage tracing demonstrated invasion of Hey2+ compact cardiomyocytes into the trabeculae and ectopic trabecular expression of the Prdm16 transcription factor, indicating defective ventricular wall patterning and maturation. Postnatally, Hey2+-derived cardiomyocytes became restricted to the outer/compact myocardium in mutants, while the inner/trabecular myocardium underwent accelerated hypertrophy concurrent with Prdm16 downregulation. Mice with a Mybpc3 missense variant also exhibited Hey2+ myocardial lineage expansion into trabeculae but no increased proliferation, implicating additional mechanisms beyond Hey2 regulation. Postnatal Prdm16 restoration, via transgenic expression in Mybpc3-null mice effectively attenuated hypertrophy, establishing a causal link between Mybpc3 loss, Prdm16 decline, and pathological remodeling. CONCLUSIONSMybpc3 governs ventricular wall maturation by regulating cardiomyocyte proliferation, patterning, and maturation, partly via Prdm16. Disruption of these developmental programs precedes and drives adult HCM, highlighting a developmental role for sarcomeric proteins, and revealing postnatal Prdm16 modulation as an antihypertrophic therapeutic strategy.

BackgroundArrhythmogenic cardiomyopathy (ACM) is a heritable nonischemic cardiomyopathy and a leading cause of sudden cardiac death. Although inflammation is a pathological hallmark of ACM, the contribution of peptidylarginine deiminase 4 (PAD4)-dependent neutrophil extracellular trap (NET) formation and myeloperoxidase (MPO) to disease progression remains poorly defined. MethodsTo define the role of PAD4-dependent NETosis and MPO signaling in ACM disease progression homozygous desmoglein-2 mutant (Dsg2mut/mut) mice were utilized. We employed genetic and pharmacological approaches to determine the efficacy of targeting PAD4 and MPO on cardiac function, arrhythmogenic burden, myocardial fibrosis, inflammatory signaling, and gap junction integrity. Cardiac phenotyping included echocardiography, electrocardiography, histology, inflammatory profiling, and biochemical assays. ResultsMarkers of PAD4-dependent NETosis were elevated in Dsg2mut/mut hearts as early as 4 weeks of age, prior to cardiac dysfunction. Genetic deletion of Pad4 significantly preserved left ventricular function, reduced ectopics, attenuated myocardial fibrosis, and suppressed proinflammatory and profibrotic cytokines. MPO levels were increased in Dsg2mut/mut hearts, and genetic ablation of Mpo preserved cardiac function, reduced arrhythmic burden, prevented myocardial fibrosis, and restored connexin-43 phosphorylation and localization. Furthermore, pharmacological MPO-inhibition improved cardiac function, reduced arrhythmias, and attenuated inflammatory signaling, though myocardial fibrosis was not fully prevented. Notably, hearts from patients with ACM demonstrated increased MPO signal in both cardiomyocytes and non-cardiomyocyte populations compared with donor controls. ConclusionsPAD4-dependent NETosis and MPO signaling are key drivers of inflammation, fibrosis, and arrhythmogenesis in early disease onset in ACM. Targeting neutrophil-mediated pathways represents a promising therapeutic strategy to mitigate disease progression in ACM. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIPAD4-dependent NET formation is activated early in ACM and directly contributes to myocardial inflammation, fibrosis, arrhythmias, and cardiac dysfunction. C_LIO_LIGenetic ablation of Pad4 or Mpo preserves cardiac function, reduces arrhythmogenic burden, and attenuates proinflammatory and profibrotic signaling in a Dsg2 mutant model of ACM. C_LIO_LIPharmacological inhibition of MPO improves cardiac function and electrical stability, identifying neutrophil-derived pathways as modifiable drivers of disease. C_LI What Are the Clinical Implications?O_LINeutrophil-mediated inflammation represents a clinically relevant mechanism in ACM that may be targeted without global immunosuppression. C_LIO_LIMPO inhibition may offer a novel disease-modifying strategy to reduce arrhythmias and preserve cardiac function in patients with ACM. C_LIO_LINeutrophil- and NET-associated biomarkers may improve early risk stratification and therapeutic decision-making in genetically susceptible individuals. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/718596v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@54ea46org.highwire.dtl.DTLVardef@e0a417org.highwire.dtl.DTLVardef@350c83org.highwire.dtl.DTLVardef@c879e6_HPS_FORMAT_FIGEXP M_FIG C_FIG (A) Signaling pathway for PAD4-dependent NETosis. (B) Illustration of neutrophil undergoing NETosis resulting in the release of MPO and DNA histone complexes. (C) Effects of MPO release on cardiac tissue of ACM mice

BackgroundCalcium release deficiency syndrome (CRDS) is a recently described inherited channelopathy caused by loss-of-function variants in RYR2. Clinically, CRDS patients present with lethal ventricular arrhythmias which are not reproduced on exercise stress testing, unlike catecholaminergic polymorphic ventricular tachycardia. A hallmark trigger identified for CRDS mimics a long-burst, long-pause, short-coupled extra-stimulus (LBLPS) programmed electrical stimulation protocol, which was experimentally validated in humans and mouse models. Moreover, application of a long-burst, long-pause (LBLP) protocol alone can induce an abnormal repolarization on the first sinus beat that is unique to CRDS. However, the electrophysiological basis of CRDS in human cardiac tissue, including other triggers, are not fully understood, and whether clinically relevant arrhythmias can be observed in human stem cell models remains unknown. MethodsWe performed electrophysiological and arrhythmia inducibility studies using clinically relevant programmed electrical stimulation protocols in two-dimensional cardiac tissue generated from metabolically matured human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the CRDS variant RyR2-E4146D. High spatiotemporal optical mapping and multielectrode arrays were used for electrophysiological phenotyping. ResultsAt baseline, E4146D+/- monolayers showed no arrhythmias, similar to controls. During rapid pacing, E4146D+/- promoted electrical vulnerability by reducing the threshold for action potential duration (APD) alternans and Ca2+ alternans and increasing the propensity for spatial discordance of alternans. In response to LBLP pacing, E4146D+/- monolayers often demonstrated an abnormal repolarization response characterized by spatially dispersed APD prolongation and large Ca2+ release. Notably, LBLPS pacing produced early-after depolarization (EAD)-driven triggered activity resulting in re-entrant tissue conduction patterns, explaining the short-coupled ectopy driven arrhythmias seen in CRDS patients. Similar arrhythmias were observed when EADs developed during spatially discordant alternans. Lastly, flecainide showed efficacy in suppressing arrhythmia inducibility for the here studied variant. ConclusionsWe developed the first hiPSC model for CRDS which recapitulates clinically observed and inducible arrhythmias. Our model provides novel insights into tissue-level, re-entrant arrhythmias, which are initiated by EADs during electrically vulnerable states in CRDS human cardiac tissue and can be suppressed by flecainide. This model provides the framework for studying other CRDS variants and complex arrhythmias in hiPSC-CMs and establishes a human-based new approach method (NAM) for drug and gene therapy development for CRDS. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABS{blacksquare} We developed the first human stem cell-derived cardiomyocyte (hiPSC-CM) tissue model for calcium release deficiency syndrome (CRDS) which recapitulates its hallmark clinical features, including inducible ventricular arrhythmias with programmed electrical stimulation and post-pacing repolarization abnormalities. {blacksquare}Using genome edited and metabolically matured hiPSC-CMs combined with high spatiotemporal optical mapping, we show that tissue-level arrhythmias are initiated by early-after depolarizations (EADs) which develop during electrically vulnerable states, leading to re-entrant conduction patterns. We comprehensively characterize the features of EAD-induced triggered activity, showing that these ectopic beats promote re-entry through slower conduction velocities and shorter action potential durations. This uncovers how EAD-induced short-coupled ectopy leads to malignant ventricular arrhythmias in CRDS patients, and establishes the phenotype for future hiPSC-CM investigations. {blacksquare}We identified flecainide as an effective agent in suppressing arrhythmias on single cell and tissue levels in hiPSC-CMs for this CRDS variant, reproducing clinical results. What are the clinical implications?{blacksquare} CRDS has only recently been described as a unique channelopathy caused by loss-of-function RYR2 variants, and much of its triggers and mechanisms in human cardiomyocytes remain unclear. The arrhythmias observed are often not related to exercise, and exercise stress testing does not reproduce these abnormalities. No human models exist to date which closely recapitulate the triggers shown to induce tissue-level arrhythmias in patients and mouse models. Our model demonstrates that programmed electrical stimulation, without pharmacological {beta}-adrenergic stimulation, can reliably induce the same arrhythmias seen clinically, enabling accurate disease modeling and drug development. {blacksquare}Combining programmed electrical stimulation in cardiac tissue derived from genome-edited hiPSC-CMs with high spatiotemporal optical mapping is a robust and novel approach to identify the mechanisms of complex, tissue-level arrhythmias which remain underexplored, such as short-coupled ventricular fibrillation, in a patient-specific and translational manner.

BACKGROUNDInactivation of ANGPTL3 (angiopoietin-like protein 3, A3) is a proven therapeutic strategy for lowering plasma lipid levels independently of the LDL receptor (LDLR), yet the optimal approach to inactivate A3 remains unclear. A3 is proteolytically cleaved and circulates as full-length (A3-FL), N-terminal (A3-Nter) and C-terminal (A3-Cter) fragments. The specific contribution of each form of A3, and of its paralog, ANGPTL8 (A8), in modulating circulating levels of ApoB-Containing Lipoproteins (ABCLs) remain poorly defined. Clarifying these relationships will inform next-generation A3-directed therapies. METHODSWe performed liver perfusion studies to directly compare the number and composition of VLDL particles secreted from mice with and without A3. To amplify effects on cholesterol metabolism, we generated Ldlr-/- mice expressing wildtype A3 (A3-WT), A3-FL or A3-Nter, with or without co-expression of A8, and analyzed plasma lipids, circulating A3 and A8 complexes, and intravascular lipase activities. Complementary in vitro assays and structural modeling were used to assess relative endothelial lipase (EL) inhibition by A3 alone or in complex with A8. RESULTSLiver perfusion studies revealed that A3 inactivation does not alter the rates of hepatic secretion of VLDL in wildtype or Ldlr-/- mice. Inactivation of A8 alone lowered plasma LDL-cholesterol (C) levels by [~]20%, an effect dependent upon the expression of both EL and A3. Maximal inhibition of lipoprotein lipase (LPL) required co-expression of A8 plus both A3-FL and A3-Nter, indicating that A3 cleavage, in addition to A8 expression, is essential for maximal LPL inhibition. In contrast, A8 expression, but not A3 cleavage, was required for optimal EL inhibition. CONCLUSIONSA8 acts in concert with A3 to differentially modulate LPL- and EL-mediated lipolysis, which antagonizes hepatic clearance of newly-secreted atherogenic ABCLs. This mechanistic framework refines our understanding of A3-targeted lipid lowering and highlights the therapeutic potential of dual A3- plus A8-directed strategies to treat dyslipidemia and prevent atherosclerotic cardiovascular disease. Clinical perspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIInactivation of A3 lowers circulating ABCL levels without altering hepatic secretion rates of VLDL-ApoB or -TG. C_LIO_LIProteolytic cleavage of A3 is required for maximal inhibition of LPL. C_LIO_LIInactivation of A8 lowers LDL-C levels through an A3- and EL-dependent, but LDLR-independent, mechanism. C_LI What are the clinical implications?O_LICombining A8 inhibition with A3-inactivating therapies offers a strategy to achieve greater reduction in LDL-C levels and atherosclerotic cardiovascular risk. C_LI

BackgroundPathogenic variants in PR domain containing 16 (PRDM16) cause pediatric and adult cardiomyopathies characterized by ventricular dilation, systolic dysfunction, and impaired metabolic maturation. Cardiac deficiency of PRDM16 alters metabolic gene expression and long-chain fatty acid (FA) metabolites. However, the downstream mediators involved are not well characterized. Furthermore, whether improving mitochondrial FA metabolism can prevent PRDM16-associated cardiomyopathy is currently unknown. MethodsIn vivo and in vitro approaches using patient-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and mouse models with Prdm16 deletion/mutation were employed. Transcriptomics and proteomics analyses were conducted, and adeno-associated virus (AAV)-mediated therapy was tested. ResultsHere, we show that a defect in FA metabolism is an early hallmark of PRDM16 cardiac deficiency. We show, for the first time, that PERM1 is a direct downstream target of PRDM16 and is involved in the regulation of FA metabolism through coordinated action with PGC1. Most importantly, neonatal delivery of AAV9-Perm1 in cardiac-specific Prdm16 knockout (Prdm16 cKO) mice markedly improved contractile parameters, reduced left ventricular (LV) dilation, and extended survival. These cardioprotective effects of PERM1 gene therapy occurred independent of restoring FA oxidation. Transcriptional and proteomic analyses of AAV-Perm1-treated Prdm16 cKO mice demonstrated significant improvements in mitochondrial cristae architecture, preservation of sarcomere organization, reduced cardiomyocyte apoptosis, attenuated myocardial fibrosis, and diminished cardiac remodeling. ConclusionsWe identify PERM1 as a direct downstream effector of PRDM16 and uncover a previously unrecognized PRDM16-PGC1-PERM1 axis essential for FA metabolic regulation in the heart. Perm1 gene therapy ameliorated PRDM16-associated cardiomyopathy through post-transcriptional mechanisms involving preservation of mitochondrial and sarcomere integrity. The current study provides preclinical evidence suggesting that Perm1 gene therapy may be a promising therapeutic target to improve the cardiac outcomes of patients affected by pathogenic PRDM16 variants.

Background: Among cardiac measures, diastolic parameters demonstrate the earliest and most consistent age-related changes. This can be leveraged to develop a continuous left ventricular (LV) Diastolic Age from routine echocardiographic parameters. Analogous to how epigenetic clocks weight molecular markers against mortality risk, we calibrated Diastolic Age by weighting echocardiographic features against the validated PREVENT-Heart Failure (HF) risk score. Methods: We analyzed 1,952 participants from the Project Baseline Health Study (median age 50 [36-64] years, 54% female). The measure was derived using partial least-squares regression anchored on PREVENT-HF and calibrated within a healthy reference subgroup. External validation was performed in the WASE (n=1,708) and Stanford Cardiovascular Aging (n=313) cohorts. Associations with ASE-defined LV diastolic dysfunction (LVDD), epigenetic clocks, and major adverse cardiovascular events (MACE) were examined. Results: Diastolic Age correlated strongly with chronological age (r=0.78) with robust external validation (WASE r=0.76; Stanford r=0.82; calibration slopes {approx}1.0). It increased progressively across grades of diastolic dysfunction and discriminated LVDD with an AUC of 0.89 (95% CI 0.87-0.92), and was independently associated with hypertension, diabetes, and elevated C-reactive protein. While correlated with the Levine (r=0.76) and Horvath (r=0.41) epigenetic clocks, residual analyses indicated that Diastolic Age captures a distinct cardiac-specific dimension of biological aging. Over median follow-up of 4.2 years, it independently predicted MACE (HR 2.30, 95% CI 1.70-3.18), with accelerated diastolic aging across all age groups among those with events. Discrimination was comparable to ASE-defined LVDD (C-index 0.83 vs. 0.82). Conclusion: Diastolic Age provides a continuous, echocardiography-derived measure of cardiac biological aging that complements categorical diastolic grading and epigenetic aging clocks, and independently predicts cardiovascular outcomes.

BackgroundSympathetic modulation via the stellate ganglia is increasingly recognized as a contributor to ventricular arrhythmogenesis after myocardial infarction. However, the mechanisms by which autonomic remodeling interacts with chronic infarct substrates to shape arrhythmic vulnerability remain incompletely understood. ObjectivesTo test the hypothesis that left- and right-sided stellate ganglion-mediated SNS modulation differentially reshapes ventricular arrhythmic vulnerability in chronic post-infarcted substrates, and that the RVI detects changes in vulnerability beyond conventional stimulation-based inducibility. MethodsFourteen patient-specific ventricular models with chronic post-infarcted remodeling were reconstructed from imaging data. A total of 336 simulations were performed under different combinations of stellate ganglion modulation, border zone remodeling, and fibroblast density. Arrhythmic vulnerability was quantified using 3D RVI mapping during paced rhythms and compared with conventional stimulation-based inducibility outcomes. ResultsStellate ganglion modulation induced marked, regionally heterogeneous changes in repolarization timing, resulting in lower and more negative RVI values in vulnerable regions. More negative RVI values reflect increased propensity for wavefront-waveback interaction and reentry initiation. Across the cohort, stellate modulation consistently decreased RVImin, even when inducibility outcomes remained unchanged. These findings indicate that SNS modulation can create a substrate more permissive to reentry independently of whether ventricular arrhythmia is triggered during programmed stimulation. ConclusionsStellate ganglion-mediated sympathetic modulation dynamically reshapes ventricular arrhythmic vulnerability in chronic post-infarcted substrates. RVI provides a spatially resolved, vulnerability-based metric that complements inducibility testing by revealing autonomic-substrate interactions underlying arrhythmogenesis Condensed AbstractSympathetic modulation via the stellate ganglia can alter ventricular repolarization and promote arrhythmogenesis after myocardial infarction, yet clinical responses remain heterogeneous. Using 14 patient-specific post-infarction ventricular models, we simulated left- and right-sided stellate modulation across combinations of border zone remodeling and fibrosis (336 simulations). Stellate modulation induced regionally heterogeneous repolarization shortening and reduced RVI values, even when programmed stimulation inducibility remained unchanged. These findings suggest that RVI captures substrate-level vulnerability beyond binary induction testing and may improve mechanistic assessment of autonomic-substrate interactions in chronic infarct substrates.

Mitral valve prolapse (MVP) is the most common cause of primary mitral regurgitation and is associated with the development of malignant arrhythmias, often in the context of myocardial fibrosis. The genetic architecture of MVP, and whether there are genetic factors explaining why only some individuals with MVP have adverse outcomes, remains poorly understood. We performed a meta-analysis of genome-wide association studies (GWAS) for MVP encompassing 21,517 cases among a total sample size of over 2.2 million individuals. We discovered 89 genomic risk loci for MVP, of which 72 were novel findings. Prioritization of causal genes and pathways using epigenetic and transcriptomic data from mitral valve and extra-valvular tissues replicated known gene associations to MVP including those involved in TGF-{beta} signaling and extracellular matrix biology, but additionally emphasized a role in MVP for biological pathways relevant to cardiomyocyte biology. Accordingly, we identified several MVP risk loci with pleiotropy to cardiomyopathies, especially hypertrophic cardiomyopathy, and demonstrated a significant genetic correlation between MVP and hypertrophic cardiomyopathy. Finally, we interrogated snRNA-seq data in human papillary muscle tissue from two individuals with severe MVP, characterizing genes associated with both risk of papillary muscle fibrosis and MVP.

Background: Coronary artery bypass grafting (CABG) to physiologically non-significant coronary artery stenosis may result in graft failure due to competitive native flow. We evaluated whether an instantaneous wave-free ratio (iFR)-guided revascularization strategy improves graft patency and clinical outcomes compared to conventional angiography-guided CABG. Methods: In this prospective, randomized, single-blinded trial, patients with multivessel disease and at least one angiographically intermediate stenosis (50%-75%) were randomized to either CABG guided by angiography alone or angiography supplemented with iFR assessment groups. The primary endpoint was graft patency (occlusion or hypoperfusion of the graft) evaluated by coronary computed tomography angiography (CCTA) at 2, 12, and 36 months. Results: At 36 months, 78% of the patients completed follow-up. Left internal mammary artery (LIMA)-to-left anterior descending (LAD) artery graft patency was significantly higher in the iFR-guided group than in the angiography-guided group (80.5% vs. 56.8%; absolute risk difference, 23.7% [95% CI, 3.7%-43.8%]; RR, 1.42 [95% CI, 1.03-1.95]; P = 0.03). Saphenous vein graft patency also improved with iFR guidance (90.2% vs. 70.3%; P = 0.046). Major adverse cardiac and cerebrovascular events (MACCE) were similar between groups (28% vs. 20%; RR, 1.40 [95% CI, 0.69-2.85]; P = 0.48). Conclusions: iFR-guided CABG advocates significantly improved mid-term graft patency compared with angiography-guided CABG by optimizing surgical target selection and reducing competitive flow.

BackgroundTranscatheter aortic valve replacement has transformed the management of aortic stenosis; however, adverse outcomes such as leaflet thrombosis and hypoattenuating leaflet thickening remain clinically significant concerns. Flow disturbances resulting from valve canting may alter local hemodynamics and promote thrombogenic conditions. We investigated how modest transcatheter heart valve canting alters cusp-specific sinus flow and washout and promotes localized thrombogenic microenvironments associated with leaflet surface thrombus formation using particle image velocimetry, a physiologic blood loop, and tissue analysis. MethodsA patient-derived aortic root model was used to evaluate the hemodynamic and thrombogenic effects of THV canting at -10{degrees} (anti-curvature), 0{degrees} (neutral), and +10{degrees} (along-curvature). High-resolution particle image velocimetry quantified sinus flow fields and washout characteristics, and complementary whole-blood loop experiments enabled histologic assessment of leaflet-associated thrombus formation. ResultsCanting redistributed systolic jet orientation and sinus recirculation in a direction-dependent manner while preserving global hemodynamic measurements. The most spatially constrained cusp showed the largest increase in stasis and the slowest washout. In the right coronary cusp, anti-curvature canting increased the fraction of sinus area with velocity magnitude <0.05 m/s to 92% versus 43% in neutral and 10% in along-curvature deployments, and prolonged neo-sinus (T90) washout to 4.7 cycles versus 2.9 and 1.8 cycles, respectively. Histology localized surface-adherent platelet/fibrin thrombus to these poorly washed regions, most prominently on the right coronary cusp leaflet in anti-curvature deployments. Left and noncoronary cusp responses shifted with tilt direction, indicating redistribution rather than uniform worsening of thrombogenic conditions. ConclusionsEven modest noncoaxial deployment is sufficient to create sinus-resolved throm-bogenic microenvironments that are not captured by global gradient or effective orifice area. Deployment configuration is therefore a modifiable determinant of post-TAVR leaflet throm-bosis risk and may contribute to HALT.

Importance: Health systems are increasingly adopting race-neutral cardiovascular risk prediction tools, yet no study has examined how these choices redistribute preventive treatment at the point of clinical decision-making, particularly for Black individuals who already bear a disproportionate cardiovascular burden. Objective: To evaluate how including race, substituting social determinants of health (SDoH), or excluding both reshapes cardiovascular risk classification, calibration, fairness, and clinical decisions. Design: Retrospective cohort study with repeated cross-validation and integrated decision-focused evaluation, using CARDIA study data with baseline measures from 2010 and cardiovascular outcomes through 2021. Setting: Community-based longitudinal cohort recruited across multiple U.S. cities. Participants: 3,241 Black and White adults without known cardiovascular disease at baseline. Main Outcomes and Measures: Three models predicting 10-year incident cardiovascular disease were compared on predictive performance, calibration, fairness metrics, and realized clinical utility at the ACC/AHA 7.5% preventive treatment threshold. Results: Among 3,241 participants (46% Black, mean age 50 years, 6.9% CVD incidence), overall performance was similar across models (AUC 0.762 to 0.768). Predictor choice substantially reshaped clinical decisions at the guideline threshold. The SDoH-based model improved parity metrics but produced systematic underprediction and concentrated new overtreatment among Black participants. The clinical-only model further improved parity metrics but generated new undertreatment, with four cases of untreated CVD and none avoided. No single evaluative dimension captured the full equity consequences. Conclusions and Relevance: Parity metrics improved under both race-neutral models, yet both produced clinical harms concentrated among Black participants not apparent in population-average metrics. The case for race removal has rested on conceptual grounds, but comprehensive empirical evaluation is necessary before health systems can be confident their model choices truly serve those most at risk.

Aims: Although metabolic dysregulation is implicated in DCM, the involvement of metabolic syndrome (MetS) remains unclear. This study aims to systematically examine MetS in DCM pathogenesis. Materials and methods: By leveraging 378,837 UK Biobank participants, instead of the conventional binary MetS, we calculated a continuous metabolic risk score (MRS) and evaluated its influence on DCM risk within a multi-model evidence framework. Bidirectional weighted quantile sum regression identified key MRS components, a nested case-control study assessed 14-year pre-diagnosis MRS trajectories, mediation analyses evaluated MRS mediating lifestyle-DCM links and inflammation mediating MRS-DCM relationships, and Mendelian randomization (MR) evaluated causality for genetically predicted MetS and components on DCM. Results: During a median follow-up period of 13.4 years (interquartile range 12.7~14.1 years), 820 (0.2%) participants developed DCM. Higher MRS (HR=1.26 [1.18~1.34]) was associated with increased DCM risk, and such an association persisted across all robustness assessments even among non-MetS individuals. Waist circumference (WC, HR=1.36 [1.28~1.45], weight=0.58) and glycated hemoglobin (HR=1.23 [1.16~1.30], weight=0.22) dominated MRS' risk contribution. The trajectories of MRS diverged in cases approximately 10 years pre-diagnosis. MRS mediated 5.1~26.2% of lifestyle-related DCM risk, while inflammation mediated 16.4% of the MRS-DCM association. MR analysis further confirmed causal effects of MetS (OR=1.65 [1.45~1.88]), WC (OR=1.79 [1.58~2.03]) on DCM risk. Conclusions: Metabolic dysfunction, which was dominated by central adiposity and hyperglycemia, plays a key role in the occurrence of DCM. Early intervention targeting metabolic factors may prevent DCM onset.

Abstract Introduction: Cardiovascular disease is a leading cause of maternal and neonatal morbidity and mortality in the UK. Its prevalence in pregnancy continues to rise, driven by both improved survival of women with congenital and inherited heart disease into reproductive age and an increasing burden of acquired cardiovascular risk factors. However, its natural history and optimal management remain poorly defined. Current research is limited by small sample sizes, drawn from highly selected patient cohorts from individual units. The aim of the PREGnancy, HEART Health, and Cardiovascular Disease (PREG-HEART) study is to develop a patient driven, clinically relevant, digital platform to understand the epidemiology of cardiovascular disease in pregnancy and support clinical trials of management strategies. This paper provides the protocol for PREG-HEART, which will start with a 6-month pilot study. Methods and analysis: PREG-HEART will utilise an online, direct-to-patient platform to enrol patients with cardiovascular disease in pregnancy alongside healthy pregnant controls. Enrolled women will be invited to provide self-reported demographic and clinical data and consent to linkage with national health records for long-term follow up. We will also seek consent for storage and analysis of leftover clinical biosamples and to re-contact participants, enabling recruitment into sub-studies and clinical trials. Planned analysis for the pilot study at 6 months will assess feasibility, including recruitment rates, case-mix of cardiovascular diagnoses, and participant geographical, socio-economic, and ethnic background compared to the UK general pregnant population. Findings from the pilot study will inform subsequent phases of PREG-HEART, which will explore associations between different cardiovascular diagnoses and adverse cardiovascular, obstetric, and neonatal events. We will work closely with patients and clinicians to define priority research questions and use the PREG-HEART platform to support a range of observational and interventional studies to address these. Ethics: This study was approved by the West Midlands Solihull Research Ethics Committee. Registration details: PREG-HEART has been registered prospectively on the ISRCTN registry (ISRCTN11700499)

Importance: Assessment of cardiovascular health (CVH) during may unmask latent metabolic vulnerability and indicate long-term disease risk. However, the prognostic value of the AHA's Life's Essential 8 (LE8) framework during pregnancy remains uncertain. Objective: To evaluate CVH during using a modified Life's Essential 8 (mLE8) score in association with time to incident cardiometabolic disease. Design: Prospective cohort study with electronic medical record (EMR) surveillance for 7 years postpartum (August 2018-March 2026). Adjusted accelerated time-to-failure models estimated mLE8 associations with incident conditions. Setting: A population-based prenatal cohort recruited from a large academic medical system in South Carolina. Participants: Singleton pregnancies in individuals aged 18 to 44 years without pre-existing diabetes or cardiovascular disease (CVD) Exposures: A 7-component mLE8 score assessed during pregnancy, incorporating hypertensive disorders of pregnancy (HDP), 50-g glucose tolerance test results, pre-pregnancy body mass index, smoking status, sleep adequacy, diet quality, and physical activity. Scores ranged from 0 to 100, with higher scores indicating more favorable CVH. Main Outcomes and Measures: Post-delivery incident cardiometabolic conditions captured through EMRs and classified as chronic hypertensive conditions, chronic metabolic conditions (e.g., dyslipidemia, impaired glucose regulation), and CVD (e.g. cardiac arrest, cardiomyopathy). Time to incident diagnosis was measured in days from delivery. Results: Among 1,225 pregnancies (mean age, 25.0 [5.3] years), 499 incident cardiometabolic events occurred over a median follow-up of 6.2 (2.8) years. Each 10-point higher mLE8 score was associated with a longer time to incident diagnosis of chronic hypertensive conditions (time ratio [TR], 1.26; 95% CI, 1.11, 1.42) and chronic metabolic conditions (TR, 1.20; 95% CI, 1.11, 1.29). Healthier HDP, glucose, BMI, and sleep scores were most strongly associated with longer time to diagnosis of chronic metabolic disease. Results were robust to sensitivity analyses excluding individuals who developed gestational diabetes or HDP. Conclusions and Relevance: In this racially diverse, low-income cohort study of 1,225 pregnancies, better CVH during pregnancy was associated with a longer time to incident post-delivery diagnosis of cardiometabolic conditions. Pregnancy-based CVH assessment may help identify individuals with elevated and emerging cardiometabolic risk who could benefit from early, targeted intervention and enhanced longitudinal surveillance.

Background: Heart failure (HF) is a major and growing public health problem, and prior studies support a meaningful genetic contribution to HF susceptibility. Clinically, HF is commonly categorized into the major clinical sub-types of HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), which differ in pathophysiology and clinical profiles. However, previous genome-wide association studies have focused on autosomal variation and have routinely excluded the X chromosome, leaving X-linked genetic contributions to HF and its subtypes under-characterized. Methods: We performed X-chromosome wide association study (XWAS) utilizing directly genotyped data from 590,568 Million Veteran Program participants, including 90,694 HF cases across European, African, Hispanic, and Asian Americans. Sex- and ancestry-stratified logistic regression was used with XWAS quality control measures, adjusting for age and population structure, followed by fixed-effects multi-ancestry meta-analysis. Functional annotation, gene-based testing, fine-mapping, and colocalization were performed. We replicated genetic associations with all-cause HF in the UK Biobank. Results: In the multi-ancestry meta-analysis, we identified five X-chromosome-wide significant loci for all-cause HF, five for HFrEF, and one locus for HFpEF in males. No loci reached significance in female-specific analyses. In sex-combined analyses, we identified six loci for all-cause HF and four for HFrEF. The strongest and most emphasized signals mapped to genes were BRWD3, FHL1, and CHRDL1. Ancestry-specific analyses revealed additional loci, including NDP and WDR44 in African ancestry and PHF8 in Hispanic ancestry. One locus, BRWD3, was replicated in UK Biobank HF cohort. Integrated post-GWAS analyses (fine-mapping, colocalization and pleiotropy trait association studies) reinforced the biological plausibility of the X-linked signals. Conclusions: This multi-ancestry, sex-stratified XWAS identifies X-linked genetic contributions to HF and its subtypes and highlights the role of X-chromosome in heart failure pathogenesis.

BackgroundHypertension is the leading modifiable risk factor for ischemic stroke, yet the adequacy of preventative hypertension care in routine clinical practice remains suboptimal. Whether gaps in hypertension management represent missed opportunities for stroke prevention remains unclear. ObjectiveTo evaluate the association between hypertension care delivery and the risk of incident ischemic stroke. MethodsWe conducted a retrospective, matched, nested case-control study among adults with hypertension using electronic health record data from a large regional health system (2010-2024). Patients with a first-ever ischemic stroke were matched 1:2 to controls on age, sex, race and ethnicity, and calendar time. Three care metrics were assessed during follow-up: (1) outpatient visits with blood pressure (BP) measurement per year; (2) number of antihypertensive medication ingredients; and (3) medication intensification score. Conditional logistic regression estimated adjusted odds ratios (aORs). ResultsThe study included 13,476 cases and 26,952 matched controls (N = 40,428). Mean (SD) age was 64.8 (12.2) years, 54.1% were female, and mean follow-up was 2,497 (1,308) days. Cases had fewer BP visits per year (median, 2.50 vs. 3.01; p < 0.001), similar number of medication ingredients (2.00 vs 2.00), and lower treatment intensification scores (-0.211 vs - 0.125). In adjusted models, >5 BP visits per year was associated with lower stroke odds (aOR, 0.55; 95% CI, 0.51-0.59) compared with [&le;]1 visit. Use of 2-3 medication ingredients (vs 0) was also associated with reduced stroke odds (aOR, 0.80; 95% CI, 0.75-0.86), whereas >3 ingredients was not significant. The highest quartile of treatment intensification showed the strongest association (aOR, 0.47; 95% CI, 0.44-0.51). Findings were consistent across subgroup and sensitivity analyses, including strata defined by baseline SBP and follow-up SBP. ConclusionsGreater engagement in hypertension care was associated with lower odds of ischemic stroke, suggesting that gaps in routine management may represent missed opportunities for prevention.

Background: Cardiogenic shock (CS) remains associated with high short-term mortality despite contemporary advances in care. The association between institutional cardiac capability and outcomes?particularly among transferred patients and after accounting for clinical instability?remains incompletely defined. Objectives: To evaluate the association between hierarchical hospital cardiac capability and in-hospital mortality using a latent measure of acute physiologic severity. Methods: Using the National Inpatient Sample (2016?2022), hospitals were classified into five hierarchical tiers ranging from non-PCI (Tier 1) to heart transplant/durable LVAD centers (Tier 5). Generalized structural equation modeling (GSEM) assessed the relationship between hospital tier and mortality. A latent "Acute Severity" construct?comprising cardiac arrest, acute kidney and liver injury, and mechanical ventilation?was incorporated to model the effects of clinical instability Results: Among an estimated 1,177,180 CS hospitalizations, most occurred at cardiac surgical and transplant/LVAD centers. Crude mortality declined stepwise from non-PCI hospitals (64.5%) to transplant/LVAD centers (36.5%). After adjustment, higher hospital tier was independently associated with lower mortality (Tier 2 OR 0.43 [95% CI 0.38?0.48]; Tier 3 OR 0.37 [0.32?0.43]; Tier 4 OR 0.33 [0.30?0.38]; Tier 5 OR 0.35 [0.31?0.40]). Although transfer-in status was associated with increased mortality (OR 1.39 [1.33?1.46]), this association was attenuated at cardiac surgical and transplant/LVAD centers, consistent with a mitigation of transfer associated risk. Conclusions: Higher hospital cardiac capability is independently associated with lower mortality in CS. Advanced centers are associated with mitigation transfer-associated risk, supporting regionalized hub-and-spoke systems with early referral to high-capability centers.