Circulation

BackgroundElevated lipoprotein(a) [Lp(a)] is causally implicated in atherosclerotic cardiovascular disease, but its prospective association with incident ischemic stroke in real-world clinical populations remains incompletely characterized. Observational data are complicated by testing-indication bias and aggressive preventive management in identified high-Lp(a) patients. MethodsWe conducted a retrospective cohort study using the TriNetX US Collaborative Network (66-67 healthcare organizations). Adults with Lp(a) measurements (LOINC 10835-7; January 2015-December 2025) were categorized as C-HIGH (Lp(a) [&ge;]50 mg/dL) or C-LOW (<50 mg/dL) and balanced by 1:1 propensity score matching on cardiovascular diagnoses, medications, tobacco history, and four laboratory variables. Pre-specified analyses included an alternative cutoff ([&ge;]30 mg/dL), dose-response evaluation across three strata, and a 2-year landmark analysis. ResultsAfter expanded propensity score matching, the primary analysis included 97,882 matched adults (48,941 per arm). Incident ischemic stroke/TIA occurred in 2.45% vs 2.69% (Cox HR 0.956, 95% CI 0.878-1.041; log-rank p=0.299). The Lp(a) [&ge;]30 mg/dL sensitivity analysis (121,076 matched) yielded HR 0.947 (0.878-1.023; p=0.168). Dose-response analysis showed no significant association at any stratum. A 2-year landmark analysis confirmed a null late-period effect (HR 1.071, 0.905-1.268; p=0.427). A post-hoc composite (stroke/TIA, cardiac arrest, heart failure) was null (HR 0.979; p=0.512). A broader MACE-like composite including MI yielded a nominally significant Cox HR of 1.058 (1.004- 1.116; p=0.034), with entirely null crude estimates, attributable to differential follow-up time. ConclusionsElevated Lp(a) was not associated with incident ischemic stroke or TIA across multiple thresholds and follow-up windows in this large federated cohort. These real-world findings are consistent with testing-indication bias and treatment attenuation in clinically identified high-Lp(a) populations.

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.

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@34b48forg.highwire.dtl.DTLVardef@3a2be1org.highwire.dtl.DTLVardef@116e8e6org.highwire.dtl.DTLVardef@1147b94_HPS_FORMAT_FIGEXP M_FIG C_FIG

Acute myocardial infarction (MI) is associated with severe metabolic and oxidative stress that triggers cardiomyocyte death, pro-inflammatory signaling and progressive structural remodeling frequently culminating in heart failure. Although significant advances in reperfusion therapy improved acute survival in patients, therapeutic strategies that directly target intracellular processes in response to injury remain limited. One key response mechanism, autophagy, is rapidly activated to ameliorate ischemic stress. Yet, defective autophagic flux may exacerbate cardiomyocyte injury and maladaptive tissue remodeling. Here we identify FYCO1 as a cardiomyocyte- enriched key regulator of autophagy that enhances autophagic flux and promotes myocardial resilience following ischemic injury. Using cardiomyocyte-specific FYCO1 transgenic mice subjected to permanent coronary ligation, we demonstrate that FYCO1 overexpression limits infarct expansion, reduces cardiomyocyte injury, and preserves cardiac function during remodeling. In vivo RFP-EGFP-LC3 autophagy reporter analyses reveal that FYCO1 promotes a sustained increase of autophagic flux by coordinating autophagosome formation and efficient autolysosomal clearance. Transcriptomic profiling identifies a cardioprotective gene program in FYCO1-Tg animals subjected to MI, with suppression of proinflammatory, proapoptotic and stress-response pathways. Systemic serum cytokine and chemokine profiling as well as transcriptomic analyses of myocardium confirm reduced inflammatory signaling and subsequent reduction in macrophage recruitment into the infarct border zone. Together these findings position FYCO1 as a key regulator of cardiomyocyte autophagy and reveal a previously unrecognized link between autophagy and inflammation in shaping cardiac remodeling following myocardial infarction. FYCO1-mediated autophagy promotes myocardial preservation and functional recovery, highlighting autophagic flux as a promising target for cardioprotective interventions.

BackgroundInflammation is an emerging target for stroke prevention, but additional therapeutic candidates are needed. Experimental and observational studies implicate tumor necrosis factor (TNF) in atherosclerotic plaque progression and cardiovascular events. We integrated plasma proteomics from population-based studies and prospective stroke cohorts with single-cell and spatial transcriptomic profiling of human atherosclerotic plaque to investigate TNF signaling in stroke pathogenesis. MethodsWe assessed associations between 34 TNF-superfamily proteins (Olink Explore) and incident ischemic stroke among 47,529 UK Biobank participants without cardiovascular disease. We performed an individual-participant data (IPD) meta-analysis of four prospective cohorts with ischemic stroke (n=2,180) to examine associations between TNF- and recurrent vascular events. We characterised plaque-level TNF biology using single-cell RNA sequencing of 259,116 cells (62 donors) and Xenium spatial transcriptomics (12 donors) with human carotid plaques. ResultsIn UK Biobank, higher circulating TNF pathway proteins were independently associated with incident stroke after multivariable adjustment, including TNF, TNFR1, and TNFR2 (Hazard Ratio [HR] per SD increase, 1.14, [95% CI 1.07-1.20], 1.22, [1.14-1.31], and 1.15 [1.09-1.21], respectively. An additional 15 TNF superfamily members were also associated with incident stroke. In the IPD analysis of stroke cohorts, TNF- was associated with recurrent stroke (risk ratio [RR] 1.50, 95% CI 1.14-1.98, top vs. bottom third of TNF-) and MACE (RR 1.54, 1.18-2.02) after adjustment for cardiovascular risk factors and secondary prevention medications (537 MACE events, 6793 person-years follow up). In single-cell RNA plaque sequencing, TNF and TNF pathway genes were broadly expressed across immune cell populations. In spatial transcriptomics, TNF detection increased progressively from media to fibrous cap (Odds Ratio 2.32 vs media, 95% CI 1.94-2.78, p<0.001). At the fibrous cap, CD8+ effector T cells demonstrated 4.1-fold enrichment for TNF expression despite comprising only 3% of fibrous cap cells. ConclusionsTNF signaling is independently associated with incident ischemic stroke and recurrent MACE after stroke. TNF is enriched in human carotid plaque at the fibrous cap, in macrophages and CD8+ effector T cells. These results support evaluation of TNF-targeted therapies for stroke prevention.

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.

Cardiac fibrosis driven by persistent myofibroblast activation is a major contributor to adverse ventricular remodeling and heart failure. Bromodomain and extra-terminal domain (BET) inhibition reduces fibrosis and hypertrophy in preclinical models, but direct targeting of the BET co-activator BRD4 is limited by family homology and potential systemic toxicity. Sertad4 (SERTA domain containing protein 4) is a BRD4-dependent gene induced in activated cardiac fibroblasts, yet its role in cardiac pathology is unknown. Here, we examined Sertad4 expression and function in human heart failure and in murine myocardial infarction (MI). SERTAD4 protein was increased in left ventricular tissue from heart failure patients compared with non-failing controls. In Sertad4/LacZ reporter mice, MI triggered strong Sertad4 activation localized to the infarct scar and border zone, with minimal expression in remote myocardium; single-nucleus RNA sequencing further demonstrated that Sertad4 expression is predominantly fibroblast-restricted and significantly upregulated after MI. To test causality, we subjected global Sertad4 knockout mice to 28-day left anterior descending coronary artery ligation. Sertad4 deletion attenuated post-MI remodeling, reduced hypertrophy and ventricular dilation, and preserved systolic function. Consistent with improved structure and function, knockout hearts exhibited reduced cardiomyocyte cross-sectional area and decreased expression of fibrosis and hypertrophy associated genes. Together, these findings identify Sertad4 as a fibroblast enriched regulator of pathological remodeling and suggest that targeting Sertad4 may offer a more cell type-selective alternative to direct BET/BRD4 inhibition for limiting cardiac fibrosis and progression to heart failure

BackgroundPreeclampsia is a leading cause of maternal and perinatal morbidity and mortality, and a major contributor to low birth weight. Beta blockers (BB) and calcium channel blockers (CCB) are the most commonly recommended agents to treat hypertension in pregnancy. Yet it remains unknown whether these agents alter the risk of preeclampsia (PE), and if so, whether effects arise through maternal physiology or through direct fetal mechanisms. ObjectivesTo use drug-target Mendelian randomization (MR) to estimate the effects of genetically-proxied inhibition of beta-adrenergic and L-type calcium-channel targets on PE risk, birth weight, partitioned into maternal and fetal genetic components, and gestational age (GA). MethodsWe constructed instruments from genome-wide significant, LD-independent variants within prespecified windows around systolic blood pressure (SBP) modulating drug targets in addition to a genome-wide SBP instrument (European ancestry). Outcomes comprised of PE (16,349 cases / 595,135 controls), maternal and fetal genetic effects on birth weight (n{approx}210,267 and n{approx}298,142), and GA (n{approx}151,987). Two-sample MR estimated effects per 5mmHg decrease in SBP. Bayesian colocalization assessed shared causal variants. Multiple testing was controlled with Benjamini-Hochberg correction. ResultsGenetically lower SBP was associated with reduced PE risk and modest increases in birth weight and GA. BB (ADRB1) target inhibition showed no convincing reduction in PE risk but was associated with lower birth weight, with associations predominantly through direct fetal genetic effects and strong colocalization at ADRB1 with fetal birth-weight signals. In contrast, CCB targets collectively associated with lower PE risk without consistent evidence of fetal growth impairment; colocalization support for individual CCB loci was limited. Sensitivity analyses (heterogeneity, pleiotropy) did not materially alter these patterns where instrument counts permitted. ConclusionsDrug-target MR suggests that BB pathways are unlikely to meaningfully reduce PE and are linked to reduced fetal growth - chiefly via direct fetal mechanisms. In contrast, CCB pathways are associated with lower PE risk and largely neutral fetal growth effects. These findings support prioritizing CCBs for evaluation in comparative trials of PE prevention.

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@8e9712org.highwire.dtl.DTLVardef@16043f5org.highwire.dtl.DTLVardef@10d8ea2org.highwire.dtl.DTLVardef@10f3566_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.

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.

AbstractO_ST_ABSBackgroundC_ST_ABSGuidelines recommend that patients with coronary artery disease (CAD) lower their low-density lipoprotein cholesterol (LDL-C) using maximally tolerated statin therapy to prevent recurrent events. MethodsWe analyzed the prevalence of statin nonuse and an LDL-C [&ge;]70 mg/dL in patients [&ge;]18 years of age in the Get With The Guidelines-CAD registry with known CAD who were hospitalized for a new myocardial infarction or unstable angina in 2023-2024. Data collection on statin use and LDL-C at arrival is optional in the registry. ResultsAmong 34,003 patients included (mean age 68 years; 71% male; 73% white), 31.6% did not use a statin before admission. The prevalence of statin nonuse was higher in women than in men (adjusted prevalence ratio [aPR] 1.08; 95% confidence interval [95%CI] 1.04, 1.14). LDL-C was not documented in 30.7% of patients. Among patients not using and using a statin, 74.6% and 49.8%, respectively, had an LDL-C [&ge;]70 mg/dL. Women were more likely than men to have an LDL-C [&ge;]70 mg/dL, whether using or not using a statin (aPR 1.18 [95%CI 1.13, 1.24] and 1.08 [95%CI 1.04, 1.12], respectively). Black and Hispanic patients were more likely to have an LDL-C [&ge;]70 mg/dL compared to their white counterparts (aPR 1.30 [95%CI 1.24, 1.37] and 1.11 [95%CI 1.03, 1.19], respectively) among those using a statin. There were no statistically significant differences in LDL-C by race/ethnicity among those not using a statin. ConclusionTargeted quality improvement initiatives are needed to address ambulatory cholesterol treatment gaps in patients with known CAD. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIIn a contemporary national registry of patients with known coronary artery disease hospitalized for recurrent acute coronary syndromes, about one-third were not using statin therapy prior to admission. C_LIO_LIApproximately three-quarters of statin nonusers and one-half of statin users had an LDL-C level [&ge;]70 mg/dL at admission, indicating substantial residual risk despite current guideline recommendations. C_LIO_LIWomen and Black and Hispanic patients were more likely to have inadequately controlled LDL-C, particularly among those already receiving statin therapy. C_LI What Are the Clinical Implications?O_LIPreventable ambulatory cholesterol treatment gaps frequently occur before recurrent coronary events, underscoring the need for more guideline-recommended outpatient lipid management. C_LIO_LIRoutine LDL-C monitoring and timely intensification of lipid-lowering therapy, including high-intensity statins and add-on therapies when indicated, should be prioritized after coronary events. C_LIO_LITargeted quality improvement strategies in the ambulatory setting are needed to address persistent cholesterol treatment gaps in secondary prevention care, including sex- and race/ethnicity-related disparities. C_LI

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.

ImportanceStandard cardiovascular risk scores fail to predict a substantial fraction of incident vascular clinical events in the general population. Whether circulating neurofilament light chain (NfL), a blood-based biomarker of neuronal axonal injury, independently predicts major cardiovascular or cerebrovascular disease outcomes in adults without known baseline clinical disease has not been tested. ObjectiveTo determine whether plasma NfL is independently associated with incident cardiac and brain vascular events in community-recruited adults and whether it adds prognostic information beyond established clinical risk factors. Design, Setting, and ParticipantsProspective cohort analysis within the UK Biobank. Plasma NfL was quantified using the Olink Explore proximity extension assay in 50,043 adults aged 40-69 years at recruitment. After excluding 3,914 participants with baseline known disease, the primary analysis included 46,129 adults. Incident events were ascertained via registry linkage over a median follow-up of 9.6 years. ExposuresPlasma NfL, quantified in Olink Normalized Protein eXpression (NPX) units. Main Outcomes and MeasuresPrimary outcome: major cardiovascular event (MVE), defined as the composite of cardiovascular death, nonfatal stroke, and nonfatal MI. Secondary outcomes: individual MVE components, heart failure hospitalization, and all-cause mortality. ResultsAmong 46,129 participants free of baseline disease diagnoses, there were 2,912 incident MVE events. After adjustment for age, sex, BMI, smoking, hypertension, diabetes, and renal function, each one-NPX-unit increase in NfL was independently associated with MVE (aHR 1.46 (95% CI 1.36-1.57; P < .001)), nonfatal stroke (aHR 1.38 (95% CI 1.22-1.57; P < .001)), MI (aHR 1.35 (95% CI 1.22-1.50; P < .001)), cardiovascular death (aHR 1.79 (95% CI 1.59-2.01; P < .001)), heart failure hospitalization (aHR 1.50 (95% CI 1.36-1.65; P < .001)), and all-cause mortality (aHR 1.21 (95% CI 1.18-1.25; P < .001)). The associations were log-linear with no evidence of a threshold or saturation effect. Results were consistent in a sensitivity analysis including the full cohort with baseline vascular disease diagnoses. Addition of NfL to traditional risk factors improved 10-year discrimination most for cardiovascular death (C-statistic 0.809 to 0.817; {Delta}C = 0.007), heart failure ({Delta}C = 0.006), and stroke ({Delta}C = 0.008), with a smaller increment for the MVE composite. Conclusions and RelevancePlasma NfL was independently associated with incident cardiovascular and cerebrovascular outcomes among community-recruited adults after comprehensive risk-factor adjustments. These findings suggest that blood NfL levels may serve as a biomarker of subclinical vascular disease, strengthening early detection efforts and prompting further diagnostic evaluation.

COL4A1-related disorders cause early-onset stroke, intracerebral haemorrhage, visual impairment and kidney disease, often affecting children and young adults, yet no disease-modifying therapies exist. These disorders arise from pathogenic COL4A1 variants that disrupt type IV collagen and impair small-vessel integrity, leading to cerebral small-vessel disease and endothelial dysfunction. We performed a mechanism-guided screen in human brain endothelial cells using a CRISPR-engineered COL4A1 p.G755R line and patient-specific COL4A1 p.G773R iPSC-derived endothelial cells. Simvastatin, L-carnosine, and XPD-101 restored impaired endothelial proliferation, migration, and other markers of endothelial function, including transendothelial electrical resistance (TEER). In a Col4a1Svc/+ mouse model, simvastatin increased pre-weaning survival, improved functional behaviour and reduced cerebral microhaemorrhage burden. These findings identify mechanism-informed candidates that rescue COL4A1-mutant endothelial dysfunction in vitro, with simvastatin demonstrating in vivo efficacy, supporting prioritisation for further preclinical development.

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.