Circulation: Heart Failure

Background. Patients with heart failure and reduced ejection fraction (HFrEF) commonly show signs of systemic inflammation. Interleukin-1 (IL-1) is a pro-inflammatory cytokine, known to modulate cardiac function. We aimed to determine the effects of treatment with anakinra, recombinant IL-1 receptor antagonist (IL-1Ra), on plasma IL-1Ra levels. Methods. We measured IL-1Ra levels at baseline and longest available follow-up to 24 weeks in 63 patients (44 males, 40 self-identified Black-Americans) with recent hospitalization for HFrEF, and systemic inflammation (C reactive protein [CRP] levels >2 mg/L) who were assigned to anakinra (N=42 [66.7%]) or placebo (N=21 [33.3%]) as part of the REDHART2 clinical trial (NCT0014686). Cardiorespiratory fitness was measured as peak oxygen consumption (peak VO2). Results. Baseline plasma IL-1Ra levels were 380 pg/ml (290 to 1046). On-treatment IL-1Ra levels were significantly higher in the patients treated with anakinra vs placebo (3,994 pg/ml [3,372 to 5,000] vs 492 pg/ml [304 to 1370], P<0.001). The longest available follow-up was 6 weeks in 10 patients (15.9%), 12 weeks in 12 patients (19%) and 24 weeks in 41 patients (65.1%). On-treatment IL-1Ra levels and interval change in IL-1Ra showed a modest inverse correlation with on-treatment CRP levels (R=-0.269, P=0.033 and R=-0.355, P=0.004, respectively) and no statistically significant correlations with peak VO2 values (P>0.05). Conclusions. Patients with recently decompensated HFrEF and systemic inflammation treated with recombinant IL-1Ra, anakinra, have a significant several-fold increase in plasma IL-1Ra levels. On-treatment IL-1Ra levels however show only a modest correlation with CRP levels and not with peak VO2.

Aims: Assessment of treatment response in HFrEF has largely relied on left ventricular (LV)-centric parameters, yet the left atrium (LA) plays a central role in modulating LV filling and reflects the cumulative hemodynamic burden. Whether discordant recovery between LV and LA function carries distinct prognostic implications in patients treated with ARNI-based therapy remains unknown. Methods and results: From the multicenter STRATS-HF-ARNI registry, 1,182 patients with HFrEF who underwent serial echocardiography at baseline and one-year follow-up were included. Patients were classified into four strain recovery phenotypes according to the direction of change in LVGLS and LASr at one year: Group A, concordant recovery (57.4%); Group B, discordant atrial non-recovery (11.2%); Group C, discordant ventricular non-recovery (15.6%); and Group D, concordant non-recovery (16.0%). Clinical outcomes included all-cause mortality, cardiovascular mortality, and HF hospitalization. Despite achieving LV functional improvement, Group B exhibited persistent LASr deterioration, accompanied by less favorable hemodynamic trajectories compared with Group A. On multivariable Cox regression, Group B was associated with significantly higher risks of all-cause mortality (adjusted hazard ratio [aHR] 3.53, 95% confidence interval [CI] 1.60-7.79) and cardiovascular mortality (aHR 5.68, 95% CI 1.91-16.92), comparable to Group D. Group C demonstrated higher HF hospitalization risk (aHR 2.25, 95% CI 1.31-3.86). The adverse prognostic impact of discordant atrial non-recovery was consistently observed across subgroups stratified by baseline LVGLS and LASr levels. Conclusion: In HFrEF patients treated with ARNI-based therapy, persistent LA dysfunction despite LV functional improvement identifies a high-risk phenotype comparable to concordant non-recovery. These findings suggest that concurrent assessment of LV and LA strain may provide incremental prognostic value beyond LV-centric metrics alone.

Background: Progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) can lead to worsening congestion requiring diuretic intensification (DI), heart failure (HF)-related hospitalizations (HFH), and death. Tafamidis was the only approved ATTR-CM therapy in the US from 2019 until the 2024 approval of acoramidis, which achieves near-complete ([&ge;]90%) TTR stabilization. As head-to-head trials are lacking, real-world comparative effectiveness (CE) data are needed to guide treatment selection. Objective: To evaluate real-world CE of acoramidis versus tafamidis in newly treated patients with ATTR-CM. Methods: Retrospective study using Komodo Healthcare Map (R) US claims data tokenized to Claritas. Patients newly initiating acoramidis or tafamidis between 12/11/2024 and 04/30/2025 with [&ge;]1 prescription claim (first defined as index date) and [&ge;]6 months of continuous enrollment preindex date were included and followed until disenrollment, death, treatment switch, or study end date (07/31/2025). Outcomes included DI (initiation or dose-equivalent escalation of oral loop diuretics, parenteral loop diuretic use, or addition of thiazide-like diuretic) and a composite of DI, HFH (inpatient admission with a HF-related ICD-10-CM diagnosis code in any position), and mortality. Propensity score weighting balanced baseline characteristics, disease severity, comorbidity burden, and baseline medication use. Time-to-event outcomes were assessed using weighted Cox proportional hazards models. Results: After weighting, acoramidis (n=170) and tafamidis (weighted sample size=448) patients were comparable at baseline (mean age, 78.6 vs 78.7 years; male, 80.0% vs 80.2%) with mean follow-up of 139 and 143 days, respectively. DI cumulative incidence curves separated early and remained divergent, with acoramidis significantly reducing the hazard of DI events by 43% compared with tafamidis (11.8% vs 20.5%; HR, 0.57; 95% CI, 0.35-0.92; P=0.021). Acoramidis also had a significantly lower risk of composite events, with a 34% reduction in hazard compared with tafamidis (17.6% vs 26.4%; HR, 0.66; 95% CI, 0.44-0.99; P=0.046). Conclusions: In this first real-world CE study of newly treated patients, acoramidis had significantly lower risk of DI events and composite events of DI, HFH, and mortality than tafamidis, potentially supporting improved clinical stability with acoramidis initiation. Additional evaluation with longer follow-up, larger cohorts, and/or prospective clinical outcomes is warranted.

PurposeObstructive sleep apnea (OSA) is a common comorbidity in heart failure (HF) patients with prevalence increasing as HF severity worsens. While CPAP/BiPAP has been shown to reduce disease burden and mortality in the general HF population, it is unclear whether these benefits extend to patients with left ventricular assist devices (LVADs). We sought to determine whether OSA affects long-term survival in newly implanted LVAD patients and whether CPAP/BiPAP treatment confers mortality benefits. MethodsThis single-center retrospective study included patients who underwent LVAD implantation between January 2007 and February 2022. Recipients were stratified by OSA status (OSA vs No-OSA), and those with OSA were further categorized based on CPAP/BiPAP compliance. Comparative statistics and Kaplan-Meier survival analyses were performed, with log-rank tests used to compare groups and assess survival differences. A Cox proportional hazards model was conducted to evaluate the association between risk factors and survival among patients with OSA and No-OSA. ResultsBefore LVAD implantation, patients with OSA had higher body mass index, hypertension, and a higher rate of implantable cardioverter-defibrillator placement than those without OSA. OSA was not associated with increased postoperative complications. Although survival did not differ significantly between OSA and No-OSA patients (p=0.33), CPAP/BiPAP-compliant OSA patients had significantly better survival than noncompliant patients (p=0.0099). ConclusionsLVAD patients with OSA who consistently use CPAP/BiPAP have better survival than those who do not. CPAP/BiPAP is a simple, low-risk treatment that can reduce mortality in this population. Therefore, increased perioperative screening for OSA should be considered for patients receiving LVADs. Multicenter studies are needed to confirm our findings further.

Abstract Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathy constitute the principal phenotypes of primary cardiomyopathy, yet both lack sufficient therapeutic options. Integrating genetic insights with detailed cardiac phenotyping offers a promising strategy to prioritize targets and elucidate their mechanisms of action. Methods: We conducted an three-stage analysis. First, drug-target Mendelian randomization (MR) was performed using cis-acting protein (pQTL) and expression (eQTL) quantitative trait loci as genetic instruments for potential drug targets. Second, we examined causal associations between 82 cardiac magnetic resonance (CMR)-derived imaging traits and HCM/DCM risk in a CMR-based MR analysis. Third, mediation MR was employed to quantify the proportion of the genetic effect of prioritized drug targets on cardiomyopathy risk that was mediated through specific CMR phenotypes. Results: Our analyses identified 19 and 13 potential therapeutic targets for HCM and DCM, respectively. CMR-based MR revealed that HCM risk was causally associated with increased right ventricular ejection fraction (RVEF) and greater left ventricular wall thickness, whereas DCM risk was linked to ventricular dilation, impaired myocardial strain, and altered aortic dimensions. Critically, mediation analysis established that these CMR traits served as significant intermediate pathways. The protective effect of ALPK3 on HCM risk was mediated through a reduction in myocardial wall thickness. Conversely, the effects of PDLIM5, HSPA4, and FBXO32 on DCM risk were exerted in part via alterations in aortic dimensions. Conclusion: This integrative genetic and imaging study systematically identify candidate therapeutic targets for HCM and DCM and delineates the specific CMR phenotypes through which they likely exert their causal effects. Our findings advance the understanding of disease pathogenesis and highlight new possibilities for improving the diagnosis and management of cardiomyopathy.

AimsCaveolae are plasmalemmal microdomains regulating stretch-dependent, nitric oxide (NO), and other signalling pathways governing myocardial structure, function and resilience. We have reported that global deletion of the scaffold protein cavin-1 disrupts caveolar biogenesis and impairs ventricular compliance and tolerance to ischaemic injury. However, cardiomyocyte-specific and sex-dependent roles of cavin-1 and caveolar complexes remain unresolved. Methods and ResultsWe generated a floxed Cavin-1 transgenic mouse, enabling cardiomyocyte-specific knockdown via adeno-associated virus (AAV) mediated expression of iCre recombinase driven by a cardiac-specific troponin T promoter. Knockdown was confirmed by RNA, protein, and immunofluorescence analyses, and cardiac function was assessed via echocardiography, left ventricular pressure-volume (PV) catheterisation, and ex vivo PV analysis of perfused hearts. Conditionally deleted hearts and myocytes exhibited up to 50% knockdown of Cavin-1 mRNA together with 15% deficiency in muscle-specific Caveolin-3, 70% depletion of caveolae, and mislocalisation of NO synthase (NOS) within cardiomyocytes. This was associated with elevated heart rate and shortened PR interval; reduced intraventricular and systolic blood pressures and peripheral resistance; and sex-dependent impairment of ventricular filling (females only). Diastolic dysfunction was detectable ex vivo, to a greater extent in male vs. female hearts. Mechanisms were sex-dependent, linked to interstitial fibrosis in females and NOS overactivity (inhibited by 100 {micro}M L-NAME) in males. Female hearts also exhibited increased susceptibility to ischaemia-reperfusion injury. Coronary function appeared preserved in both sexes, with intact reactive hyperaemic responses. ConclusionThis model identifies cardiomyocyte caveolae and cavin-1 as key determinants of myocardial function and compliance, involving sex-dependent remodelling and NOS signalling. By linking cardiomyocyte disruption to whole-organ and -body dysfunction, this model provides mechanistic insight into impaired function in heart failure and ageing. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/717104v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1aabf7forg.highwire.dtl.DTLVardef@1026839org.highwire.dtl.DTLVardef@108ad11org.highwire.dtl.DTLVardef@9a6dfd_HPS_FORMAT_FIGEXP M_FIG C_FIG

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.

Cardiovascular disease (CVD) remains the leading cause of mortality in the United States, despite being largely preventable through effective management of risk factors. This study evaluates the impact of Phase II cardiac rehabilitation (CR) on functional capacity and quality of life, using data from the Montana Outcomes Project Cardiac Rehabilitation Registry. Functional capacity improvements were assessed via the six-minute walk test (6MWT) and Dartmouth COOP questionnaire, with statistical analyses exploring the influence of CR session attendance, demographic factors, and referring diagnoses. Results demonstrated significant gains in 6MWT, with a mean improvement of 330.73 feet (p < .0001), and quality of life scores across all subgroups. A dose-response relationship was observed, indicating greater improvements with increased CR sessions (p < .0001), though diminishing returns were observed beyond 24-35 visits. Demographic factors and complex conditions influenced outcomes, underscoring the need for tailored strategies to enhance CR access and effectiveness. These findings highlight the critical role of CR in improving patient outcomes and emphasize the importance of addressing barriers to participation in underserved populations.

BackgroundThe adult mammalian heart lacks the regenerative potential required to replenish depleted cardiomyocytes and restore cardiac function after injury. Ischemic cardiac injury contributes to heart failure, a leading cause of death worldwide. Neonatal mice possess the capacity to regenerate injured myocardium and macrophages contribute to this process. The mechanisms contributing to the regenerative crosstalk between macrophages and cardiomyocytes remain incompletely elucidated and offer potential to inform future therapeutic strategies. MethodsTo test the immune contribution during cardiac regeneration, we studied the response to myocardial ischemia in neonatal mice after silencing myeloid hypoxia inducible factor 1 (Hif1) and reconstituting HIF-dependent mitogens. In parallel, we examined epigenetic and transcriptional signatures of the cardiac macrophage response and focused on intercellular crosstalk with cardiomyocytes. ResultsIn myeloid Hif1 deficient mice, cardiac regenerative function was lost after coronary ligation. This manifested through loss of ventricular systolic function and elevated myocardial scarring. HIF1 was found to be activated in resident-type cardiac macrophages after ischemic insult. Hypoxia stimulated macrophages to secrete insulin-like growth factor 1 (IGF-1), and this required Hif1. Parallel multiomic analysis revealed epigenetic regenerative signatures. ConclusionsThe data reveal an age-restricted requirement for myeloid Hif1 in neonatal cardiac regeneration, likely through IGF-1 signaling.

Background: Heart failure with reduced ejection fraction is a leading cause of death worldwide, characterized by impaired left ventricular systolic function. Contractile, structural, and electrophysiological changes underpin this impairment, but how these changes collectively determine ventricular function remains unclear. We hypothesize that their integrated action involves a complex mechanical interplay at the myocardial mesoscale level, intermediate between individual cardiomyocytes and the global left ventricle. Methods: We acquired high-resolution magnetic resonance images of healthy individuals and patients with myocardial infarction, and developed an analytical method to characterize in vivo contraction patterns in millimeter-sized myocardial units (i.e., at the mesoscale). Furthermore, we employed computational models to examine how mesoscale contraction patterns relate to the contraction mechanism, structure, and electrophysiology of the left ventricle. Results: At the left ventricular mesoscale, we observed that weakly contracting myocardial units are transiently elongated by the contraction of adjacent, more strongly contracting units. These mesoscale interactions generate a ?tug-of-war? that pervades the left ventricle in healthy hearts and becomes particularly prominent following myocardial infarction. This behavior is macroscopically invisible as the contraction patterns of opposing units cancel each other out, but it nevertheless shapes the efficiency of mechanical performance. In the healthy heart, recruitment of more uniformly contracting units (i.e., reduction in tug-of-war) supports augmented contractility during acute stress. However, following myocardial infarction, excessive tug-of-war contributes to impaired contractile efficiency and performance. Computational modelling showed that the ventricular contraction mechanism, structure, and electrophysiology underpin this behavior in healthy hearts and exacerbate it in disease. Conclusion: Left ventricular systolic function is characterized by a myocardial tug-of-war at the mesoscale, which contributes to the heart's adaptability in health and its vulnerability in disease. These findings introduce a new concept for understanding left ventricular function and a novel analytical approach for investigating its failure.

Backgound: Accurate assessment of diastolic function and left ventricular (LV) filling pressure is central to heart failure diagnosis and risk stratification. Contemporary guideline algorithms rely on complex parameters that are not consistently available in routine clinical practice. Objective: To compare the diagnostic and prognostic performance of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) and 2025 ASE guidelines with a deep learning model based on routinely acquired echocardiographic variables. Methods: This study evaluated the guideline-based algorithms and a deep learning model in participants from the Atherosclerosis Risk in Communities (ARIC) cohort (n=5450) for prognostication and two invasive hemodynamic validation cohorts from the United States (n=83) and Japan (n=130) for detection of elevated left ventricular filling pressure. Results: In the ARIC cohort, the deep learning model demonstrated superior prognostic performance compared with the 2016 and 2025 guidelines (C-index: 0.676 vs. 0.638 and 0.602, respectively; both p<0.001). Similar findings were observed among participants with preserved ejection fraction (C-index: 0.660 vs. 0.628 and 0.590; both p<0.001), with improved performance compared with the H2FPEF score (C-index: 0.660 vs. 0.607; p<0.001). In the US hemodynamic validation cohort, the deep learning model showed higher diagnostic performance than the 2025 guidelines (AUC: 0.879 vs. 0.822; p=0.041) and similar performance compared with the 2016 guidelines (AUC: 0.879 vs. 0.812; p=0.138). In the Japanese hemodynamic validation cohort, the deep learning model outperformed both guidelines (AUC: 0.816 vs. 0.634 and 0.694; both p<0.05). Conclusions: A deep learning model leveraging routinely available echocardiographic parameters demonstrated improved diagnostic and prognostic performance compared with contemporary guideline-based approaches, potentially offering a scalable alternative for assessing diastolic function and left ventricular filling pressures.

Abstract Aims: While traditional anthropometric indices are established cardiovascular predictors, their prognostic value for incident infective endocarditis (IE) remains undefined. Methods: We included 386,859 participants (mean age 57.0 years; 52.9% female) from the UK Biobank between 2006 and 2010 with standardized baseline data on BMI, waist circumference (WC), waist-to-height ratio (WhtR), and the triglyceride-glucose (TyG) index.Multivariable Cox proportional hazard models with restricted cubic splines were used to estimate the hazard ratio (HR) of these indices, adjusting for demographic and clinical risk factors. Results: Over 16.87 median years (25th, 16.02; 75th, 17.60 percentile) of follow-up, there were a total of 1,124 incident IE events. During the follow-up period, 38,342 total deaths were recorded, of which 8,524 were cardiovascular disease (CVD)-related.Overall, compared to individuals with normal weight and baseline metabolic indices, those in the fourth quartile of WC, WHtR, and TyG index exhibited the highest risk of incident IE. Compared to other metabolic indices, WC (HR = 1.53, 95% CI 1.23?1.90,P < 0.001) and WHtR (HR = 1.46, 95% CI 1.20?1.78,P < 0.001) demonstrated higher relative increases in risk associated with IE. Furthermore, the risk of IE was significantly elevated among the younger population with abdominal obesity and concomitant diabetes. However, no significant increase in IE risk was observed among participants with pre-existing valvular heart disease (P = 0.796). Conclusion: Compared with BMI, higher WC and WHtR were robustly associated with increased risk of IE, even after adjusting for traditional risk factors. Furthermore, the risk of IE was markedly elevated among younger individuals with abdominal obesity and diabetes.

BackgroundIt has been demonstrated that stem cell transplantation promotes healing of the infarcted heart through paracrine effects. However, the therapeutic potential of exosomes secreted by hiPSC-derived epicardial cells (hEP-Exos) for treating infarcted hearts remains unclear. Myocardial infarction (MI) can trigger EP activation, increasing EP paracrine function. Therefore, this study aims to determine and compare the cardioprotective effects of exosomes secreted by hEPs under normoxic (Exo-N) and hypoxic (Exo-H) conditions in MI mice and to explore the underlying mechanisms. MethodsTwo types of exosomes were collected by ultracentrifugation and delivered via intramyocardial injection in a murine MI model. The protective effects of Exo-N and Exo-H on the infarcted heart were assessed using echocardiography, histological examination, and immunofluorescence analysis. Additionally, microRNA sequencing, luciferase activity assays, and miRNA gain-and loss-of-function experiments were performed to identify enriched miRNAs and investigate their roles in different exosome populations. ResultsIn vitro, both Exo-N and Exo-H enhanced the migration and tube-formation capacities in human umbilical vein endothelial cells (HUVECs) and reduced the apoptosis in hiPSC-derived cardiomyocytes (hCMs) under oxygen-glucose deprivation (OGD), with Exo-H exhibiting a stronger effect. In vivo, both Exo-N and Exo-H significantly improved contractile function, reduced infarct size, and mitigated adverse remodeling in mouse hearts with MI, accompanied by increased cardiomyocyte survival and angiogenesis, with Exo-H showing superior efficacy. Mechanistically, miRNA sequencing revealed distinct cargo profiles between Exo-N and Exo-H. miR-214-3p was identified as a key mediator of the enhanced therapeutic potency of Exo-H. miR-214-3p promoted EC angiogenesis by suppressing vasohibin-1 and attenuated cardiomyocyte mitochondrial fission and apoptosis by suppressing mitochondrial elongation factor 2 (MIEF2). ConclusionsThis study demonstrates that administration of hEP-Exos, particularly Exo-H, provides robust cardioprotection by enhancing cardiomyocyte survival and angiogenesis, potentially mediated by miR-214-3p. These findings suggest that conditioned hEP-Exos could be a promising and effective acellular therapeutic option for treating MI.

Introduction: Spontaneous coronary artery dissection (SCAD) is frequently accompanied by persistent symptoms of unknown pathogenesis after the index event. Autonomic dysfunction is a plausible mechanism for these but has not been systematically characterized. We quantified antecedent and contemporary autonomic symptoms in survivors of SCAD and examined their associations with cardiac and extra-cardiac symptoms and health-related quality of life. Methods: This cross-sectional study recruited 227 volunteers from multiple countries with a self-reported history of SCAD. Participants completed validated patient-reported measures, including the Composite Autonomic Symptom Score-31 (COMPASS-31), Anxiety Sensitivity Index-3 (ASI-3), and EuroQol-5 Dimension-5L (EQ-5D-5L). They also completed an internally derived retrospective autonomic predisposition score assessing symptoms during adolescence and early adulthood. Results: Participants were predominantly female (97.8%), median age 53 (47-58) years, and were surveyed a median of 3 (1-5) years after their index SCAD event. 21.6% reported SCAD recurrence. Moderate autonomic symptom burden (COMPASS-31 20) was present in 56.4% and severe burden (40) in 16.3%. History of antecedent autonomic symptoms was the strongest independent predictor of contemporary autonomic symptom burden after adjustment for demographic and clinical covariates (=0.514; P <0.001). Greater autonomic symptom burden independently predicted lower EQ-5D health utility (=0.150; P=0.029) and was associated with the ASI-3 physical concerns (=0.232; P <0.001), but not social concerns domain. Autonomic symptoms were not associated with SCAD recurrence. Conclusion: Symptoms of autonomic dysregulation are common in survivors of SCAD and are associated with reduced quality of life. Their association with antecedent dysautonomic features during adolescence and early adulthood suggests a longstanding predisposition, the significance of which warrants further evaluation.

Introduction: Smoking cessation after acute coronary syndrome (ACS) is a Class I recommendation, yet prescription pharmacotherapy use remains low and its real-world cardiovascular effectiveness when added to nicotine replacement therapy (NRT) is poorly characterized. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network (67 healthcare organizations). Adults hospitalized with ACS who received NRT within one month, serving as a proxy for active smoking status, were identified. Two co-primary propensity-matched (1:1, 50 covariates, caliper 0.10 SD) comparisons evaluated bupropion + NRT and varenicline + NRT individually versus NRT alone; a supportive analysis evaluated combined pharmacotherapy versus NRT alone. All-cause mortality was the primary endpoint. Secondary outcomes included MACE, heart failure exacerbations, major bleeding, TIA/stroke, emergency rehospitalizations, and cardiac rehabilitation utilization, assessed at 6 months and 1 year via Kaplan-Meier analysis. Hazard ratios (HRs) greater than 1.0 indicate higher hazard in the NRT-only group. Results: After matching, the combined analysis comprised 8,574 pairs, the bupropion analysis 4,654 pairs, and the varenicline analysis 2,126 pairs. At 1 year, the combined pharmacotherapy group had significantly lower all-cause mortality (HR 1.26, 95% CI 1.16-1.37), MACE (HR 1.16, 95% CI 1.12-1.21), heart failure exacerbations (HR 1.16, 95% CI 1.08-1.25), major bleeding (HR 1.18, 95% CI 1.08-1.28), and greater cardiac rehabilitation utilization (HR 0.82, 95% CI 0.74-0.92; all p < 0.001). TIA/stroke did not differ significantly. Six-month results were consistent. Both varenicline and bupropion individually showed lower mortality and MACE. A urinary tract infection falsification endpoint showed no between-group differences, supporting matching validity. The pharmacotherapy group had higher rates of new-onset depression, driven predominantly by bupropion recipients. Conclusions: In this propensity-matched real-world analysis, adding prescription smoking cessation pharmacotherapy to NRT after ACS was associated with lower mortality and fewer adverse cardiovascular events, supporting broader integration into post-ACS care pathways.

Introduction: Accurate stratification of hard atherosclerotic cardiovascular disease (ASCVD) risk remains challenging despite advances in prevention. Liver function biomarkers (LFBs), particularly gamma - glutamyl transferase (GGT), have been linked to cardiovascular outcomes, yet their contribution to hard ASCVD risk prediction is not well defined. Methods: This study analyzed data from the National Health and Nutrition Examination Survey (NHANES, 2005 - 2018) to assess cross - sectional associations between LFBs and 10 - year hard ASCVD risk estimated by the ACC/AHA Pooled Cohort Equations. Multivariable regression, restricted cubic splines, and mediation analyses were applied to examine independent and dose - response relationships. External validation was performed in the China Health and Retirement Longitudinal Study (CHARLS) and NHANES using machine learning models (CoxBoost, Naive Bayes and Random Forest). Results: Among 5,731 NHANES participants, GGT showed an independent linear association with hard ASCVD risk (P - trend = 0.003), partly mediated by systolic blood pressure (44.8%), HbA1c (19.0%), and high density lipoprotein cholesterol (13.4%). Machine learning (ML) models incorporating GGT, alkaline phosphatase (ALP), and globulin alongside traditional risk factors improved predictive accuracy, with Naive Bayes achieving an AUC of 0.751 in NHANES validation. Conclusions: GGT is an independent and biologically plausible biomarker of hard ASCVD risk, acting through cardiometabolic pathways. Incorporating LFBs into risk prediction models, particularly with machine learning, enhances risk stratification and may facilitate early identification of high - risk individuals.

IntroductionPreterm pre-eclampsia is associated with increased risk of later cardiovascular disease. This study examines cardiometabolic health 3-6 years post-preterm pre-eclampsia and explores whether early postnatal cardiovascular phenotypes relate to later cardiovascular morbidity. MethodsPICk-UP trial participants who experienced preterm pre-eclampsia underwent assessments including anthropometry, blood pressure (BP), arteriography, echocardiography, biomarkers and cardiac magnetic resonance (CMR) imaging 3-6 years postpartum. The primary outcome was hypertension prevalence, with secondary outcomes including cardiac fibrosis, remodelling, and function, obesity, and lipid abnormalities. Associations between baseline, pregnancy and postnatal characteristics with the primary and secondary outcomes were explored. ResultsForty-five women were included; 37 underwent echocardiography and 20 had CMR. At 3-6 years, 53% had hypertension, 32% developed de novo hypertension, 30% had adverse left ventricular (LV) remodelling, 49% had diastolic dysfunction, and 27% were obese. Myocardial fibrosis was detected in 35% of CMR participants. No cardiovascular measures changed from 6 months postpartum to 3-6 years. Women who developed hypertension demonstrated higher BP and LV mass index, from 6 weeks postpartum, with distinct postnatal BP trajectories. Women with myocardial fibrosis exhibited higher sFlt and CRP concentrations from 6 weeks postpartum, with sFlt correlating with native T1 at 3-6 years. DiscussionWomen with prior preterm pre-eclampsia show significant cardiometabolic morbidity 3-6 years postpartum. Early postnatal phenotypes indicate long-term cardiovascular risk. Persistent anti-angiogenic imbalance and inflammation may contribute to myocardial fibrosis. Early BP, weight, and biomarker measurement may help identify at-risk women, warranting further studies on optimising postnatal care to mitigate cardiovascular risk after preterm pre-eclampsia.

Introduction: Hypertrophic Cardiomyopathy (HCM) is a disease defined by the development of left ventricle hypertrophy. One of the most commonly mutated genes in HCM is cardiac myosin binding protein C (MYBPC3). MYBPC3 protein localizes to the cardiomyocyte sarcomere, but studies have reported detection of both MYBPC3 RNA and protein in non-cardiomyocyte cell populations. Therefore, it was unclear if MYBPC3 expression in non-cardiomyocyte cell populations altered the development of cardiomyopathy caused by MYBPC3 protein deficiency. Methods: We utilized genetically modified murine models with germline deletion of Mybpc3 exons 3 to 5 (Mybpc3-/-) or cardiomyocyte specific deletion of Mybpc3 exons 3 to 5 (Mybpc3fl/fl ; Myh6-Cre). Gene expression was assessed using quantitative RT-PCR. Whole tissue protein levels were assessed using immunoblots. Immunohistochemistry and proximity ligation assays were performed to evaluate in situ protein expression. Echocardiography was utilized to measure left ventricular structure and function. Results: Mybpc3 mRNA was detected in multiple organs including the heart, lung and blood from both humans and mice. Utilizing transgenic murine models with germline or cardiomyocyte specific deletion of Mybpc3 exons 3-5, we discovered that the Mybpc3 mRNA detected in extracardiac locations originated primarily from cardiomyocytes. Likewise, MYBPC3 protein was identified in myocardial tissue but not in other organs and cardiomyocytes were the only cell population in myocardial tissue that had detectable MYBPC3 protein. Importantly, cardiomyocyte deletion of Mybpc3 caused similar pathological myocardial remodeling and alterations in left ventricular function compared to germline deletion of Mybpc3 in all cell populations. Conclusions: Our results show that cardiomyocytes are the primary cell source of Mybpc3 mRNA detected in extracardiac organs and they are the principal cell type responsible for the cardiomyopathy caused by MYBPC3 protein deficiency. These results suggest that selective targeting of cardiomyocytes should be the most efficient approach to treat cardiomyopathies associated with MYBPC3 deficiency.

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.

Background: Increased epicardial adipose tissue volume (EATV) is a potentially important risk marker for coronary artery disease (CAD) available from cardiac computed tomography (CT) images. Sex-differences and effects of age and body size on EATV have been insufficiently explored, and no reliable reference values exist. Consequently, EATV has yet to find its deserved use in clinical practice. Objectives: To define normal values by sex and age, the best normalization procedure for EATV to neutralize effects of body-size, explore the relationship between normalized EATV and cardiac risk, and propose a clinically meaningful cut-off. Methods: AI-based automated EATV data from the general population (n=25,155) and a clinical cohort (n=2,482) with suspected CAD was normalized to height, BSA and heart volumes. Correlation between EATV and EAT attenuation was tested with Spearman?s rank correlation and linear regression to find the optimal normalization. Normalized EATV was compared to high-risk by SCORE2 and obstructive CAD in the population cohort. A cut-off including 95% of cases with obstructive CAD was defined in the general population and tested in the clinical cohort. Results: EATV varied with sex and age across cohorts. Normalization of EATV to total heart volume (EATVh) was superior by all metrics and neutralized the effects of sex. High-risk by SCORE2 and the prevalence of obstructive CAD increased over quartiles of EATVh in the population cohort, and significantly higher EATVh was seen with obstructive CAD in both cohorts. A cut-off of 0.1 in EATVh had a negative predictive value for obstructive CAD of 97.1% in the general population and 88.9% in the clinical cohort. Conclusions: EATV varies considerably with sex, age and body size. Normalization to heart volume outperformed other procedures, and EATVh is a useful marker of obstructive CAD in both the general population and symptomatic patients.