Circulation

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.

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

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

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

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.

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.

BackgroundGenetic studies using cardiac magnetic resonance (CMR) imaging have identified loci related to cardiac shape, but most focus on static morphology. The value of a dynamic cardiac shape atlas capturing both shape and function remains unknown. MethodsA dynamic shape atlas comprising CMR-derived shape models at end-diastole and end-systole was combined with genetic and outcome data in 36,992 UK Biobank participants. Dynamic shape principal components (PCs) describing >1% of variance were characterized, and tested for associations with prevalent and incident cardiometabolic diseases, including ischemic heart disease (IHD), heart failure (HF), significant atrioventricular block (AVB), and atrial fibrillation (AF), and independent predictive power alongside standard CMR measures. Genome-wide association studies (GWAS) were performed to identify candidate genes and biological pathways, and polygenic risk scores (PRS) were assessed for disease associations. Mendelian randomization (MR) was performed to test causality of observed disease associations. ResultsWe identified 14 dynamic cardiac shape PCs capturing 83.3% of total dynamic cardiac shape variance. These PCs captured distinct functional remodeling patterns such as variation in annular plane systolic excursion, while remaining only modestly correlated with standard CMR measures. All 14 PCs were associated with at least one incident cardiometabolic disease, with the strongest associations observed for incident IHD, HF, and AVB. Notably, incorporating dynamic shape PCs improved the prediction of incident IHD beyond standard CMR measures. GWAS identified 75 genetic loci associated with dynamic shape, including 14 variants previously unreported for cardiac traits, and candidate genes demonstrated enrichment in pathways related to cardiac development and contractile function. PRS derived from dynamic shape loci were significantly associated with multiple outcomes, most prominently HF. MR identified significant causal relationships between several PCs and cardiometabolic disease. ConclusionsDynamic cardiac shape features capture aspects of cardiac structure and function not fully represented by standard CMR measures. These features are strongly associated with incident cardiometabolic disease and provide new insights into the genetic architecture of cardiac remodeling. Clinical perspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIGenetic and outcome relationships with a dynamic statistical shape model capturing both left and right ventricles at end-diastole and end-systole. C_LIO_LIDemonstration of incremental value over existing cardiac shape models, through capture of functional remodeling not represented by standard imaging measures. C_LIO_LIIdentification of genetic susceptibility loci for dynamic cardiac shape, including 14 variants not previously reported for cardiac traits. C_LI What are the clinical implications?O_LIThe results enhance our understanding of the genetic architecture of dynamic cardiac shape and function in the general population and clarify their relationships with other cardiovascular endophenotypes and incident cardiometabolic diseases. C_LIO_LINewly identified candidate genes expand the biological pathways implicated in cardiac remodeling and provide targets for future functional and mechanistic studies. C_LIO_LIThe improved prediction of incident cardiometabolic disease, particularly ischemic heart disease, achieved by adding dynamic shape PCs to traditional CMR measures suggests potential value for their inclusion in evaluation of patients. C_LI

Vaccine adjuvants are critical for enhancing immune responses and sustaining antibody production. Although their safety profiles are well established, assessments have largely focused on metabolic and excretory organs such as the liver and kidneys, with limited attention to the heart. Here, we systematically evaluated the cardiac effects of five representative adjuvants in mice: alum, MF59, AS03, Sigma Adjuvant Systems, and lipid A. None of the adjuvants impaired baseline cardiac contractile function. Notably, lipid A uniquely enhanced mitochondrial respiratory capacity in rat and human induced pluripotent stem cell-derived cardiomyocytes and promoted mitochondrial membrane hyperpolarization. We next examined its therapeutic potential in a doxorubicin (Dox)-induced heart failure model characterized by mitochondrial dysfunction. Co-administration of lipid A with influenza hemagglutinin (HA) antigen significantly ameliorated cardiac dysfunction. In parallel, lipid A prevented the Dox-induced decline in anti-HA antibody titers, an effect associated with preservation of splenic B cell populations. Collectively, these findings reveal a previously unappreciated cytoprotective dimension of lipid A, demonstrating that it not only potentiates immune responses but also counteracts chemotherapy-induced functional decline by enhancing mitochondrial activity.

Increased literature support the pathogenetic role of dysfunctional energetic metabolism in the setup and progression of organ damage and failure. Genetic diseases often offer the possibility to investigate pathogenetic mechanisms. In particular, excessive cardiac damage is the most frequent cause of mortality in Fabry disease (FD), a genetic condition caused by deficient -galactosidase A (GLA) activity, leading to globotriaosylceramide (Gb3) accumulation. Beyond Gb3 storage, metabolic alterations and mitochondrial dysfunction, supported by in vitro evidence or studies in other tissues, may contribute to FD cardiomyopathy. This study investigated, for the first time, the mechanisms of mitochondrial involvement in FD, its role in determining cardiac manifestations, and its potential as a therapeutic target. We used a humanized FD mouse model (R301Q-Tg/GLA knockout), along with derived embryonic fibroblasts and neonatal and adult cardiomyocytes, to assess mitochondrial function across the lifespan. FD cells showed impaired mitophagy, reduced mitochondrial respiration, and increased reactive oxygen species production. Importantly, this mitochondrial dysfunction exacerbated the lysosomal deficit in FD cells, forming a vicious cycle. In cardiomyocytes, these alterations progressed with age, leading to the accumulation of dysfunctional mitochondria, energetic failure, and, in adult hearts, terminal mitochondrial damage and apoptosis. These events ultimately result in cardiac remodeling and dysfunction, including hypertrophy and diastolic impairment. Indeed, L-arginine supplementation, which promotes NO/PGC-1-dependent mitochondrial rescue, prevented the development of cardiac abnormalities in FD mice. Our findings identify early mitochondrial dysfunction as a key driver of FD cardiomyopathy and support mitochondrial targeting, including L-arginine supplementation, as a promising adjuvant therapeutic strategy. The mechanistic link between lysosomal dysfunction, altered mitochondrial turnover, and energetic collapse emerges as a key targetable pathway in organ damage, extending beyond FD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/718770v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@2a5c4borg.highwire.dtl.DTLVardef@1117767org.highwire.dtl.DTLVardef@1b634c5org.highwire.dtl.DTLVardef@1429b6c_HPS_FORMAT_FIGEXP M_FIG C_FIG Cardiac manifestations vs mitochondrial alterations in Fabry disease: the visible tip and the hidden base of the icebergCardiac manifestations in hR301Q Tg/KO mice become evident from 9 months of age. However, mitochondrial homeostasis is perturbed much earlier (neonatal to young stages), with impaired mitophagy, reduced mitochondrial respiration and membrane potential, increased ROS production and PGC-1 downregulation. At later stages, from 6 months of age, mitochondrial dysfunction progresses and begins to impact cellular energetics, as indicated by reduced ETC expression and the onset of energetic deficit (ATP reduction). The resulting energetic collapse, together with progressive mitochondrial leakage, leads to cardiomyocyte hypertrophy, apoptosis, and dysfunction, which become detectable from 9 months of age, when clinical signs emerge. These findings support a mechanistic model in which 1) lysosomal incompetence due to GLA deficit is the initiating event inducing impairment of mitophagy; 2) Unsuccessful mitophagy, induces downregulation of PGC-1a-dependent mitogenesis; 3) exhausted mitochondria accumulate, inducing energetic collapse (able to exacerbate lysosomal dysfunction and further perturb mitophagy in a vitious cycle); 4) ultimate mitochondrial leakage induces Cytochrome C release and apoptosis activation. This cascade of molecular events is responsible for clinical manifestations, and mitochondrial targeting prevents cardiac organ damage. Significance statementFabry disease is a rare genetic disorder in which cardiac complications are a major cause of death, yet underlying mechanisms remain unclear. Here, we identify mitochondrial dysfunction as an early pathogenic event associated with impaired mitophagy, whereby defective mitochondrial quality control both results from and exacerbates lysosomal dysfunction, creating a self-reinforcing cycle that drives disease progression. Using a humanized model, we demonstrate that mitochondrial dysfunction is a key determinant of cardiac phenotype in vivo, driving energetic failure, oxidative stress, and cardiac damage. Importantly, L-arginine treatment restores mitochondrial function and prevents cardiac abnormalities. Our findings define a broadly relevant pathogenic axis linking lysosomal dysfunction, mitophagy failure, and mitochondrial impairment, that lead to impaired energetic metabolism and consequent cardiac hypertrophy, independently from GB3 accumulation. The implications of our study go beyond Fabry disease and support the therapeutic targeting of cellular energy homeostasis to prevent and treat organ damage and failure in chronic diseases. IMPORTANTO_LIManuscripts submitted to Review Commons are peer reviewed in a journal-agnostic way. C_LIO_LIUpon transfer of the peer reviewed preprint to a journal, the referee reports will be available in full to the handling editor. C_LIO_LIThe identity of the referees will NOT be communicated to the authors unless the reviewers choose to sign their report. C_LIO_LIThe identity of the referee will be confidentially disclosed to any affiliate journals to which the manuscript is transferred. C_LI GUIDELINESO_LIFor reviewers: https://www.reviewcommons.org/reviewers C_LIO_LIFor authors: https://www.reviewcommons.org/authors C_LI CONTACTThe Review Commons office can be contacted directly at: office@reviewcommons.org

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.

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.

BackgroundAccurate assessment of left ventricular outflow tract (LVOT) gradients is critical for hypertrophic cardiomyopathy (HCM) management, yet Doppler-based measurements are technically demanding and require expertise. ObjectiveTo develop a multi-view deep learning model capable of classifying LVOT obstruction (> 20mmHg) using routine 2D echocardiographic windows without reliance on Doppler imaging. MethodsWe trained and externally validated a cross-attention-based video-to-video fusion framework that integrated EchoPrime-derived video representations from three standard transthoracic echocardiographic views to classify LVOT gradients. ResultsTraining was performed on a derivation cohort (N = 1833) from a tertiary care system in the United States, with model performance evaluated on an internal held-out test set (N = 275) and a Korean external validation cohort (N = 46). Single-view baselines showed limited discrimination (external AUROCs 0.47-0.70). Conversely, domain-specific foundational model (EchoPrime) achieved superior single-view performance (AUROCs 0.75-0.80 internal; 0.79-0.83 external), highlighting the importance of echo-specific pretraining and temporal modeling. The proposed multi-view fusion further enhanced predictive performance, with the late fusion model reaching an AUROC of 0.84 on the external cohort with significant population-shift. ConclusionsThese results suggest LVOT physiology is encoded in routine 2D imaging and can be leveraged for clinically relevant gradient classification without Doppler input- proposed AI-guided strategy demonstrates substantial cost savings compared with the screen-all approach. By integrating complementary spatial-temporal information across multiple views, our approach generalizes robustly across populations and may enable real-time decision support, extend LVOT assessment to portable or resource-limited settings, and complement Doppler-based evaluation for longitudinal HCM management.

Sickle cell disease (SCD) is associated with substantial cardiovascular morbidity, but echocardiographic data from Latin American populations remain scarce. We aimed to characterise the structural, functional, and haemodynamic echocardiographic profile of adults with SCD attending a tertiary referral centre in Cali, Colombia. We conducted an observational, cross-sectional study based on systematic review of medical records and transthoracic echocardiography reports of consecutive adult patients ([&ge;]18 years) with confirmed SCD evaluated between January 2022 and December 2024. Patients with complex congenital heart disease, severe valvular disease of unrelated aetiology, pregnancy, or echocardiograms of insufficient quality were excluded. Of 669 patients screened, 57 met inclusion criteria. Reporting followed STROBE recommendations. The median age was 24 years (interquartile range [IQR] 21-32) and 59.6% were female; the SS genotype was the most frequent (76.4%) and 71.4% were on hydroxyurea. Median haemoglobin was 10.2 g/dL (IQR 9.3-11.4) and median NT-proBNP 491 pg/mL (IQR 98-1290). Most patients had preserved left ventricular dimensions and systolic function (median ejection fraction 63%, IQR 57-66.5; mean global longitudinal strain -18.9% {+/-} 2.9). Right ventricular function was preserved (mean tricuspid annular plane systolic excursion 25.4 {+/-} 4.6 mm). Left ventricular geometry was normal in 42.1%, with concentric remodelling in 24.6%, concentric hypertrophy in 21.1%, and eccentric hypertrophy in 12.3%. Diastolic function was normal in 71.4%. Valvular disease, when present, was predominantly mild. Tricuspid regurgitation velocity exceeded 2.5 m/s in 29.8% of patients and exceeded 3.0 m/s in 10.5%, identifying a substantial subgroup at intermediate-to-high probability of pulmonary hypertension. In this Colombian cohort of relatively young adults with SCD, cardiac structure and biventricular function were largely preserved, but nearly one-third of patients had echocardiographic findings suggestive of pulmonary hypertension. These findings support the routine use of transthoracic echocardiography as an accessible tool for early cardiovascular risk stratification in adults with SCD in low- and middle-income settings.

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.

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

ObjectiveLevetiracetam is commonly prescribed for seizure prophylaxis after acute ischemic stroke (AIS) and often continued beyond discharge. While its short-term effectiveness for preventing post-stroke seizures is established, it is unclear whether prolonged use improves survival, particularly in older adults. We estimated the effect of continued levetiracetam use on 90-day mortality among Medicare beneficiaries after AIS. MethodsUsing Traditional Medicare claims data (2008-2021), we identified beneficiaries aged [&ge;]66 years hospitalized for AIS who initiated outpatient levetiracetam within 90 days of discharge. After one month of continued post-stroke use of levetiracetam (start of follow-up), we compared 90-day mortality between patients with a new levetiracetam dispensation within a 14-day grace period post-follow up and those without one. We performed cloning, censoring and weighting to address immortal time bias and estimated standardized mortality risks, risk differences, and 95% confidence intervals (CI). ResultsAmong 3,212 eligible beneficiaries, 1,779 (55.4%) received a new levetiracetam dispensation within the 14-day grace period. Median age was 76 years (IQR 70-83); 57.8% were female. After adjustment for demographics, hospitalization characteristics, timing of initiation, and comorbidities, continued use was associated with lower 90-day mortality than discontinuation (53 vs 62 deaths per 1,000; risk difference -9 per 1,000; 95% CI: (-12,-5)). The reduction was observed primarily among patients aged [&ge;]75 years. SignificanceAmong older Medicare beneficiaries who initiated levetiracetam after AIS, continued outpatient use was associated with modestly lower 90-day mortality, particularly in those aged [&ge;]75 years. These findings suggest potential benefits of levetiracetam continuation beyond the immediate post-stroke period.

Survival during infection depends on both pathogen clearance and the ability to tolerate infection-induced physiological changes. Metabolic adaptations are a central component of this tolerance, but the mechanisms underlying these responses remain incompletely defined. Here, we identify white adipose tissue (WAT) lipolysis as a central regulator of metabolic tolerance to infection. In patients with sepsis, higher circulating non-esterified fatty acid (NEFA) levels were associated with reduced mortality. In mouse models of polymicrobial sepsis, infection induced robust adipose lipolysis and increased circulating NEFAs. Genetic ablation of adipose triglyceride lipase (ATGL) in adipose tissue impaired lipolysis, leading to hypothermia, bradycardia, and increased mortality without altering immune cell populations or pathogen burden, consistent with a defect in tolerance rather than resistance. Mechanistically, lipolysis-derived NEFAs, but not glycerol, were required for protection, as restoring circulating NEFAs rescued autonomic stability and survival in adipose tissue ATGL-deficient mice. Infection-induced lipolysis was redundantly regulated and did not depend on any single upstream signaling pathway. Both pharmacologic activation of lipolysis using a {beta}3-adrenergic agonist and exogenous fatty acid supplementation increased circulating NEFAs, improved survival, and promoted tolerance in mice. Consistent with these findings, analysis of real-world electronic health record data demonstrated that septic patients receiving FDA-approved {beta}3-adrenergic agonists had reduced mortality or hospice discharge in a propensity-matched cohort. Together, these results identify WAT lipolysis and circulating fatty acids as key mediators of tolerance to infection and support a therapeutic strategy based on repurposing clinically available {beta}3-adrenergic agonists to improve outcomes in sepsis. One Sentence SummaryWhite adipose tissue lipolysis promotes metabolic tolerance to infection through circulating fatty acids and is associated with improved survival in sepsis

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.

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.

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.