Frontiers in Cardiovascular Medicine

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.

AimsPercutaneous coronary intervention has improved survival following myocardial infarction, yet strategies to further reduce infarct size are limited. This study investigates the role of cytotoxic {gamma}{delta}-T cells in ischemic cardiomyocyte death and potential therapeutic interventions to reduce infarct size. MethodsGenetic and pharmacological approaches were used to delete {gamma}{delta}-T cells and their specific proteins to assess their involvement in cardiomyocyte death using mouse models of permanent ligation (PL) and ischemia/reperfusion (IR). Results{gamma}{delta}-T cells accumulated in infarct zones within 6h post-PL, expressing IFN-{gamma}, TNF-, granzyme B, and perforin. Their deletion reduced infarct size by 73% (PL) and 64% (IR). They induced cardiomyocyte death via apoptosis, gasdermin E-dependent pyroptosis, and MLKL-dependent necroptosis; {gamma}{delta}-T cell depletion reduced apoptosis by 80% and pyroptosis by 38%, with perforin deletion yielding similar effects. Necroptosis, attributed to combined IFN-{gamma}/TNF- cytotoxicity, decreased by 67%. Cytoplasmic DNA (cDNA) in stressed cardiomyocytes activated the cGAS/STING pathway, inducing expression of chemoattractant MCP-1 and death signal RAE-1. These signals recruited and activated {gamma}{delta}-T cells, which then triggered the death of the stressed cardiomyocytes. STING inhibition suppressed these expressions, reducing {gamma}{delta}-T cell accumulation and infarct size. NKG2D-deficient {gamma}{delta}-T cells prevented activation and reduced infarct size. Administration of an anti-IFNAR antibody at PL onset markedly reduced infarct size. ConclusionEarly activation of cytotoxic {gamma}{delta}-T cells via cardiomyocyte stress signals contributes significantly to immunogenic cardiomyocyte death. Targeting the STING pathway and type I interferon signalling presents a promising therapeutic avenue to mitigate infarct size and improve outcomes.

BackgoundAccurate 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. ObjectiveTo 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. MethodsThis 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. ResultsIn 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). ConclusionsA 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.

BackgroundIncreased 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. ObjectivesTo 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. MethodsAI-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 Spearmans 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. ResultsEATV 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. ConclusionsEATV 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.

Background: Individuals with coronary artery disease (CAD) are at higher risk of cognitive decline and dementia, in which gray matter cerebral blood flow (CBF) plays a critical role. This study investigated the effects of High Intensity Interval Training (HIIT) and HIIT plus resistance training (RT) on CBF and other health outcomes in individuals with CAD. Methods: This trial included 105 participants with CAD (age 62.1 (SD 6.6) years, 21% women) randomly assigned to HIIT+RT (n=37), HIIT (n=35) or usual care (n=33). The primary outcome was the change in global CBF from baseline to 12-week follow-up. Secondary outcomes included: region-specific CBF (hippocampus, precuneus, and anterior/posterior cingulate cortex), cognitive function (general cognition, episodic memory, processing speed, working memory and executive function/attentional control), peak oxygen uptake (VO2peak), muscular fitness (30s sit-to-stand) and body composition [weight, body mass index (BMI), and fat and muscle mass). Data were analyzed using available-case intention-to-treat constrained (baseline-adjusted) linear mixed models. Predefined subgroup analyses were conducted for age, sex, education, and baseline level of the outcome studied. Results: No significant between-group differences were observed in CBF changes in the whole sample. However, participants with lower CBF at baseline showed greater CBF increases in the HIIT group compared to both usual care (+7.1 ml/100g/min, P=0.02) and HIIT+RT (+5.53 ml/100g/min, P=0.04). No effects were observed on regional CBF or cognition. Both exercise groups improved VO2peak compared to usual care (HIIT+RT: +2.6; HIIT: +2.5 mL/kg/min, both P<0.001). Only HIIT+RT increased muscular fitness (vs usual care: +3.3; vs HIIT: +3.1 repetitions, both P<0.001), and only HIIT decreased BMI (vs usual care: -0.47; vs HIIT+RT: -0.44 kg/m2, both P<0.03). No life-threatening events or deaths occurred during 1995 training sessions in the exercise groups, nor in the usual care group. Conclusion: Twelve weeks of HIIT+RT or HIIT did not increase CBF in the whole sample with CAD, but HIIT effectively increased CBF in those who had poorer CBF at baseline. While no cognitive benefits were observed, we found exercise-specific improvements in other clinically relevant outcomes, such as VO2peak, muscular fitness, and BMI.

Background: Pediatric dilated cardiomyopathy (DCM) is a leading cause of heart failure and transplantation, with variable prognosis and high early mortality. This study developed and validated a nomogram predicting short-term mortality risk to guide clinical decisions. Methods: The data were sourced from the Pediatric Cardiomyopathy Database at Shandong Provincial Hospital. Cox regression analysis was conducted to determine outcome-associated factors, and a nomogram was developed to estimate 1, 3, and 5year mortality risks for children with DCM. Model effectiveness was assessed through the concordance index (C-index) and area under the receiver operating characteristic curve (AUC). Additionally, calibration curves and decision curve analysis (DCA) were employed to evaluate the model's predictive accuracy and clinical relevance. Results: A cohort of 106 children diagnosed with primary DCM and who underwent genetic analysis was studied, with a median diagnostic age of 10 months (ranging from 5 to 84 months), comprising 50 girls (47.2%). The rate of detecting genetic mutations was 28.3%, uncovering 14 gene variants linked to DCM, with TTN mutations being the most common. Both univariate and multivariate Cox regression analyses indicated that both sex and NT-proBNP levels had a significant impact on survival rates among pediatric DCM patients.The model exhibited strong discriminative performance, calibration, and clinical net benefit, as assessed by the C-index, calibration plots, and decision curve analysis (DCA). Conclusions: The prediction model created in this research shows strong accuracy in forecasting survival rates at 1, 3, and 5 years for children with DCM, highlighting its significant relevance in clinical settings.

AimsHypoplastic left heart syndrome (HLHS) is a severe congenital heart disease characterized by ventricular hypoplasia and impaired cardiac function. Clinically, inhaled nitric oxide (NO) therapy is used to reduce pulmonary vascular resistance and improve cardiopulmonary stability in HLHS patients. However, whether NO signaling contributes to HLHS pathogenesis remains unknown. Cytoglobin (CYGB) is a heme protein traditionally thought to limit NO bioavailability. Unexpectedly, our recent work shows that CYGB/Cygb enhances NO signaling through activation of the nitric oxide synthase-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway. In zebrafish embryos, Cygb-dependent NO signaling is required for normal cilia motility and for the establishment of correct cardiac laterality. Here, our aim was to determine whether Cygb-dependent NO-sGC signaling linked to cilia function regulates cardiac morphogenesis and contributes to ventricular hypoplasia in HLHS. Methods and ResultsWe found that loss of Cygb (cygb2) in zebrafish disrupts NO-sGC signaling during cardiogenesis, altering cardiac progenitor organization and migration within the anterior lateral plate mesoderm (ALPM). Disruption of these processes impairs heart tube morphogenesis, thereby producing a compact ventricle with increased wall thickness despite preserved cardiomyocyte number, reduced ventricle size and decreased stroke volume, recapitulating key features of HLHS. Genetic disruption of the sGC -subunit (gucy1a1) and pharmacological NO scavenging phenocopy the cygb2 mutant phenotype, resulting in reduced cGMP levels, compact ventricular architecture and decreased stroke volume (SV). Consistently, restoration of NO-sGC signaling in cygb2 mutants rescues early cardiac progenitor patterning, ventricular morphology and SV. ConclusionsThese findings identify Cygb-dependent NO-sGC signaling as a critical developmental pathway for ventricular development and performance, temporally linking cardiac progenitor dynamics to cilia-dependent signaling associated with left-right patterning. This study further suggests that pharmacological activation of sGC may provide a therapeutic strategy for hypoplastic ventricular disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/711730v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@e266corg.highwire.dtl.DTLVardef@fca897org.highwire.dtl.DTLVardef@1a06fc2org.highwire.dtl.DTLVardef@93acd_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundFabry disease (O_SCPLOWFDC_SCPLOW) is a rare and severe disease affecting multiple organ systems. However, its non-specific and heterogeneous presentation poses a critical challenge for early diagnosis, often delaying necessary treatment. In re-cent years, imaging-based biomarkers have been increasingly proposed to improve the understanding of O_SCPLOWFDC_SCPLOW and aid its diagnosis. This study presents a comprehensive comparative analysis of several previously proposed imaging-based cardiac biomarkers to assess their potential for diagnostic use. MethodsWe have developed a fully automated image analysis pipeline for quantifying cardiac metrics based on short-axis cine O_SCPLOWCMRC_SCPLOW data available on the UK Biobank. ResultsBased on the UK Biobank cohort, our analyses confirm the diagnostic relevance of the maximum myocardial wall thickness, a metric that mimics the current clinical practice for diagnosing left ventricular hypertrophy. Initial evidence also suggests that the PM/LV ratio, which measures the papillary muscle hypertrophy as the ratio between the areas of the papillary muscles and the left ventricular cavity, has potential prognostic relevance. ConclusionThis study contributes towards a better understanding of the cardiac presentation of FD, which may support future research in improving the diagnostic process. Additionally, our analysis pipeline can serve as a valuable basis for additional data analysis of imaging-based biomarkers for O_SCPLOWFDC_SCPLOW and other diseases.

PurposeSpatial distribution of coronary artery calcium (CAC) may provide additional prognostic value in patients undergoing SPECT and PET myocardial perfusion imaging (MPI). We aimed to automatically identify CAC in proximal segments from attenuation correction CT (CTAC) scans using artificial intelligence (AI) and to evaluate prognostic significance in two large international multicenter registries. MethodsFrom hybrid MPI/CT imaging (N=43,099) across 15 sites, we included 4,552 most relevant patients with 1) no prior coronary artery disease; 2) AI-derived mild CAC scores (1-99); and 3) normal perfusion (stress total perfusion deficit <5%). The independent associations between AI-identified proximal CAC and major adverse cardiovascular events (MACE) and all-cause mortality (ACM) were evaluated using multivariable Cox regression, likelihood ratio test (LRT), and continuous net reclassification index (NRI). ResultsAmong the patients with mild CAC and normal perfusion (mean age 65{+/-}12 years, 51% male), 1,730 (38%) had proximal CAC. Over 3.6 (inter-quartile interval 2.1, 5.2) years follow-up, 599 (13%) and 444 (10%) patients had MACE or ACM, respectively. Proximal CAC was associated with an increased risk of MACE (adjusted hazard ratio [HR] 1.24, 95% CI 1.03-1.48, P=0.02) and ACM (adjusted HR 1.25, 95% CI 1.01-1.53, P=0.04) after the adjustment of CAC score and density, clinical risk factors, and perfusion deficit. Proximal CAC improved the risk stratification of MACE (LRT P=0.02; NRI 12%) and ACM (LRT P=0.04; NRI 12%). ConclusionIn patients with mild CAC and normal perfusion, AI detection of proximal CAC identified a higher-risk group for adverse outcomes, highlighting its prognostic utility. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/26350808v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1f489d9org.highwire.dtl.DTLVardef@18637ccorg.highwire.dtl.DTLVardef@b97275org.highwire.dtl.DTLVardef@1099c38_HPS_FORMAT_FIGEXP M_FIG C_FIG From patients who underwent hybrid myocardial perfusion imaging (MPI) from 15 sites, we analyzed those without prior coronary artery disease (CAD), mild coronary artery calcium (CAC) scores (1-99), and normal perfusion (stress total perfusion deficit <5%). A previously developed AI model was used to identify CAC lesions in proximal coronary segments on CT attenuation correction maps (CTAC). We evaluated associations with major adverse cardiovascular events (MACE) and all-cause mortality (ACM), showing risk stratification of proximal CAC and improvement by net reclassification index (NRI). CAC lesion color: green, left anterior descending artery (LAD) with left main artery; red, left circumflex artery (LCX); yellow, right coronary artery (RCA). Adjusted hazard ratios (HRs) are shown with 95% confidence intervals.

Background: Aortic stenosis (AS) is a progressive valvular disease associated with poor prognosis once symptoms develop, yet routine echocardiographic screening is impractical. While artificial intelligence (AI)-based electrocardiogram (ECG) models have shown promise for AS detection, it remains unclear whether they primarily reflect conventional left ventricular hypertrophy (LVH) voltage criteria or capture additional ECG features. Methods and Results: We developed a deep learning model using 244,816 ECGs from 51,713 patients across six academic institutions in Japan (CLIDAS database). AS labels were derived from inpatient Diagnosis Procedure Combination (DPC) codes. The model achieved an area under the receiver operating characteristic curve (AUC) of 0.849 (95% confidence interval 0.832-0.865) in the independent test cohort, with consistent performance across institutions, sex, and age. At a threshold of 0.1, sensitivity was 79.1%, specificity was 73.9%, and negative predictive value (NPV) was 98.0%. Conventional LVH voltage criteria (Sokolow-Lyon AUC 0.706; Cornell AUC 0.692) showed lower performance, and adding them to the AI model conferred no incremental benefit (AUC 0.849 vs. 0.847). Gradient-weighted class activation mapping (Grad-CAM) revealed predominant attention around QRS complexes in limb leads, beyond regions typically assessed in LVH evaluation. Conclusions: This multicenter AI-ECG model demonstrated strong discrimination for AS and captured ECG features beyond conventional LVH voltage criteria. The high NPV supports its use as a rule-out pre-screening tool.

PurposeLeft ventricular hypertrophy (LVH) is a major complication of chronic hypertension and an independent risk factor for cardiovascular morbidity and mortality. There are currently no clinically validated markers available to identify hypertensive individuals at risk for developing LVH. In hearts of hypertensive rats, we previously described metabolic changes that precede LVH development, including in branched-chain amino acid (BCAA) metabolism. This study investigated whether cardiac leucine uptake, measured with dynamic 5-[18F]fluoroleucine positron emission tomography-computed tomography ([18F]FLE-PET/CT), was impaired and could serve as an in vivo marker for hypertension-induced LVH development. ProceduresWe synthesized [18F]FLE following established radiochemistry protocols and performed dynamic [18F]FLE-PET/CT imaging in 3-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) control rats (n = 4 per group). Cardiac magnetic resonance (CMR) imaging was conducted on the same animals for structural co-registration. A dual-output reversible two-tissue compartment model with spill-over (SP) and partial volume (PV) corrections was developed to quantify the first-pass rate constant (K1) and total distribution volume (Vt = K1/k2) for [18F]FLE. Protein expression of L-type amino acid transporter 1 (LAT1) and branched-chain keto acid dehydrogenase (BCKDH) phosphorylation status were assessed by immunoblotting of isolated heart tissue. ResultsSHR demonstrated markedly lower first-pass leucine uptake rates (K1) and total distribution volumes (Vt) compared with WKY rats, consistent with reduced cardiac BCAA uptake. Concurrently, LAT1 (SLC7A5) expression was significantly reduced in SHR hearts compatible with decreased leucine uptake. Elevated BCKDH phosphorylation at Ser293 in SHR hearts indicated diminished BCKDH enzymatic activity and impaired BCAA catabolism. ConclusionsDynamic cardiac [18F]FLE-PET imaging successfully detects decreased leucine uptake in hypertensive rat hearts at 3 months of age, before LVH is established at 5 months. Reduced cardiac leucine uptake may thus serve as a surrogate marker for impaired cardiac BCAA metabolism and early in vivo indicator of cardiometabolic dysfunction that precedes LVH. The imaging approach holds translational potential for identifying hypertensive patients at risk for LVH progression.

BackgroundCardiovascular disease (CVD) prevention is limited by the major challenge of low long-term adherence to effective lifestyle regimens. Arterial stiffness (measured by carotid-femoral pulse wave velocity, cfPWV) and maximal cardiorespiratory fitness (measured by VO2max), are modifiable risk factors for CVD but require sustained lifestyle change. Wearable technology provides continuous measurement and offers a scalable platform to deliver health interventions. A combination of continuous monitoring with a wearable device and an artificial intelligence (AI) -based coach personalized for individual data and preferences could be a powerful, low-barrier tool for achieving sustainable cardiovascular health benefits by directly addressing the adherence challenge. ObjectiveWe will study the comparative effectiveness of a wearable and an interactive app-based AI coaching intervention promoting moderate exercise on improving gold-standard cfPWV and VO2max. This will be compared to a supervised high-intensity interval training (HIIT) group (benchmark with known benefits for VO2max) and a control group using only Oura Ring (passive monitoring). We will also conduct a detailed Process Evaluation (structured interviews) to study the feasibility and experience of interacting with the AI coach. MethodsThis randomized controlled trial recruited 165 eligible sedentary participants aged 30-65 years. Co-primary outcomes cfPWV and VO2max were measured at baseline and will be repeated after 12 weeks. Participants were equally randomized into three groups: an AI-based coaching group (steady-state exercise), a HIIT group (supervised exercise) and a control group (usual low activity). The AI-based coaching group receives personalized guidance using large language model (LLM) technology. All participants wear Oura Ring and are blinded to cardiovascular health metrics provided by the ring. ResultsThe recruitment for the study began in October 2024 and will end when 165 men and women have been recruited. Data collection for the study is scheduled to conclude early 2026. Data collection is ongoing. ConclusionsThis study will evaluate if a highly scalable, AI-based coaching intervention can achieve comparable gains in CV structural health (cfPWV) and functional capacity VO2max relative to a resource-intensive supervised HIIT benchmark. The findings will provide essential evidence on the use of digital health tools to promote sustainable exercise adherence. ClinicalTrials.gov registration identifierNCT06644014 (Registered: 2024-10-15)

BackgroundAn elevated calcium-phosphate product (CPP), defined as a product of serum calcium and serum phosphate, is a hallmark of CKD-mineral and bone disorder and has been implicated in accelerated coronary artery calcification, arterial stiffness, and left ventricular hypertrophy. These pathological changes contribute to adverse cardiovascular outcomes. While prior studies have shown worse percutaneous coronary outcomes (PCI) outcomes in CKD patients overall, the prognostic impact of CPP levels remains underexplored. The objective is to evaluate post-PCI outcomes in CKD patients with and without hypercalcemia and hyperphosphatemia. MethodsA retrospective cohort analysis was conducted using the TriNetX U.S. Collaborative Network, focusing on adult patients with CKD undergoing PCI. Patients were grouped based on serum calcium and phosphorus levels, with those having hypercalcemia and hyperphosphatemia compared to those without. Diagnoses and procedures were identified using ICD-10 and CPT codes. Propensity score matching was applied to account for differences between groups. Post PCI outcomes were analyzed. Primary outcome was all-cause mortality. Secondary outcomes encompass coronary artery bypass grafting (CABG), myocardial infarction (MI), in-stent re-stenosis [redo PCI] and target vessel revascularization, heart failure (HF) exacerbations, and peri-/ post-procedural complications were assessed within a 5-year follow-up period. Kaplan-Meier analysis with log-rank was used for statistical comparisons, with significance set at p<0.05. ResultsThe elevated CPP group was significantly associated with increased post-PCI all-cause mortality [hazard ratio (HR) 1.428], in-stent restenosis [HR 1.589], heart failure exacerbations [HR 1.492], and recurrent angina or MI [HR 1.396]. No significant differences were found in rates of post PCI CABG, periprocedural complications (postprocedural cardiac insufficiency, postprocedural cardiac arrest, postprocedural heart failure, intraoperative cerebrovascular infarction, postprocedural cerebrovascular infarction, and intraoperative cardiac arrest), or redo PCI. ConclusionIn this propensity score-matched analysis, elevated CPP in CKD patients undergoing PCI was independently associated with worse outcomes, including higher mortality and cardiovascular event rates. These findings highlight the prognostic value of CPP and the need for closer metabolic monitoring and individualized risk stratification. O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/26347359v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@198df1forg.highwire.dtl.DTLVardef@160722borg.highwire.dtl.DTLVardef@e796fforg.highwire.dtl.DTLVardef@6a40d6_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundThis study aimed to investigate whether combined PD-1/CTLA-4 immune checkpoint inhibition predisposes the heart to a hyperinflammatory state, thereby exacerbating cardiac injury following acute myocardial infarction (MI), a critical unresolved question in cardio-oncology. MethodsMyocardial infarction was induced in Pd1-/-Ctla4+/- mice, a genetic model mimicking combined checkpoint inhibition. Key mechanistic insights were gained through in vivodepletion of CD8+ T cells (using anti-CD8a antibody) and pharmacological inhibition of the JAK-STAT1 pathway (using Tofacitinib). Cardiac function, structural injury, and immune responses were comprehensively assessed via echocardiography, flow cytometry, immunofluorescence, and molecular analyses. ResultsCompared to wild-type controls, Pd1-/-Ctla4+/- mice exhibited significantly increased post-MI mortality, worse cardiac function, and larger infarct size. Mechanistically, the aggravated injury was driven by an amplified infiltration of activated, IFN-{gamma}-producing CD8+ T cells, which activated the JAK-STAT1 pathway in macrophages, polarizing them towards a pro-inflammatory state. Depleting CD8+ T cells or inhibiting the JAK-STAT1 pathway effectively attenuated macrophage-driven inflammation and improved all aspects of post-MI injury. ConclusionsCombined PD-1/CTLA-4 blockade exacerbates post-infarction cardiac injury by promoting CD8+ T cell-mediated activation of macrophages via the JAK-STAT1 axis. This work elucidates MI as a context-dependent immune-related adverse event in ICI therapy and identifies CD8+ T cells and the JAK-STAT1 pathway as promising therapeutic targets for cardioprotection in these patients. RESEARCH PERSPECTIVEO_ST_ABSWhat Is New?C_ST_ABSO_LIThis study identifies acute myocardial infarction (MI) as a potential, context-dependent immune-related adverse event in the setting of combined PD-1/CTLA-4 checkpoint inhibition, shifting the paradigm beyond the classic focus on myocarditis. C_LIO_LIIt elucidates a novel pathogenic axis where combined checkpoint deficiency exacerbates post-MI injury specifically through CD8+ T cell-derived IFN-{gamma}, which activates macrophages via the JAK-STAT1 pathway. C_LI What Question Should Be Addressed Next?O_LIFuture studies should employ anti-PD-1/CTLA-4 monoclonal antibodies in wild-type or humanized mouse models to validate findings and better recapitulate the pharmacokinetics of clinical ICI therapy, strengthening translational relevance. C_LIO_LIThe long-term consequences of this primed inflammatory state on chronic cardiac remodeling, heart failure development, and the potential interplay with atherosclerosis warrant further investigation. C_LI

Abstract Objective: The onset of hypertension occurs at a younger age in China, and the relationship between health literacy and quality of life among middle-aged and older hypertensive patients remains unclear. This study explored whether perceived social support and self-efficacy mediate the association between health literacy and quality of life in middle-aged and older hypertensive patients. Methods: A questionnaire was administered to 1,015 middle-aged and older hypertensive adults from communities in six central provinces of China. The EQ-5D scale, Perceived Social Support (PSS) scale, Self-Efficacy Scale (SES), and Health Literacy Scale (HLS) were used to assess quality of life, social support, self-efficacy, and health literacy, respectively. Mplus 8.3 software was used to construct a structural equation model for path analysis. Results: The mean PSS, SES, HLS, EQ-5D, and EQ-VAS scores were 15.57{+/-}3.45, 10.61{+/-}2.41, 9.49{+/-}2.86, 0.88{+/-}0.18, and 71.06{+/-}17.49, respectively. Health literacy and quality of life scores significantly differed among middle-aged and older hypertensive patients, and both showed positive correlations with perceived social support and self-efficacy (both P<0.001). Perceived social support and self-efficacy exhibited a chain mediated effect on the relationship between health literacy and quality of life (EQ-5D utility index and EQ-VAS), accounting for 28.57% of the total effect of the EQ-5D utility index and 27.26% of that of the EQ-VAS. This study is the first to elucidate the mechanism by which health literacy influences quality of life in middle-aged and older hypertensive patients through the chain-mediated effect of perceived social support and self-efficacy. Conclusion : Health literacy is significantly correlated with quality of life in middle-aged and older hypertensive patients. This correlation can directly or indirectly explain the impact on quality of life through mediating pathways involving perceived social support and self-efficacy. Keywords: hypertensive patients, perceived social support, self-efficacy, health literacy, quality of life, mediating effect

BackgroundPredictors of arterial health impairment from childhood to adolescence remain largely unknown. We investigated associations of childhood cardiometabolic risk factors with several measures of arterial health in adolescence. MethodsAltogether, 222 children were examined at age 7-9 years and eight years later at age 15-17 years. Body fat percentage (BF%), glucose, insulin, lipids, blood pressure (BP), and inflammation biomarkers were measured and homeostatic model assessment for insulin resistance (HOMA-IR), a metabolic syndrome score (MetSscore), and an inflammation score were calculated at baseline. Pulse wave velocity (PWV) and cardio-ankle vascular index (CAVI) were assessed using impedance cardiography and carotid intima-media thickness (cIMT), carotid distensibility (cDIST), Youngs elastic modulus (YEM), and stiffness index (SI) using ultrasonography. Associations of childhood cardiometabolic risk factors with measures of arterial health were analyzed using linear regression models adjusted for childhood age and sex. ResultsBF% was positively associated with PWV (standardized regression coefficient {beta}=0.207, p=0.008), CAVI ({beta}=0.171, p=0.031), cIMT ({beta}=0.146, p=0.034), and YEM ({beta}=0.164, p=0.016). HOMA-IR was positively associated with PWV ({beta}=0.242, p=0.001) and CAVI ({beta}=0.216, p=0.004) and inversely with cDIST ({beta}=-0.162, p=0.015). MetSscore was positively associated with PWV ({beta}=0.266, p<0.001), CAVI ({beta}=0.219, p=0.004), and YEM ({beta}=0.141, p=0.032) and inversely with cDIST ({beta}=-0.140, p=0.035). SBP was positively associated with PWV ({beta}=0.257, p<0.001) and YEM ({beta}=0.156, p=0.018) and inversely with cDIST ({beta}=0.169, p=0.012). ConclusionIncreased adiposity, insulin resistance, elevated SBP, and cardiometabolic risk factor clustering in childhood association of arterial stiffness and reduced arterial distensibility in adolescence, emphasizing prevention of cardiovascular diseases since childhood.

Background: Cardiovascular magnetic resonance (CMR) quantification of the left ventricular (LV) volumes and ejection fraction (EF) typically involves manual segmentation of many short axis (SAx) and long axis (LAx) slices of the left ventricle. The scan time and the number of breath holds is proportional to the number of slices. We aimed to evaluate a geometric model of the left ventricle that could enable planimetry from a reduced number of slices. We sought to determine whether acceptable accuracy was retained for evaluating the End Diastolic Volume (EDV), End Systolic Volume (ESV), Stroke Volume (SV), and EF to provide a rapid and reliable clinical alternative. Methods: A cohort of 342 patients, median age: 54 (40 - 65) years, with full-stack CMR examinations was used. Nine geometrical combinations were evaluated: 3, 4 or 5 short axis slices and one of three LAx orientations (2-chamber, 3-chamber or 4-chamber) by retrospectively decimating the full-stack acquisition. LV volumes were calculated as a sum of trapezoidal approximations for apical and mid-cavity slices and a generalized prismoidal model at the base. The accuracy of the volume calculations was quantified against the full-stack reference for the EDV, ESV, SV, and EF using concordance correlation coefficient (CCC), two-way repeated measures ANOVA, pairwise tests, and Bayes factor log10(BF10) analysis. Results: The choice of the long axis (LAx) view was the most influential driver of accuracy (g2 = 0.104, for EDV), approximately 50 times more impactful than the number of SAx slices (g2 = 0.002, for EDV). Volumes calculated using the combination of 2-chamber LAx view and 5 SAx slices had the highest concordance with the full stack (CCC>0.90). While the estimated absolute volumes displayed a systematic negative bias, EF and SV remained highly robust due to bias cancellation. For a 2ch + 5 SAx protocol, EF bias was just 0.83% (LoA: -6.18 to 7.84%), with a minimum detectable change (MDC) of 7.01%, compared to 8.7% reported for expert human readers, suggesting strong concordance. Bayesian paired-samples t-tests yielded log10(BF10) = 6.42 in favor of 5 SAx over 3 SAx, constituting decisive evidence on the Jeffreys scale. The bias and limits of agreement (LoA) for stroke volume and ejection fraction were found to be lower than scan-rescan reproducibility in literature. Conclusion: This reduced-slice geometric model allows for reduced number of breath holds compared to a conventional full-stack CMR acquisition and provides an acceptable accuracy with bias less than scan-rescan variability.

BackgroundLate gadolinium enhancement (LGE) quantification by cardiovascular magnetic resonance is central to risk stratification in hypertrophic cardiomyopathy (HCM), yet conventional techniques require contour tracing and region-of-interest (ROI) placement, which may reduce reproducibility and increase analysis time. We developed a novel visual standardized approach, the Visual Standardized Quantification of LGE (VISTAQ), that does not require myocardial contouring, arbitrary ROI positioning, or dedicated post-processing software. MethodsIn this multicenter, multivendor retrospective study, LGE images from 400 patients (100 prior myocardial infarction, 250 HCM, 50 other non-ischemic heart diseases) were analyzed. VISTAQ subdivides each myocardial segment into transmural mini-segments and classifies LGE visually using predefined criteria, expressing global LGE burden as the percentage of positive mini-segments. Reproducibility was assessed in 250 patients across different observer expertise levels using intraclass correlation coefficients (ICC) and Bland-Altman analysis. In 100 HCM patients, VISTAQ was compared with conventional methods (mean+2SD, +5SD, +6SD, FWHM, visual thresholding). Prognostic performance was evaluated in 250 HCM patients over a median 5-year follow-up. ResultsVISTAQ demonstrated excellent intra- and inter-observer reproducibility (ICC up to 0.98 and 0.97, respectively), consistent across disease subtypes. Compared with conventional techniques, VISTAQ showed similar ICC to FWHM but significantly lower net and absolute inter-observer differences (median absolute difference 1.3%). Mean+2SD markedly overestimated LGE, whereas mean+6SD slightly underestimated LGE compared with VISTAQ, mean+5SD, FWHM, and visual thresholding. Analysis time was substantially shorter with VISTAQ (median 105 vs. 375 seconds, p<0.0001). During follow-up, 21 hard cardiac events occurred in HCM population. An LGE threshold >10% predicted events with higher accuracy using VISTAQ (AUC 0.90; sensitivity 85%; specificity 94%) compared with mean+6SD (AUC 0.75; sensitivity 57%; specificity 93%). ConclusionsVISTAQ provides highly reproducible, time-efficient LGE quantification without dedicated software and demonstrates non-inferior prognostic discrimination in HCM compared with conventional threshold-based techniques.

AimsWhile traditional anthropometric indices are established cardiovascular predictors, their prognostic value for incident infective endocarditis (IE) remains undefined. MethodsWe 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. ResultsOver 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). ConclusionCompared 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/26351534v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@a281e7org.highwire.dtl.DTLVardef@fe7fb0org.highwire.dtl.DTLVardef@7108a1org.highwire.dtl.DTLVardef@edb9a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

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.