Frontiers in Cardiovascular Medicine

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.

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.

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.

BackgroundPulmonary artery (PA) wave reflection is a key determinant of right ventricular (RV) afterload. RV function is the most important factor determining long-term prognosis in patients with surgically repaired tetralogy of Fallot (rTOF). This study aimed to evaluate PA wave reflection in rTOF using RV pressure phase plane (PPP) analysis, and to identify the clinical, morphological, and hemodynamic characteristics associated with increased PA wave reflection in patients with rTOF. MethodsAugmentation pressure (AugPr) during late systole was quantified using the inflection point of systolic dP/dt on the PPP. The ratio of AugPr to RV systolic pressure (RVSP) was defined as the AugPr index. The study included 87 patients with rTOF (mean age, 15.9 {+/-} 10.0 years), 17 control subjects (13.3 {+/-} 6.3 years), and seven patients with pulmonary arterial hypertension (PAH) (16.4 {+/-} 11.7 years). The rTOF cohort was categorized according to surgical procedure: pulmonary valve-sparing repair (PVS, n = 5), transannular patch repair (TAP, n = 34), and the Rastelli procedure (n = 48). ResultsThe prevalence of AugPr was 0% in the control group, 100% in the PAH group, and 26.4% in the rTOF group (p < 0.0001). Among the surgical subgroups, the prevalence was 0% in PVS, 14.7% in TAP, and 41.7% in the Rastelli group (p < 0.0027). AugPr and the AugPr index were significantly higher in the Rastelli group than in the other two groups (p = 0.0447 and 0.0433, respectively). In addition, AugPr showed significant correlations with RVSP, RV outflow tract obstruction, maximal dP/dt, and pulmonary regurgitation grade (all p < 0.05). ConclusionsPA wave reflection can be clearly visualized using PPP. The Rastelli group demonstrated a higher prevalence and magnitude of PA wave reflection, suggesting a greater increase in RV afterload compared with other surgical repair types.

Rheumatic heart disease (RHD) is a leading preventable cause of cardiac death in children in low and middle-income countries. Nepals epidemiological data come mainly from auscultation surveys that miss subclinical disease, and no echocardiographic screening study had been conducted in Dhanusha district, a densely populated, low-income region in southern Nepal. We aimed to determine the prevalence of borderline and definite RHD among school children (6-16 years) in Dhanusha using the 2012 World Heart Federation (WHF) echocardiographic criteria, identify independent predictors, and quantify school-level clustering via the intraclass correlation coefficient (ICC). In a cross-sectional study (January 2023-December 2024), we screened 4,536 children from 8 public schools selected by four-stage cluster sampling. RHD was classified by WHF 2012 criteria; predictors were identified using random-effects logistic regression with school as random intercept. Ethical approval was from the Nepal Health Research Council (Protocol No. 155/2023). Overall prevalence of borderline or definite RHD was 18.7 per 1,000 (95% CI 15.1-23.0); definite RHD was 6.8 per 1,000 (95% CI 4.7-9.7) and borderline RHD 11.9 per 1,000 (95% CI 9.0-15.5). Prevalence was higher in girls (23.3 per 1,000) than boys (13.6 per 1,000; P=0.02), with the peak in girls aged 10-14 years (26.0 per 1,000). Subclinical disease accounted for 64.7% of cases; auscultation sensitivity was 35.3%. Mitral valve involvement predominated. Female sex was the sole independent predictor (OR 1.60, 95% CI 1.02-2.53; P=0.043). The school-level ICC was 0.19 (95% CI 0.07-0.44; P<0.001), giving a design effect of {approx}109. The echocardiographic RHD burden in Dhanusha (18.7 per 1,000) is the highest documented in Nepal. Two-thirds of cases are subclinical. Female sex and school attended explain a similar amount of variance in RHD risk, supporting school-targeted screening and informing sample size planning for future cluster-based surveillance.

Patients with Fontan circulation face evolving risk for cardiovascular morbidity and mortality, yet the interplay between cardiac function, vascular properties, and circulating proteins is incompletely defined. We hypothesized that biochemical biomarkers and multimodal cardiovascular profile differ significantly between Fontan patients and controls, and that selected markers may serve as predictors of reduced single ventricle function. We conducted a prospective observational study at a tertiary pediatric heart center including 31 individuals with Fontan circulation and 52 matched controls. Cardiac function was assessed by echocardiography; vascular phenotyping included carotid intima-media thickness, central and peripheral blood pressure, augmentation index corrected for heart rate, carotid-femoral pulse wave velocity, aging index, and reactive hyperemia index. Compared to controls, the Fontan group had increased pulse wave reflection and central systolic pressure as well as decreased echocardiographic markers of systolic and diastolic function, while pulse wave velocity and other vascular parameters were not significantly different between the groups. Levels of 92 circulating cardiovascular biomarkers were quantified in a subset of 25 of the Fontan cohort and 81 controls using a proximity extension assay. Twenty-two biomarkers differed significantly in the Fontan group compared to controls, including FGF23, REN, HAOX1, and IL17D. Levels of several of these biomarkers correlated with patient age. Most importantly, HAOX1 (a peroxisomal oxidase linked to redox metabolism) and FGF23 (a bone-derived hormone regulating phosphate and vitamin D homeostasis) correlated negatively with ejection fraction within the Fontan group. By contrast, BNP was not associated with cardiac function in the Fontan group. None of the biomarkers correlated with central arterial parameters. In summary, central arterial hemodynamics and biomarkers such as FGF23 and HOAX1 may improve monitoring of cardiovascular function in single ventricle patients with Fontan circulation.

Background: Red cell distribution width (RDW), a readily available hematological parameter reflecting erythrocyte size heterogeneity, has been increasingly recognized as a prognostic marker in congestive heart failure (CHF), with elevated levels independently associated with adverse outcomes. However, RDW-derived composite indices-particularly the RDW-to-platelet ratio (RPR) and RDW-to-hemoglobin ratio (RHR), which integrate inflammatory, hemostatic, and oxygen-delivery pathways-remain largely unexplored in CHF populations. Whether these indices provide incremental prognostic value beyond RDW alone in critically ill patients with CHF has not been established. Methods: This retrospective cohort study included 30,409 participants from the MIMIC-IV and eICU-CRD databases. Multivariable logistic regression, restricted cubic spline (RCS) analysis, and subgroup analyses were employed to evaluate the associations between RDW, RDW-derived indices (RPR and RHR), and in-hospital mortality in patients with congestive heart failure. Results: Based on a pooled cohort of 30,409 patients with CHF from the MIMIC-IV and multi-center eICU-CRD databases (15,983 and 14,426, respectively), 16,295 (53.6%) were male and 14,114 were female, with a median age of 71.7 years. The mean RDW was 16.0 {+/-} 2.5, and the overall in-hospital mortality rate was 12.6%. Higher RDW quintiles were associated with progressively increased in-hospital mortality. In the fully adjusted model, RDW, RPR, and RHR were all significantly associated with increased in-hospital mortality, with adjusted odds ratios (ORs) of 2.46 (95% CI: 2.17-2.79) for RDW, 1.55 (95% CI: 1.38-1.73) for RPR, and 2.43 (95% CI: 2.09-2.82) for RHR. Sensitivity analyses using restricted cubic splines demonstrated that the association between RDW and RHR with in-hospital mortality was linear (P for nonlinearity > 0.05), whereas that for RPR exhibited a non-linear pattern (P = 0.02 for non-linearity). Conclusions. Elevated RDW, RPR, and RHR were independently associated with increased in-hospital mortality in patients with congestive heart failure. Notably, RPR exhibited a non-linear threshold association with in-hospital mortality.

ObjectivesTo evaluate the therapeutic potential of BMP-7 mRNA-lipid nanoparticle formulation in attenuating cardiac fibrosis and improving function in non-ischemic heart failure, and to assess its impact on endothelial phenotype and function under pro endothelial-to-mesenchymal transition (EndMT) conditions. BackgroundDespite advances in neurohormonal blockade, heart failure (HF) progression remains driven in part by fibrotic remodeling. Endothelial-to-mesenchymal transition (EndMT) has emerged as a contributor to myocardial fibrosis, while recent work suggests endothelial phenotypic plasticity may also participate in myocardial recovery. Bone morphogenetic protein-7 (BMP-7) is a known anti-fibrotic regulator, but effective therapeutic delivery strategies remain limited. MethodsA patent pending, custom-designed BMP-7 mRNA formulated in lipid nanoparticles (AET-1978) was administered subcutaneously in a murine model of non-ischemic HF induced by L-NAME and angiotensin II. Cardiac function and fibrosis were assessed by echocardiography and histology. In an invitro EndMT model, human umbilical vascular endothelial cells (HUVECs) were treated with BMP-7 mRNA and endothelial and mesenchymal morphology, and markers were assessed along with endothelial functional tests. ResultsAET-1978 therapy significantly improved left ventricular systolic and diastolic function and reduced myocardial fibrosis compared with untreated HF mice, without evidence of renal or hepatic toxicity. In vitro, BMP-7 mRNA delivery restored endothelial morphology, suppressed EndMT-associated mesenchymal and profibrotic marker expression while preserving nitric oxide production, lipoprotein uptake, and angiogenic capacity of the HUVECs. ConclusionsA novel formulation of BMP-7-mRNA-LNP called AET-1978 represents a novel, transient, non-integrating strategy to attenuate fibrotic remodeling and improve cardiac function in heart failure, with supportive evidence of being anti endothelial to mesenchymal transition. HighlightsO_LIA novel BMP-7 mRNA-lipid nanoparticle formulation delivered as a subcutaneous injection attenuated myocardial fibrosis and improved systolic and diastolic function in a murine model of non-ischemic heart failure. C_LIO_LIBMP-7 mRNA therapy preserved endothelial phenotype and suppressed endothelial-to-mesenchymal transition in an in vitro platform of human umbilical vascular endothelial cells. C_LIO_LIBMP-7 mRNA therapy preserved endothelial function including restoration of nitric oxide production, lipoprotein uptake, and angiogenic capacity in vitro. C_LIO_LIThis study introduces AET-1978, a transient, non-integrating mRNA therapeutic platform, as a novel approach to target residual fibrotic pathways in heart failure using a clinically scalable delivery route. C_LI

Background: Exercise-based cardiac rehabilitation (CR) improves peak oxygen uptake ([V]O2peak) in patients with coronary heart disease (CHD); however, whether women and men exhibit similar adaptations across the steps of O2 transport remains unknown. We aimed to compare the ventilatory and circulatory determinants of [V]O2peak changes between women and men with CHD following a structured exercise training program. Methods: A total of 28 women (27%) and 75 men (73%) with CHD, matched for age, body mass index, and [V]O2peak (% predicted), underwent maximal cardiopulmonary exercise testing (CPET) before and after 12 weeks of CR. [V]O2peak and minute ventilation ([V]E) were measured breath by breath. Heart rate and cardiac output ([Q]c)were assessed non-invasively using impedance cardiography. Exercise efficiency ({Delta}[V]O2/{Delta}W), alveolar ventilation ([V]A), ventilatory efficiency (OUES), O2 pulse, arteriovenous oxygen content difference (C(a-[v])O2) and gross muscular efficiency (W) were calculated using standard equations. Mixed model analyses (sex x time) were used to compare training-induced changes between sexes. Results: At baseline, values of [V]O2peak (absolute and normalized by fat free mass), [V]E, [V]A, O2 pulse, C(a-[v])O2, {Delta}[V]O2/{Delta}W, W were significantly lower in women than in men with CHD (group effect, p<0.01). [V]O2peak normalized by fat-free mass improved similarly in both sexes after CR (p<0.0001, no significant sex x time interaction). Pulmonary convection ([V]E, [V]A), ventilatory efficiency (OUES), circulatory convection ([Q]c, cardiac index, O2 pulse), and peripheral gross muscular efficiency (W) all improved similarly after CR in women and men (effect sizeXtime effect, p<0.05, no significant group x time interaction). The prevalence of responder categories did not differ between sexes (p=0.826). Conclusion: Women and men with CHD demonstrated equivalent O2 transport phenotype adaptations after CR, with comparable improvements across the O2 transport chain (pulmonary, circulatory, and peripheral determinants of [V]O2peak).

BackgroundDoxorubicin (DOX) causes sex-specific cardiotoxicity. Metabolic impairment is a well-established cardiotoxic effect of DOX treatment that can contribute to other detrimental effects such as increased reactive oxygen species, reduced ATP, inflammation etc. We hypothesized that preserving cardiac metabolism by exercise can attenuate DOX cardiotoxicity. MethodsMale and female C57BL/6J mice at 15 weeks of age were randomly assigned to one of four groups, 1) Control (sedentary), 2) EX (exercised, treadmill running), 3) DOX (doxorubicin at 5 mg/kg/week for 6 weeks), and 4) EXDOX (exercise + doxorubicin). Echocardiography was performed every other week during the 6-week protocol to measure cardiac mechanical function. At the end of the protocol, optical mapping and seahorse analysis were performed to measure electrophysiology and metabolism, respectively. RNA sequencing, cytokine array assay and transmission electron microscopy were also performed to determine sex-specific mechanisms of DOX cardiotoxicity. ResultsDOX reduced stroke volume and left ventricular diameter in males only and exercise did not prevent these effects of DOX. In female mice, DOX prolonged action potential duration (APD) and slowed conduction velocity (CV), and importantly, exercise prevented DOX-induced CV slowing. Exercise-induced cardioprotection against DOX in female mice was associated with preservation of aerobic metabolism and attenuation of inflammation which modulated ion channel gene expression. Specifically, Cacna1c was increased in both DOX and EXDOX females, but not in males and correlated with APD prolongation. Interestingly, despite CV slowing, Gja1 and Scn5a were increased. However, increased Kcnj8 along with metabolic impairment could cause membrane hyperpolarization and underlie CV slowing. ConclusionsDOX cardiotoxicity is sex specific. Mechanical dysfunction is more prevalent in DOX-treated males while arrhythmogenic electrical remodeling is more prevalent in DOX-treated females. Exercise therapy during DOX did not prevent DOX induced mechanical dysfunction in male hearts but attenuated electrical remodeling in females by preserving metabolism and attenuating inflammation.

Background: Quantitative lipid assessment is central to identifying rupture-prone coronary plaques and represents a therapeutic target for lipid-lowering therapy. Near-infrared spectroscopy (NIRS)-derived lipid core burden index (LCBI) is well validated and widely used for detecting lipid-rich lesions. Optical frequency domain imaging (OFDI) is increasingly adopted for guiding percutaneous coronary intervention (PCI) due to its high-resolution structural imaging capabilities. Depolarization-sensitive OFDI (depOFDI) provides intrinsic lipid contrast and may enable combined structural and compositional plaque characterization within a single OFDI-based platform. Objective: To define an OFDI-derived lipid metric and evaluate its agreement with NIRS-derived LCBI. Methods: Thirty-three patients underwent both polarization-sensitive OFDI and NIRS-intravascular ultrasound imaging during PCI. After exclusion of 4 datasets, 29 co-registered pullbacks were analyzed. A signal-to-noise-corrected depolarization metric was used to identify lipid-rich regions and generate depOFDI chemograms. maxLCBI4mm value and location, as well as total LCBI, were computed and compared with NIRS. Results: depOFDI demonstrated strong agreement with NIRS, showing high correlation for maxLCBI4mm (r^2 = 0.862) and total LCBI (r^2 = 0.867), along with strong spatial concordance for the location of the maxLCBI4mm (r^2 = 0.900). Bland-Altman analysis of LCBI4mm showed minimal bias (10.7) with 95% limits of agreement of [81.4 to 102.8]. Conclusions: depOFDI enables accurate quantification of lipid burden alongside the high-resolution structural information inherently provided by OFDI. Because depolarization metrics can be derived from polarization-diverse detection available in many commercial OFDI systems, this approach provides a practical pathway toward comprehensive plaque characterization within existing PCI workflows, without the need for additional imaging modalities.

Background: Left atrial (LA) stiffness index is a non-invasive echocardiographic parameter reflecting left ventricular filling pressure; however, its prognostic significance in hypertension remains unclear. We aimed to assess the prognostic value of the longitudinal change in LA stiffness index in patients with hypertension. Methods: We analyzed 1,442 hypertensive patients from the STRATS-HHD registry who underwent echocardiography including LA and left ventricular (LV) strain at baseline and 6-18 months. Patients were categorized into four groups according to longitudinal changes in LA stiffness index: normal-normal, improved, aggravated, and persistently stiff. The primary outcome was a composite of hospitalization for heart failure (HHF) and cardiovascular death, and secondary outcomes included HHF and incident atrial fibrillation. Results: Among 1,442 patients, 996 (69.1%) were classified as normal-normal, 173 (12.0%) as improved, 91 (6.3%) as aggravated, and 182 (12.6%) as persistently stiff. Over 5 years, aggravated (adjusted hazard ratio [aHR] 2.175, 95% confidence interval [CI] 1.048-4.515, P=0.037) and persistently stiff (aHR 2.935, 95% CI 1.697-5.076, P<0.001) groups were associated with a higher risk of the primary outcome, whereas the improved group showed a similar risk to the normal-normal group. Similar trends were observed for HHF and for incident atrial fibrillation. Adding LA stiffness index into a model including clinical factors and LV mass index improved risk prediction for composite outcomes. Conclusions: LA stiffness index was associated with clinical outcomes in hypertensive patients, with longitudinal changes providing additional prognostic information. Assessment of its trajectory may further refine risk stratification in patients with hypertension.

Background: Coronary artery bypass grafting (CABG) remains the standard of care for complex multivessel and left main coronary artery disease. However, current preoperative planning remains largely subjective, relying on qualitative interpretation of coronary CT angiography (CCTA), operator-dependent stenosis grading, and fragmented multi-software workflows. Invasive fractional flow reserve (FFR), the reference standard for physiologic lesion assessment, is infrequently acquired preoperatively, leaving distal anastomosis planning without an objective hemodynamic basis. Methods: We developed a fully automated, AI-powered platform that converts routine CCTA into a patient-specific CABG planning workflow through five integrated modules: nnU-Net based segmentation of coronary lumen and calcification; quantitative morphological and topological characterization generating more than thirty descriptors; automated stenosis detection using a local reference-radius formulation; a nine-point composite scoring framework for distal anastomosis site selection incorporating luminal caliber, landing-zone length, calcification burden, distal perfusion reserve, and bifurcation proximity; and interactive virtual graft construction coupled to a distributed reduced-order solver for pre- and post-bypass FFR estimation. Results: Lumen segmentation achieved a mean Dice similarity coefficient of 0.96 {+/-} 0.01, whereas calcium segmentation achieved 0.73 {+/-} 0.15 on the held-out cohort. Platform-derived FFR demonstrated strong agreement with invasively measured FFR (r=0.96, mean absolute relative difference 1.73 {+/-}1.42%) across the evaluated lesions, supporting the physiologic validity of the reduced-order hemodynamic solver. End-to-end analysis from raw CCTA to hemodynamic assessment and virtual graft planning was completed in approximately seven minutes per case on a standard workstation, representing a substantial reduction in processing time compared with conventional multi-tool and CFD-based workflows. Conclusions: The proposed platform demonstrates the feasibility of rapid, reproducible, and physiology-informed CABG planning using routine CCTA. By integrating anatomical characterization, automated target-site analysis, virtual graft construction, and reduced-order hemodynamic assessment into a single workflow, the framework provides objective, quantitative surgical decision support compatible with routine clinical workflows. Keywords: Coronary artery bypass grafting (CABG); Fractional flow reserve (FFR); Coronary CT angiography (CCTA); Surgical planning

Deep-learning ECG analysis is advancing rapidly but lacks stable, physiologically interpretable indicators to anchor explainable artificial intelligence (AI). Tensor cardiography (TCG) models electrocardiographic (ECG) waveforms as differences between pairs of cumulative distribution functions (CDFs), representing collective myocardial action potential transitions. However, the original 4-CDF model has limitations in fitting P waves and complex QRST patterns. This study aimed to evaluate whether increasing the number of CDFs from 4 to 10 improves TCG fitting accuracy and to characterize normative distributions of 10-CDF parameters in healthy individuals. Participants were recruited through occupational health screening at Tobu Railway Co., Ltd. (n = 415) and from the Nippon Medical School Hospital ECG database (n = 29). Standard 12-lead ECGs from 444 healthy participants, including 345 men and 99 women with a mean age of 46.9 years, were analyzed using TCG software. Reconstruction accuracy was assessed using RMSE, paired t-tests, and Cohens d. The 10-CDF model achieved significantly lower RMSE values across all leads than the 4-CDF model, with all p values < 0.0001 and very large effect sizes. In representative leads, RMSEs for the 4-CDF versus 10-CDF models were 0.0256 versus 0.0061 in lead II, 0.0230 versus 0.0063 in lead V1, and 0.0265 versus 0.0062 in lead V5. The coefficient of determination improved from a median of 0.952 with the 4-CDF model to 0.997 with the 10-CDF model in lead II. Parameter dispersion was reduced, suggesting improved estimation stability. Two new parameters, T_mean_diff and RT_mean_duration, were derivable from the expanded model; RT_mean_duration showed significant correlations with age and body surface area. In conclusion, increasing the CDF resolution from 4 to 10 significantly enhanced ECG waveform reconstruction accuracy and parameter stability. These findings provide normative distributions of 10-CDF TCG parameters and may support future explainable AI-based ECG analysis.

Background: Higher METS-IR has been shown to be associated with a higher risk of major adverse cardiovascular events, but data are lacking regarding cardiac arrhythmias. Objectives: The aim of this study was to assess the association between METS-IR and atrial fibrillation/flutter, ventricular arrhythmia and bradyarrhythmia. Methods: Data from the Atherosclerosis Risk in Communities study spanning 1987 to 2013 was utilized for this analysis. METS-IR scores were assessed at baseline (1987-1989) and arrhythmia episodes were identified using ICD-9 codes. Multivariate-adjusted Cox proportional hazard models were constructed to evaluate the relationship between METS-IR and arrhythmia risk, with dose-response analyses conducted. In addition, we analyzed the predictive value of METS-IR for arrhythmias. Results: Over a mean follow-up of 21.9 years, 2493 cases of AF, 688 cases of bradyarrhythmia, and 1315 cases of ventricular arrhythmia were recorded. Each interquartile range increase in METS-IR was associated with a 49% higher risk of atrial fibrillation(P<0.001), 29% higher risk of bradyarrhythmia(P<0.001), and 42% higher risk of ventricular arrhythmia(P<0.001). After correction for relevant confounders, the METS-IR index was significantly and positively associated with the risk of new-onset atrial fibrillation, bradyarrhythmia, and ventricular arrhythmia (P overall<0.05, P for non-linearity>0.05). Most of the results of the subgroup analyses were not significantly different. The inclusion of METS-IR in the base model improves the predictive value of the risk of arrhythmogenesis. Conclusions: There is a significant association between METS-IR and increased risk of arrhythmias.

AimsHeart failure with preserved ejection fraction (HFpEF) afflicts millions annually and current treatments provide symptomatic relief. Here, we investigate the therapeutic potential of synthetic human Relaxin-2 (RLX) at reversing diastolic dysfunction (DD) and reducing arrhythmia vulnerability. Methods and ResultsMale ZSF1 rats were placed on a normal diet (ND, N=10 controls) or a high-fat diet (HFD, N=11), resulting in the development of DD in 11-weeks, based on serial echocardiograms (enlarged left atrium (LA), wall thickness, doppler flow: E/e). Once HFpEF was confirmed, control and HFpEF rats were randomly treated with Relaxin (400{micro}g/kg/day RLX, N=6) or the vehicle (N=5) for 2-weeks using implanted minipumps. Echocardiograms were repeated at weeks 1 and 2, then hearts were isolated, optically mapped, subjected to programmed electrical stimulation (PES) and tissues dissected for immuno-fluorescence (IF), and qPCR analysis. Circulating levels of glucose, RLX and NT-pro-ANP were measured, pre- and post-treatment. Echocardiograms indicated that RLX reversed DD by reducing LA dimensions and E/e. Optical mapping revealed that 1/3 of HFpEF hearts exhibited sustained atrial and ventricular arrhythmia which were blocked by RLX as it tended to increase conduction velocity (CV). Based on IF, RLX increased Nav1.5, Connexin-43, {beta}-catenin and Wnt1 expression. There were no significant changes in fibrosis in this HFpEF model. NT-pro-ANP was elevated in HFpEF and reduced towards control values by RLX. qPCR analysis showed that RLX decreased DKK1 and MMP1A and increased SCN5A expression compared to Vehicle treatment (N=6 and 5, respectively). ConclusionsThe ZSF1 model showed clear signs of HFpEF, including DD, enlargement of the LA, enhanced hemodynamic stress, increased vulnerability to sustained AF and VF, and elevated glucose and blood pressure. RLX treatment largely reversed DD, hemodynamic stress, and suppressed sustained arrhythmias. RLX elicited cardiac genomic changes, most likely through Wnt/canonical signaling, demonstrating RLXs potential as a therapy for HFpEF.