Search Results (429)

Background/Objectives: Hypertrophic cardiomyopathy (HCM) in childhood is associated with a risk of adverse cardiovascular events despite preserved left ventricular (LV) ejection fraction (EF). The aim of this study was to evaluate echocardiographic parameters of longitudinal LV systolic function and determine their relationship with cardiac magnetic resonance (CMR) findings and major adverse cardiovascular events (MACE) in children and adolescents with HCM. Methods: This single-centre prospective observational study enrolled 31 children and adolescents with HCM and preserved LV EF. Echocardiographic assessment included mitral annular plane systolic excursion (MAPSE), tissue Doppler mitral annulus systolic velocity (s′), mitral annular displacement index (MADI), and LV global longitudinal strain (GLS). Investigated CMR parameters encompassed LV mass, maximal wall thickness, and late gadolinium enhancement (LGE). Associations between echocardiographic and CMR findings were analyzed, and the discriminative value of longitudinal function parameters for MACE was assessed. Results: Impaired longitudinal systolic function was frequently detected in our cohort. Lower MAPSE and s′ z-scores were present in 61.3% of patients, reduced MADI in 96.8%, and reduced LV GLS in all subjects. Patients with MACE showed significantly lower MADI (p < 0.001) and worse LV GLS (p = 0.003). An exploratory LV GLS cut-off value of −12.1% showed discrimination for MACE in this cohort, with 75% sensitivity and 95.7% specificity. Echocardiographic parameters significantly correlated with CMR markers of hypertrophy and fibrosis, particularly LV GLS, which demonstrated the strongest associations with LV mass and the presence and extent of LGE. Conclusions: Echocardiographic parameters of longitudinal LV systolic function could contribute to closer clinical surveillance in children and adolescents with HCM. LV GLS may identify subtle myocardial dysfunction and provide exploratory prognostic information; however, its role in risk stratification requires prospective validation in larger pediatric HCM cohorts. Full article

Background: Left ventricular (LV) dysfunction remains the leading cause of mortality in transfusion-dependent beta-thalassemia (TDßT), yet conventional echocardiography often fails to detect early myocardial impairment. This study aimed to comprehensively evaluate LV function in children with TDßT using three-dimensional echocardiography (3DE) and speckle-tracking strain analysis, comparing diagnostic performance with conventional two-dimensional (2D) parameters. Results: 50 TDßT patients were compared to 50 matched controls and exhibited preserved conventional LV ejection fraction (EF) on 2D (65.31 ± 7.12% vs. 69.21 ± 3.87%, p = 0.001), but 3DE revealed significant ventricular dilation with higher end-diastolic volume index (75.50 ± 17.99 vs. 65.63 ± 11.86 mL/m², p = 0.002) and end-systolic volume index (22.28 ± 7.85 vs. 18.21 ± 5.14 mL/m², p = 0.003). Despite preserved 3D EF (70.79 ± 5.98% vs. 72.07 ± 5.76%, p = 0.276), global longitudinal strain (GLS) was significantly impaired (−18.56 ± 2.37% vs. −21.47 ± 1.86%, p < 0.001). 3D volumetric parameters demonstrated superior diagnostic performance (AUC for LVEDVI Z-score = 0.874) compared to conventional indices. Transfusion duration correlated strongly with ventricular volumes (r = 0.569 for EDV, p < 0.001), while serum ferritin showed no significant correlation with cardiac parameters. Conclusions: Children with TDßT develop early subclinical LV dysfunction detectable by 3DE and strain analysis despite preserved conventional systolic indices. 3D volumetry and GLS should be integrated into routine cardiac surveillance protocols to enable timely therapeutic intervention. Full article

Background: The impact of overweight and obesity on blood pressure and cardiac remodelling in pediatric congenital heart disease (CHD) remains incompletely defined, particularly across different ventricular physiologies and cardiac anatomies. Aim: To assess the association of overweight and obesity with arterial blood pressure and cardiac remodelling in pediatric and young adult patients with CHD, according to ventricular physiology and cardiac anatomy. Methods: In this observational study, pediatric CHD patients undergoing clinical and echocardiographic evaluation were classified by weight status and ventricular physiology, with additional stratification by cardiac anatomy. Associations between body mass index (BMI), arterial hypertension, and echocardiographic parameters were analyzed. Results: A total of 451 patients were included (mean age 13.1 ± 3.9 years; 74 univentricular, 377 biventricular). Overall, 16% were overweight and 7% obese. Hypertension was present in 16% and increased across BMI categories (14%, 26%, and 50%). BMI was associated with blood pressure category (p < 0.001), higher systolic blood pressure (p < 0.001), and increased left ventricular (LV) mass (p = 0.007), interventricular septal thickness (p < 0.001), and posterior wall thickness (p < 0.001), without evidence of systolic dysfunction. In adjusted models, overweight/obesity remained associated with worse blood pressure classification, both as a three-category outcome (OR 2.1, 95% CI 1.4–3.2; p < 0.001) and as a binary outcome (OR 2.3, 95% CI 1.5–3.7; p < 0.001), as well as with higher systolic blood pressure (β = 5.1 mmHg, 95% CI 2.4–7.8; p < 0.001), left ventricular mass index (LVMI) (β = 10.0, 95% CI 4.3–15.8; p < 0.001), interventricular septal thickness at end-diastole (IVSd) (p < 0.001), and left ventricular posterior wall in diastole (LVPWd) (p < 0.001), but not with diastolic blood pressure or systolic function. No significant associations were observed in univentricular patients, whereas in biventricular circulation higher BMI was consistently associated with worse blood pressure and remodeling, without systolic dysfunction. Conclusions: Excess body weight is independently associated with adverse blood pressure status and early LV structural remodelling in pediatric and young adult patients with CHD, despite preserved systolic function. These findings support early cardiovascular risk surveillance and preventive strategies targeting overweight and obesity in CHD care. Full article

Background: Frailty in older adults is linked to adverse cardiovascular outcomes, but its relationship with echocardiographic markers of diastolic function remains unclear. We examined associations between frailty measures and indices of diastolic function in community-dwelling older adults. Methods: This cross-sectional study included 537 adults aged ≥65 years from a multidisciplinary outpatient clinic. Frailty was assessed using the Fried phenotype, Clinical Frailty Scale (CFS), gait speed, and handgrip strength. Associations with diastolic indices were analyzed using multivariable regression with sequential adjustment. Sensitivity analysis was performed via matching. Results: According to the Fried phenotype, 30.8% of participants were robust, 59.7% pre-frail, and 9.5% frail. Indexed left atrial dimension (LAi) was consistently higher in frail individuals. Frailty was also associated with higher odds of elevated right ventricular systolic pressure (>35 mmHg) in unadjusted analyses. Using the CFS, individuals with a score higher than 3 had significantly higher NT-proBNP levels compared to those with a score of 1–2. Higher gait speed and handgrip strength were associated with more favorable cardiac structure, including smaller left heart chamber sizes, and lower natriuretic peptide levels. Conclusions: Frailty was independently associated with structural and functional markers of diastolic dysfunction in older adults, particularly left atrial enlargement (as captured in Fried) and NT-proBNP elevation (as captured in CFS), supporting the integration of frailty assessment into cardiovascular risk evaluation. Full article

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is released in response to increased cardiac wall stress and is used as a biomarker for volume overload and heart failure (HF). It is also elevated in atrial fibrillation (AF) and inflammation. However, in hemodialysis (HD) patients, its interpretation is complicated by reduced renal clearance, large fluid shifts between dialysis sessions, and chronic inflammation. Methods: In 123 HD patients, we examined the relationship between NT-proBNP and interdialytic weight gain, HF with preserved ejection fraction (HFpEF), left ventricular systolic dysfunction (LVSD), and AF, as well as the impact of inflammation. Clinical characteristics, laboratory data, and echocardiography (within three months) were evaluated, while serum NT-proBNP and calprotectin levels were measured by ELISA. Results: NT-proBNP showed no association with interdialytic weight gain and did not identify HFpEF. Inflammatory markers (C-reactive protein and calprotectin) correlated positively with NT-proBNP. Multivariable analysis demonstrated that LVSD, AF, and inflammation remained independent predictors of NT-proBNP levels. Although NT-proBNP levels were higher in LVSD, its diagnostic performance was poor (AUC 0.627). In contrast, NT-proBNP was significantly elevated in patients with AF and showed good diagnostic performance (AUC 0.801). Conclusions: In HD patients, NT-proBNP is not correlated with interdialytic weight gain, performs poorly as a marker of LVSD, but may serve as a useful marker of AF. Full article

Background: Cardiovascular complications are increasingly recognized in patients undergoing hematopoietic stem cell transplantation (HSCT). Early detection of subclinical myocardial dysfunction may improve risk stratification, and global longitudinal strain (GLS) is emerging as a sensitive marker of early cardiac impairment. Methods: We conducted a single-center observational cohort study including 518 adult patients undergoing autologous (n = 64) or allogeneic (n = 454) HSCT between 2004 and 2025. Baseline cardiovascular risk factors, transplant characteristics, and echocardiographic parameters—including GLS in a subset—were recorded. Abnormal GLS was defined as less negative than −20%. The primary outcome was the occurrence of cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, atrial fibrillation/flutter, pericardial effusion, pulmonary embolism, and left ventricular systolic dysfunction). Multivariable logistic regression was used to identify independent predictors. Results: Median age was 53 years; 58% were male. Cardiovascular events were predominantly atrial fibrillation, pericardial effusion, and reduced left ventricular function, whereas ischemic events were rare. Over 90% of events occurred within 100 days post-transplant. Multivariable analysis identified older age (OR 1.28 per 10-year increment; 95% CI 1.10–1.48; p = 0.002), chronic kidney disease (OR 2.44; 95% CI 1.18–5.02; p = 0.01), pre-transplant atrial fibrillation (OR 2.12; 95% CI 1.04–4.31; p = 0.03), and abnormal baseline GLS (OR 1.89; 95% CI 1.02–3.52; p = 0.04) as independent predictors. Importantly, the prognostic value of GLS remained significant after excluding clinically insignificant pericardial effusions from the composite endpoint. GLS deterioration during follow-up occurred more frequently in patients receiving reduced-intensity conditioning compared with myeloablative conditioning (25% vs. 12.7%; p = 0.006). Conclusions: Subclinical myocardial dysfunction detected by GLS identifies HSCT recipients at increased cardiovascular risk. These findings support the incorporation of strain imaging into routine pre- and post-transplant cardiovascular evaluation to enable earlier detection and guide targeted interventions. Full article

Background and Objectives: Oxidative stress is recognized as an important contributor to heart failure (HF) pathophysiology, but the relationships of individual oxidative and antioxidant biomarkers with symptomatic severity and systolic dysfunction remain insufficiently defined. This study examined circulating oxidative and nitrosative stress markers across New York Heart Association (NYHA) classes and left ventricular ejection fraction (LVEF) categories in HF and their associations with HF severity. Materials and Methods: In this case–control study, 85 patients with HF and 33 healthy controls were included. Malondialdehyde (MDA), nitrates and nitrites (NOx), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), sulfhydryl (SH) groups, and NT-proBNP were measured. Group differences were analyzed using the Kruskal–Wallis test with post hoc comparisons. Adjusted ordinal logistic regression models examined associations with NYHA class and LVEF category, and receiver operating characteristic (ROC) analysis evaluated discriminatory performance. Results: Compared with controls, all biomarkers differed significantly across NYHA classes and LVEF categories (all p < 0.001). In separate adjusted models, higher NOx, MDA, and NT-proBNP were associated with worse NYHA class and more impaired LVEF, whereas higher antioxidant marker levels were associated with lower odds of severe HF. In combined models, NOx remained independently associated with worse NYHA class (OR 1.07, 95% CI 1.04–1.11; p < 0.001), while MDA remained independently associated with more impaired LVEF (OR 1.02, 95% CI 1.00–1.03; p = 0.022). NT-proBNP showed the best discrimination for NYHA III/IV versus I/II (AUC 0.966), while among oxidative biomarkers NOx performed best for symptomatic severity (AUC 0.782) and MDA for LVEF ≤ 40% (AUC 0.751). Conclusions: HF is characterized by increased oxidative and nitrosative stress together with reduced antioxidant defense. NOx appears more closely related to symptomatic severity, whereas MDA appears more closely related to systolic dysfunction. However, NT-proBNP remained the strongest overall discriminator. NOx and MDA may provide complementary mechanistic information on redox imbalance across HF severity categories. Full article

Background and Objectives: The diagnostic accuracy of an artificial intelligence (AI)-derived initial 12-lead electrocardiogram (ECG) analysis was evaluated for early carbon monoxide-induced cardiomyopathy (CO-CMP) risk detection. Materials and Methods: Retrospective medical data of carbon monoxide poisoning (COP) cases between 1 January 2015 and 31 December 2024 were screened for the primary outcome: odds ratio (OR) for echocardiographically confirmed CO-CMP among those with high-risk probability score per the AI-derived model. Secondary outcomes included left ventricular ejection fraction (LVEF) and AI-derived probability score, critical care requirements, including intubation and intensive care unit (ICU) admission, and cardiac arrest events. Results: A total of 51 patients with acute COP were included in the final analysis, with 13 (25.5%) being diagnosed with CO-CMP. The LVEF in the CO-CMP group was lower than that in the non-CO-CMP group (40.00 ± 13.80% vs. 63.76 ± 6.24%, p < 0.001). The AI-derived probability score was higher in the CO-CMP group (11.3 [3.8–32.7] vs. 0.5 [0.2–2.2], p < 0.001). Among cardiac biomarkers, troponin I (2.37 [0.32–7.88] vs. 0.06 [0.06–0.95] ng/mL, p = 0.002) was higher in the CO-CMP group. Patients with CO-CMP required recurrent ventilator support (76.9% vs. 21.1%, p < 0.001) and ICU admission (92.3% vs. 42.1%, p = 0.003). In multivariable regression analysis, the AI-derived prediction model was independently associated with CO-CMP (OR 1.14; 95% confidence interval (CI) 1.02–1.27; p = 0.017; Firth-penalized OR 1.11; 95% CI 1.03–1.25; p < 0.001). Receiver operating characteristic analysis of the AI-derived model showed an area under the curve of 0.85 (95% CI 0.70–0.96) for the AI score alone and 0.92 (95% CI 0.83–0.99) for the Combined AI–cardiac marker model, with a sensitivity of 92.3% and specificity of 81.6%. Pairwise DeLong comparisons between the Combined AI model and comparator models did not reach statistical significance (Combined vs. AI-only, p = 0.092; Combined vs. cardiac markers, p = 0.052); however, the likelihood-ratio test for adding the AI probability score to the cardiac marker-only model demonstrated significant incremental information (χ² = 13.68, p < 0.001). Conclusions: AI-based ECG analysis showed exploratory diagnostic association with LV systolic dysfunction observed in suspected CO-CMP patients. Given the limited sample size, low events-per-variable ratio, and lack of external validation, these findings suggest that AI-ECG analysis may provide incremental information for early cardiac risk stratification in selected patients. Full article

Aging is a significant risk factor for cardiovascular diseases. The prevalence of heart failure increases with age, making it a leading cause of morbidity and mortality. We investigated age-associated changes in expression of Nuclear Factor (Erythroid-derived 2)-Like 2 (NFE2L2 or NRF2) in the myocardium of humans, rhesus monkeys, Fischer rats, and C57BL/6 mice. NRF2 is a transcription factor that orchestrates the expression of genes involved in antioxidant and detoxification responses. Analyses of RNA-seq data from the Genotype-Tissue Expression (GTEx) project, which contains left ventricular samples from 294 male donors, revealed a trend of age-associated declines in NRF2 transcripts and several of its downstream genes (SOD1, SOD2, CAT, GCLM, and AKR1B). Age-dependent decreases in NRF2 protein expression were observed in the myocardium of Rhesus monkeys and Fischer rats. To determine whether NRF2 loss contributes to myocardial aging, we evaluated cardiac function of NRF2 knockout mice (KO) at 19 and 24 months of age. At 19 months, the NRF2 KO mice exhibited diastolic dysfunction, characterized by an increased end-diastolic volume (EDV) and end-systolic volume (ESV), accompanied by a reduced ejection fraction (EF) and fractional shortening (FS), indicative of early onset of heart failure. The NRF2 KO mice displayed premature aging phenotypes and had reduced lifespans. Our findings support the trend of NRF2 signaling decline with age, and that loss of NRF2 accelerates the maladaptive cardiac remodeling and functional deterioration associated with aging. Full article

Hypertrophic Cardiomyopathy (HCM) is one of the most common inherited cardiomyopathies and remains an important cause of ventricular arrhythmias and sudden cardiac death (SCD), particularly in younger individuals. Although the annual incidence of arrhythmic death is relatively low in contemporary cohorts, identifying those patients who may benefit from primary prevention with an implantable cardioverter-defibrillator (ICD) remains a major clinical challenge. Current risk stratification strategies rely on two principal paradigms. The European approach is centered on the HCM Risk-SCD score, whereas the American approach is mainly based on major clinical risk markers. Both strategies have important strengths and limitations, reflecting the persistent difficulty of accurately predicting arrhythmic events in such a heterogeneous disease. The HCM Risk-SCD score has demonstrated robust external validation and high specificity for identifying patients at higher risk, but it may fail to recognize some vulnerable individuals who remain below conventional treatment thresholds. For this reason, several additional risk modifiers have gained increasing relevance in contemporary practice. Among them, extensive late gadolinium enhancement, left ventricular systolic dysfunction, apical aneurysm, and clinically meaningful genetic findings may provide important incremental prognostic information beyond traditional models. Emerging disease-modifying therapies, in particular Mavacamten, may also influence future risk assessment. However, whether these improvements translate into a true reduction in SCD risk remains uncertain. Importantly, the decision to implant an ICD should not depend on numerical risk alone. It should arise from a process of shared decision-making integrating estimated risk, treatment burden, competing comorbidities, age, lifestyle, and patient values. In this context, the concept of an individualized threshold of “acceptable risk” becomes central. In conclusion, prevention of SCD in HCM is moving beyond conventional scores toward a personalized and dynamic framework in which predictive tools, advanced phenotyping, evolving therapies, clinical expertise, and patient preferences are combined to guide individualized care. Full article

Background: Kawasaki disease (KD) is an acute childhood vasculitis with well-recognized coronary involvement, but subtle long-term myocardial dysfunction may persist despite preserved conventional systolic indices. Two-dimensional speckle-tracking echocardiography enables sensitive assessment of left ventricular global longitudinal strain (GLS). Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA 2020. PubMed, Scopus, Web of Science, and Google Scholar were searched for studies evaluating post-acute GLS in children or adolescents with prior KD compared with healthy controls. The outcome measure was the mean difference (MD) in GLS (KD minus control). Random-effects models were used for the primary analysis. Results: Four case–control studies involving 192 patients with prior KD and 138 healthy controls were included in the quantitative synthesis. Compared with controls, patients with prior KD had significantly less negative GLS values, indicating worse longitudinal deformation (pooled MD, 0.77%; 95% CI, 0.18 to 1.36; Z = 2.34; p = 0.019). Between-study heterogeneity was low (Q = 3.17, I² = 5.3%, tau² = 0.030). Leave-one-out analysis showed that the overall direction of effect remained positive, although confidence intervals widened when individual studies were omitted. Interpretation of the funnel plot was limited by the small number of studies. Conclusions: Children and adolescents with a history of KD demonstrate a modest but significant reduction in LV GLS during follow-up, consistent with persistent subclinical myocardial dysfunction. Speckle-tracking echocardiography may provide incremental value in the long-term cardiac assessment of selected patients with prior KD. Full article

Anthracyclines such as doxorubicin (DOX) are widely used in cancer treatment, but their benefits are offset by dose-related cardiotoxicity. Neuregulin-1β (NRG1) has been studied as a cardioprotective factor, yet its mechanisms during DOX treatment, particularly in the presence of cancer, are not well understood. This study evaluated daily recombinant NRG1 co-administered with DOX in 4T1-tumor-bearing female BALB/c mice. The mice were randomized to saline, DOX (3 mg/kg i.p. on days 0, 3, 6, 9; cumulatively 12 mg/kg) or DOX + NRG1 (20 µg/kg i.p. daily, starting one day before DOX). Body weight and tumor growth were monitored throughout treatment. Cardiac structure and function were assessed by transthoracic echocardiography at baseline and before sacrifice. Mechanistic studies included left ventricular proteomics and single-cell RNA-seq. We also used human 3D cardiac microtissues and 2D primary cardiac fibroblast-enriched cultures under defined experimental conditions, with targeted fibroblast gene perturbations. We found that early DOX exposure induced systolic dysfunction and pathological remodeling, while daily NRG1 preserved the ejection fraction and attenuated structural changes without impairing anti-tumor efficacy. Proteomic analysis identified Serping1 as one of the most strongly upregulated proteins soon after DOX exposure, an effect that was reversed by NRG1. Notably, Serping1 has not previously been implicated in anthracycline cardiotoxicity or NRG1-mediated protection. Single-cell RNA sequencing localized Serping1 expression to cardiac fibroblasts. Mechanistically, we found that Serping1 modulation was associated with altered Igfbp5 processing and fibroblast survival under DOX-induced stress; its suppression by NRG1 was linked to reduced fibroblast apoptosis and a shift toward a pro-survival-associated state. In human cardiac microtissues, NRG1 treatment or fibroblast-specific Serping1 knockdown accelerated cardiomyocyte contraction dynamics. These changes occurred without an increase in apoptosis and point to a paracrine effect of fibroblasts on cardiomyocyte function. Additionally, scRNA-seq revealed an Erbb4+ fibroblast subpopulation associated with early pro-fibrotic activation that expanded after DOX but was reduced by NRG1. Taken together, NRG1 preserved cardiac function during anthracycline treatment while maintaining anti-tumor efficacy. Our data identify fibroblast-associated signaling, particularly through Serping1, as a potential contributor to the early protective effects of NRG1. These findings add a new dimension to the understanding of NRG1 cardioprotection and suggest that fibroblast–myocyte interactions may contribute to the early cardiac response to DOX. Full article

Background/Objectives: Alcoholic cardiomyopathy (ACM) is a major preventable cause of non-ischemic dilated cardiomyopathy (DCM), yet its specific cardiac magnetic resonance (CMR) remains incompletely defined. We aimed to characterize the CMR features of ACM, focusing on late gadolinium enhancement (LGE) subpatterns and biventricular function and to compare them with idiopathic DCM. Methods: In total, 148 consecutive patients (ACM n = 20, idiopathic DCM n = 128) referred for CMR at a single center were retrospectively analyzed. Sequential logistic regression adjusted for age, sex, left ventricular ejection fraction (LVEF), and right ventricular ejection fraction (RVEF) was used to identify independent association with LGE presence. Results: LVEF did not differ between groups (32.5% vs. 35.0%, p = 0.293). ACM patients showed significantly worse RVEF (40.5% vs. 52.0%, p = 0.010) and larger indexed right ventricle (RV) volumes. Any LGE was present in 70% vs. 40% (p = 0.015); when the non-specific RV insertion point pattern (non-RV-IP) was excluded, non-RV-IP LGE was 45% vs. 22.7% (p = 0.051), with a specific midwall linear pattern (25% vs. 8%, p = 0.033). ACM was independently associated with LGE across all models with an adjusted odds ratio (OR) of 3.06 [95% CI 1.05–8.95], p = 0.041, and RV dysfunction (RVEF < 45%) (OR 4.79 [95% CI 1.60–14.32], p = 0.005). No differences in major adverse cardiovascular events (MACEs) were observed at 24 months (log-rank p = 0.697). Conclusions: ACM has a distinct CMR phenotype characterized by midwall linear LGE fibrosis and more severe RV involvement, independent of left ventricle (LV) systolic function. These exploratory findings suggest that CMR may provide clinically relevant phenotypic information in ACM beyond LVEF, warranting confirmation in prospective studies. Full article

Heart failure with reduced ejection fraction (HFrEF) is increasingly recognized as a systemic metabolic disorder. The aim of this study was to characterize amino acid-related metabolic differences between heart failure with moderately reduced ejection fraction (HFmrEF) (LVEF 40–49%) and HFrEF (LVEF < 40%) and to derive a biologically interpretable composite metabolomic index capable of discriminating between these two stages of systolic dysfunction. We conducted a cross-sectional metabolomic analysis of 42 patients stratified by left ventricular ejection fraction (LVEF < 40% vs. 40–49%). The reference group comprised patients with mildly reduced ejection fraction (LVEF 40–49%), without inclusion of individuals with preserved or normal cardiac function. Targeted amino acid profiling was performed using liquid chromatography-tandem mass spectrometry (LC–MS/MS). Metabolites were standardized and analyzed individually and in combination. A composite index (Heart Failure Amino Acid-Derived Systolic Index: HASI-40), integrating markers of proteolysis and metabolic resilience, was derived to distinguish patients with HFrEF from those with HFmrEF. Discrimination was assessed using receiver operator curve (ROC) analysis with internal validation and multivariable adjustment. Patients with LVEF < 40% exhibited a coordinated metabolic phenotype characterized by reduced methionine, sarcosine, serine, and taurine. While individual metabolites did not retain significance after multiple-testing correction, the composite HASI-40 index remained strongly associated with HFrEF (OR 5.56, 95% CI: 1.70–18.14; p = 0.004), although the wide confidence interval indicates limited precision due to sample size. The index demonstrated good discrimination with an area under the curve (AUC) of 0.862, which improved when combined with age (AUC 0.932). The index represents a standardized composite measure and does not define a diagnostic cutoff for individual patients. These findings suggest that HFmrEF and HFrEF exhibit partially distinct metabolic phenotypes despite overlapping clinical characteristics. These findings suggest that HASI-40 captures metabolic differences between patients with HFmrEF (LVEF 40–49%) and those with HFrEF (LVEF < 40%), reflecting progression toward more advanced systolic dysfunction. However, due to the absence of a control group with preserved ejection fraction, small sample size, and lack of external validation, the index should be considered exploratory and hypothesis-generating rather than clinically applicable. Full article

Metabolic syndrome (MetS) drives cardiac remodeling and fibrosis, contributing to diastolic dysfunction and heart failure with preserved ejection fraction, but chamber-specific mechanisms remain poorly defined. New Zealand White rabbits were fed a high-fat/high-sucrose diet for 28 weeks to induce experimental MetS. Systemic phenotype, cardiac structure (echocardiography), myocardial fibrosis (Picrosirius red histology), myosin/collagen gene expression (qRT-PCR), and chamber-specific proteomics were assessed across left/right atria and ventricles. The model reproduced central obesity, glucose intolerance, dyslipidemia, and mild hypertension, with concentric left ventricular hypertrophy and selective ventricular fibrosis, as follows: increased collagen in left ventricle (LV) and right ventricle (RV), unchanged in atria. Ventricular α-myosin heavy-chain gene expression was upregulated, while collagen I and α-smooth muscle actin transcripts showed ventricular-specific downregulation. Proteomics revealed atrial metabolic and cytoskeletal adaptations with minimal extracellular matrix involvement; ventricles displayed early profibrotic cues (galectin-3 in LV), metabolic inefficiency (impaired glycolysis/ATP production in LV; lipid oxidation shift in RV), and diminished provisional matrix support. Conclusions: concentric LV hypertrophy and great vessel enlargement occurred without systolic/diastolic dysfunction; ventricular-selective fibrosis, α-myosin heavy-chain upregulation, type I collagen/α-smooth muscle actin downregulation, and chamber-specific proteomic changes showed atrial adaptation versus ventricular early profibrotic/metabolic inefficiency. Full article