J Cardiovasc Transl Res
· 2026 Jul · PMID 42390624
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Chemotherapy-induced cardiotoxicity (CIC) remains a major cause of morbidity and mortality among cancer survivors, and conventional monitoring often fails to detect early subclinical cardiac injury. We propose ChemoCardi...Chemotherapy-induced cardiotoxicity (CIC) remains a major cause of morbidity and mortality among cancer survivors, and conventional monitoring often fails to detect early subclinical cardiac injury. We propose ChemoCardioNet, an explainable multimodal deep learning framework that predicts cardiotoxicity risk before clinical manifestation by integrating electrocardiograms (ECG), echocardiography, clinical variables, and serum biomarkers. The architecture combines modality-specific encoders, including 1D convolutional transformers for ECG sequences, CNN-ViT hybrid blocks for echocardiographic frames, and multilayer perceptrons for clinical and biomarker features. A cross-attention fusion transformer aligns latent representations across modalities and captures temporal evolution across chemotherapy cycles. The model outputs a probabilistic cardiotoxicity risk score with feature-level explainability using SHAP analysis. In a cohort of 1,200 patients, ChemoCardioNet achieved an AUC of 0.92, outperforming single-modality and traditional machine learning approaches by 8-12%. The model predicted cardiotoxicity approximately two cycles before detectable echocardiographic dysfunction, supporting earlier risk identification and improved cardio-oncology monitoring.
J Cardiovasc Transl Res
· 2026 Jun · PMID 42380371
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Heart failure (HF) is a heterogeneous syndrome with diverse etiologies, yet the metabolic determinants specific to its subtype remain unclear. We performed an integrative multi-omics analysis combining metabolomics, gene...Heart failure (HF) is a heterogeneous syndrome with diverse etiologies, yet the metabolic determinants specific to its subtype remain unclear. We performed an integrative multi-omics analysis combining metabolomics, genetics, and single-cell transcriptomics to characterize metabolic signatures of distinct HF subtypes. By applying Mendelian randomization of 1,091 circulating metabolites, we identified distinct metabolic patterns: lipid metabolites, particularly sphingolipids, were associated with increased HF risk, while tricarboxylic acid (TCA) cycle intermediates exhibited potential protective effects. Subtype-specific differences included lipid remodeling in coronary heart disease (CHD)-related HF, TCA metabolism in hypertension (HTN)-related HF, and amino acid pathways in overweight-related HF. Integrative analyses highlighted candidate regulators such as UPP1, NEU3, CBS, SHMT1, PLD2, OGDHL, and SULT1A1/2. Single-cell data revealed cardiomyocyte-enriched expression of OGDHL, which was consistently downregulated in experimental HF models. These findings provide insight into metabolic heterogeneity in HF and identify OGDHL as a potential regulator of cardiac metabolic remodeling.
Los J, Mensink FB, Bulut Ö
… +6 more, Hol IH, Cetinyurek-Yavuz A, Riksen NP, El Messaoudi S, Cornel JH, van Geuns RM
J Cardiovasc Transl Res
· 2026 Jun · PMID 42373877
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Myocardial infarction (MI) induces an inflammatory response that may be amenable to targeted therapy. This cohort study evaluated the systemic inflammatory burden across different infarct sizes using serial measurements...Myocardial infarction (MI) induces an inflammatory response that may be amenable to targeted therapy. This cohort study evaluated the systemic inflammatory burden across different infarct sizes using serial measurements of C-reactive protein (CRP), interleukin-6 (IL-6), and targeted inflammatory proteomics (Olink's Target 96 Inflammation panel) during hospitalization and up to 12 weeks post-MI. Baseline IL-6 concentrations were progressively higher with increasing infarct size, with differential temporal trajectories observed across infarct size strata (P for interaction < 0.001), a finding confirmed by proteomic analysis (P for interaction = 0.009). Patients with small infarct size showed no significant changes in CRP or IL-6 concentrations, yet demonstrated downregulation of urokinase (uPA) and upregulation of angiogenesis-related proteins (tumor necrosis factor-related weak inducer of apoptosis [TWEAK] and hepatocyte growth factor [HGF]), similar to those observed in patients with moderate or large infarct sizes, emphasizing the biological significance of these processes. Overall, greater myocardial injury was associated with higher inflammatory burden, highlighting IL-6 as a promising therapeutic target for acute anti-inflammatory treatment after large MI.
Balogh M, Tangos M, Patel VS
… +2 more, Hamdani N, Bagi Z
J Cardiovasc Transl Res
· 2026 Jun · PMID 42350878
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Ischemic stroke is associated with increased risk of subsequent cardiac ischemic events, yet mechanisms linking cerebral ischemia to coronary dysfunction remain unclear. We hypothesized that ischemic stroke directly impa...Ischemic stroke is associated with increased risk of subsequent cardiac ischemic events, yet mechanisms linking cerebral ischemia to coronary dysfunction remain unclear. We hypothesized that ischemic stroke directly impairs coronary microvascular function through circulating factors released after cerebral ischemia. We found that the vasodilator function of coronary arterioles (CA) was reduced in patients with prior ischemic stroke. In rats, transient middle cerebral artery occlusion impaired CA vasodilator function. Extracellular vesicles (EVs) isolated after cerebral ischemia and delivered into the rat CA lumen also impaired vasodilation. Moreover, we found that luminal delivery of RGD peptide attenuated flow-induced vasodilation in rat CA, an effect that was prevented by BQ-123, an endothelin ETA receptor antagonist. We propose that ischemic stroke directly induces coronary microvascular dysfunction via circulating EV-mediated, RGD-motif-dependent activation of endothelin signaling. This brain-heart vascular axis provides a mechanistic basis for increased post-stroke coronary risk and identifies EV-mediated pathways as potential therapeutic targets.
van Drie E, van Lint FHM, Zwart R
… +28 more, Wang J, Chen Y, Postma AV, Elferink MG, van Steenbrugge JJM, van der Zwaag PA, Jongbloed JDH, Dooijes D, van der Heide MYC, Houweling AC, Haugaa KH, Leren IS, Kostareva A, Milting H, Nguyen TV, Ho Huynh TD, Chevalier P, Delinière A, Gimeno-Blanes JR, Sabater-Molina M, Barriales-Villa R, Mazzanti A, Memmi M, Kuramoto Y, Tabata T, Wilde AAM, van Spaendonck-Zwarts KY, van Tintelen JP
J Cardiovasc Transl Res
· 2026 Jun · PMID 42350697
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Studying the global distribution of the pathogenic variant c.40_42delAGA;p.(Arg14del) in the phospholamban (PLN) gene is highly important for raising awareness among healthcare providers and may help uncover factors cont...Studying the global distribution of the pathogenic variant c.40_42delAGA;p.(Arg14del) in the phospholamban (PLN) gene is highly important for raising awareness among healthcare providers and may help uncover factors contributing to variability in the development of associated cardiomyopathy phenotypes. PLN p.(Arg14del)-positive individuals were identified through a PubMed literature search, our clinical and research networks, and ClinVar. Additionally, population prevalences were determined using publicly available genetic databases. Furthermore, haplotype analysis was conducted using haplotype markers or whole genome sequencing data to assess whether newly identified cases across different continents share common ancestry. The PLN p.(Arg14del) variant was identified in 21 countries across four continents. Haplotype marker analysis suggest that most analyzed individuals, except those from Greece, shared at least part of a common haplotype. The PLN p.(Arg14del) variant is present in at least 2000 carriers globally. While the majority share at least part of a common haplotype, suggesting a common founder, data suggest an independent mutational event in Greek patients.
Zang X, Zhang G, Kong S
… +3 more, Zhao C, Sun X, Zhang K
J Cardiovasc Transl Res
· 2026 Jun · PMID 42340518
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Heart failure (HF) is traditionally classified by etiology or ejection fraction, but these categories do not fully explain the mechanisms driving disease progression. Increasing evidence suggests that both ischemic and n...Heart failure (HF) is traditionally classified by etiology or ejection fraction, but these categories do not fully explain the mechanisms driving disease progression. Increasing evidence suggests that both ischemic and non-ischemic HF are shaped by maladaptive interactions between immune activation and metabolic remodeling. In ischemic HF, acute cardiomyocyte death and reperfusion stress trigger a phase dependent inflammatory response requiring coordinated adaptation across immune, vascular, stromal, and myocardial cells. In non-ischemic HF, chronic cardiometabolic and hemodynamic stress impairs metabolic fitness in these compartments, promoting endothelial dysfunction, mitochondrial injury, fibrosis, and loss of myocardial reserve. Despite distinct triggers, both phenotypes converge on a shared immunometabolic substrate marked by inflammatory persistence, impaired metabolic flexibility, organelle stress, redox imbalance, and fibroinflammatory remodeling. This review highlights failed immunometabolic state transitions as a unifying mechanism in HF and examines roles for immune and metabolic memory, organelle stress networks, mitochondrial lipid crosstalk, and regulated lipid peroxidation.
Yavuz YE, Alsancak Y, Tatar S
… +4 more, İncekara H, Özyeşi̇l B, Akilli H, İçli̇ A
J Cardiovasc Transl Res
· 2026 Jun · PMID 42329547
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Left ventricular thrombus (LVT) in ischemic heart failure carries embolic risk; tools to anticipate persistence are limited. We studied 190 consecutive patients with imaging-confirmed LVT managed with guideline-concordan...Left ventricular thrombus (LVT) in ischemic heart failure carries embolic risk; tools to anticipate persistence are limited. We studied 190 consecutive patients with imaging-confirmed LVT managed with guideline-concordant anticoagulation and serial echocardiography. The primary outcome was 6-month non-regression; 1-year MACE was secondary. We combined classical statistics with explainable machine learning. CatBoost yielded the best discrimination for non-regression (CV-AUC 0.76; test accuracy 0.79). SHAP highlighted left atrial diameter, pulmonary artery pressure, platelet count, and LV end-diastolic diameter as leading predictors. For 1-year outcomes, thrombus size and CHA2DS2-VA were independently associated with MACE (logistic AUC 0.71), whereas "regression vs persistence" alone was not. Baseline remodeling and coagulability markers, captured by an interpretable ML model, stratify early risk of LVT persistence and complement clinical decision-making for imaging follow-up and anticoagulation intensity.
J Cardiovasc Transl Res
· 2026 Jun · PMID 42319651
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Heart failure (HF) remains a major cause of morbidity and mortality, with ferroptosis increasingly implicated in its progression. Pim1, a serine/threonine kinase, exerts cardioprotective effects by regulating cell surviv...Heart failure (HF) remains a major cause of morbidity and mortality, with ferroptosis increasingly implicated in its progression. Pim1, a serine/threonine kinase, exerts cardioprotective effects by regulating cell survival and oxidative stress, but its role in ferroptosis during HF remains unclear. Here, HF was induced in rats by left anterior descending coronary artery ligation, followed by lentiviral-mediated Pim1 overexpression. Cardiac function, myocardial injury, fibrosis, and ferroptosis-related markers were evaluated. In vitro, H9C2 cardiomyocytes were exposed to HO or Erastin to model HF-related injury and ferroptosis. Pim1 overexpression significantly improved cardiac function, alleviated myocardial injury and fibrosis, and suppressed ferroptosis by reducing Fe²⁺, ROS, and lipid peroxidation while enhancing GSH and GPX4 activity. Mechanistically, Pim1 regulated the mTORC1/SLC7A11/GPX4 axis, whereas rapamycin abrogated these protective effects. Furthermore, the rescue experiments indicated that ferroptosis suppression is the primary mechanism of Pim1‑mediated protection. Collectively, Pim1 mitigates HF progression by inhibiting ferroptosis through mTORC1/SLC7A11/GPX4 signaling.
Wang CC, Marx M, Barth E
… +3 more, D'Amore A, Luo H, Coyan G
J Cardiovasc Transl Res
· 2026 Jun · PMID 42315675
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Given the high rate of re-intervention in patients with atrioventricular septal defects (AVSD), there is a continuing need to accurately model the complex valve anatomy and surgical repair strategies. This systematic rev...Given the high rate of re-intervention in patients with atrioventricular septal defects (AVSD), there is a continuing need to accurately model the complex valve anatomy and surgical repair strategies. This systematic review examined the current scientific landscape for modeling platforms designed to study abnormal congenital heart valves that are used or could be used for AVSD investigation. Of 1,050 sources screened, 47 were included (14 in silico; 26 in vitro; 7 in vivo). In silico models studying valve pathologies have advanced in recent years, but few targeted AVSD valves. In vitro platforms allow comparisons of repair techniques, but have yet to be applied for AVSD valve repair. In vivo studies could offer physiologically accurate platforms, but face challenges such as replicating AVSD pathologies. Multidisciplinary approaches to creating high-fidelity, reproducible, physiologically accurate AVSD valve models can transform the understanding of AVSD valve properties and repair strategies.
Zhang W, Zhang K, Xu W
… +3 more, Kan C, Sun X, Xue Y
J Cardiovasc Transl Res
· 2026 Jun · PMID 42288705
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Cardiovascular diseases (CVDs) remain the leading global cause of morbidity and mortality. Lipid-lowering, anti-inflammatory, and antioxidant strategies improve clinical outcomes but only partly prevent cardiomyocyte los...Cardiovascular diseases (CVDs) remain the leading global cause of morbidity and mortality. Lipid-lowering, anti-inflammatory, and antioxidant strategies improve clinical outcomes but only partly prevent cardiomyocyte loss and remodeling. Emerging evidence identifies ferroptosis, an iron-dependent lipid peroxidation pathway, and pyroptosis, an inflammasome-driven inflammatory cell-death program, as central drivers of myocardial injury, vascular dysfunction, and heart failure (HF) progression. These death modes are mechanistically interconnected: lipid peroxidation and mitochondrial ROS promote NLRP3 inflammasome activation, while gasdermin-mediated cytokine release disrupts iron homeostasis and accelerates oxidative injury. We synthesize current knowledge on ferroptosis-pyroptosis crosstalk in ischemia-reperfusion injury, HF, and atherosclerosis, emphasizing metabolic-immune coupling through GPX4, ACSL4, NLRP3, and GSDMD. We highlight natural products like quercetin, paeoniflorin, and curcumin as dual-pathway regulators, activating Nrf2-GPX4 and suppressing inflammasomes. Advancing ferroptosis-pyroptosis strategies needs clear intervention timing, better compound availability, and more translational research. Dual blockade of oxidative and inflammatory cell death offers promise for precise cardiovascular therapy.
J Cardiovasc Transl Res
· 2026 Jun · PMID 42262457
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Zinc is an essential trace element that plays a significant role in vascular function. This study aimed to investigate the potential association between serum zinc (SZn) concentration and cardiovascular disease (CVD) eve...Zinc is an essential trace element that plays a significant role in vascular function. This study aimed to investigate the potential association between serum zinc (SZn) concentration and cardiovascular disease (CVD) events, CVD mortality, and all-cause mortality, while also considering possible sex-specific differences. We analyzed data from 3,353 participants aged 30 years or older without a history of CVD, sourced from the fourth phase of the Tehran Lipid and Glucose Study (TLGS) conducted between 2009 and 2011. Multivariable Cox proportional hazard models were used. In men, low SZn levels were associated to a 94% increased risk of all-cause mortality (HR = 1.94, 95% CI = 1.03-3.65). Conversely, high SZn concentrations were associated with a reduced risk of CVD events (HR = 0.66, 95% CI = 0.46-0.93). No significant associations were observed in women. In men, low SZn was associated with higher all-cause mortality, whereas high SZn was inversely associated with CVD risk.
J Cardiovasc Transl Res
· 2026 Jun · PMID 42260198
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Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a vital therapy that bridges glycemic control and cardiovascular protection, fundamentally changing the way the Cardiovascular-Kidney-Metabolic (CKM) syn...Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a vital therapy that bridges glycemic control and cardiovascular protection, fundamentally changing the way the Cardiovascular-Kidney-Metabolic (CKM) syndrome is managed. This review summarises the current evidence on the molecular mechanisms of SGLT2 inhibitors, ranging from haemodynamic regulation to metabolic reprogramming, and their clinical applications in various cardiovascular diseases. We critically discuss the pharmacological characteristics of different agents, as well as the debate surrounding glucose-dependent versus glucose-independent mechanisms. Furthermore, we summarise current guideline recommendations to provide clinicians with a reference for incorporating SGLT2 inhibitors into the treatment of heart failure and other cardiovascular conditions.
J Cardiovasc Transl Res
· 2026 Jun · PMID 42260026
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Despite growing interest in tricuspid regurgitation (TR), evidence remains insufficient to define the optimal timing of intervention and therapeutic strategies, highlighting the need for robust experimental models. Exist...Despite growing interest in tricuspid regurgitation (TR), evidence remains insufficient to define the optimal timing of intervention and therapeutic strategies, highlighting the need for robust experimental models. Existing large animal models of TR use diverse approaches and can be grouped into two categories: direct valvular interventions targeting the tricuspid leaflets, annulus, or chordae, and indirect induction through mechanisms such as increased right ventricular loading, pulmonary hypertension, or pacing-induced tachycardia. Although direct valvular interventions can reproducibly induce TR and are well suited for modeling primary TR, clinically prevalent secondary TR is driven by annular dilation, leaflet tethering, and right-sided chamber remodeling rather than intrinsic valvular injury. This gap represents a major limitation in the field. In this review, we compare large animal models of TR and outline key considerations to guide model selection, with a focus on approaches that more faithfully reproduce the pathophysiology of TR for mechanistic and translational research.
Saini A, Manik, Bashir Z
… +3 more, Mehta DK, Kumari S, Das R
J Cardiovasc Transl Res
· 2026 Jun · PMID 42257817
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Glutathione, a critical component of cellular antioxidant defences, is metabolized by gamma-glutamyl transferase (GGT), an enzyme increasingly recognized for its role in cardiovascular diseases (CVD). Elevated GGT levels...Glutathione, a critical component of cellular antioxidant defences, is metabolized by gamma-glutamyl transferase (GGT), an enzyme increasingly recognized for its role in cardiovascular diseases (CVD). Elevated GGT levels have been associated with a heightened risk of conditions such as heart failure, coronary artery disease, acute coronary events, and adverse cardiovascular outcomes. This study aims to evaluate the role of serum GGT as a cardiac marker for detecting various cardiac diseases and its potential utility in clinical practice. Elevated GGT correlates with several CVD risk factors, including diabetes, hypertension, and metabolic syndrome, and is associated with acute coronary syndromes and myocardial infarction. The study results suggest that serum GGT is a promising biomarker for cardiovascular risk prediction, aiding in the assessment of disease severity and prognosis. GGT has the potential to play a pivotal role in preventive cardiology and personalized medicine, contributing to improved outcomes for patients with CVD.
Chen Y, Ye X, Zha C
… +4 more, Jin C, Chen H, Wang H, Xiao J
J Cardiovasc Transl Res
· 2026 Jun · PMID 42234286
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Myocardial ischemia-reperfusion (I/R) injury remains a leading cause of cardiovascular morbidity. However, due to the unclear underlying molecular mechanisms, effective therapeutic approaches are still lacking. This stud...Myocardial ischemia-reperfusion (I/R) injury remains a leading cause of cardiovascular morbidity. However, due to the unclear underlying molecular mechanisms, effective therapeutic approaches are still lacking. This study aims to investigate the function and downstream mechanism of the lysosomal protein prosaposin (PSAP) in regulating ceramide homeostasis and cardiomyocyte apoptosis during acute I/R injury. In our study, we found that PSAP expression was significantly downregulated in the heart subjected to acute I/R surgery. Restoration of PSAP protein via AAV9-PSAP-OE in vivo significantly reduced infarct size and attenuated cardiomyocyte apoptosis. Similarly, PSAP overexpression in OGD/R-treated primary cardiomyocytes (NRCMs) decreased apoptosis, while PSAP knockdown exacerbated apoptosis. Mechanistically, PSAP accelerates the ceramide degradation pathway by rescuing the expression of the lysosomal N-acylsphingosine amidohydrolase 1 (ASAH1), thereby attenuating I/R-induced ceramide accumulation and cardiomyocyte apoptosis. Our results reveal a novel mechanism of PSAP function and highlight its potential as a therapeutic target for acute myocardial I/R injury.
Ning X, Xu H, Zhao Q
… +12 more, Pan J, Liu X, Cao J, Li Q, Ding S, Ye C, Zhong K, Yu S, Lu F, Han L, Xu Z, Qiao F
J Cardiovasc Transl Res
· 2026 Jun · PMID 42234206
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We aimed to establish a rat TR model to further investigate the mechanisms of right heart remodeling and organ damage induced by TR. Intervention group rats (n = 6) underwent coronary stent system implantation via transj...We aimed to establish a rat TR model to further investigate the mechanisms of right heart remodeling and organ damage induced by TR. Intervention group rats (n = 6) underwent coronary stent system implantation via transjugular approach. The control group (n = 6) underwent the same procedure, except for coronary stent implantation. All rats survived at 8 weeks follow-up postoperatively. TR occurred immediately after the implantation of coronary stent in the intervention group. The right ventricular fractional area change (FAC) decreased by 33.9% compared with baseline from 0.59 ± 0.11% to 0.39 ± 0.10% (P = 0.005) and the tricuspid annular plane systolic excursion (TAPSE) decreased by 36.8% from 2.42 ± 0.31 mm to 1.53 ± 0.45 mm at 8 weeks (P < 0.001). This animal model would be suitable to further investigate the mechanisms of right ventricular remodeling and other organ damage associated with TR.