Tu T, Ning Z, He Y
… +10 more, Ma Y, Xiao Y, Zhu Z, Tang L, Li X, Yang H, Chen M, Tai S, Liu Q, Zhou S
J Cardiovasc Transl Res
· 2025 Dec · PMID 41037149
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This study aimed to investigate the underlying mechanisms of Fibroblast Growth Factor 21 (FGF21) in myocardial ischemia/reperfusion (I/R) injury. First, FGF21 was upregulated in the serum of patients with myocardial I/R...This study aimed to investigate the underlying mechanisms of Fibroblast Growth Factor 21 (FGF21) in myocardial ischemia/reperfusion (I/R) injury. First, FGF21 was upregulated in the serum of patients with myocardial I/R injury as well as in I/R hearts of mice and hypoxia/reoxygenation (H/R) neonatal rat cardiomyocytes (NRCMs). While FGF21 knockout exacerbated such injury, which was mitigated by rhFGF21. Bioinformatics analysis identified immunity-related GTPase M1 (Irgm1) as a key autophagy-related gene downregulated in ventricular tissue of FGF21 I/R mice. Impaired autophagic flux in FGF21 mice during I/R could be rescued by rhFGF21 through the signal transducers and activators of transcription 1 (STAT1) pathway. The beneficial effects of rhFGF21 in reducing H/R injury were limited in Irgm1 knockdown NRCMs. This study suggested that FGF21 deficiency intensifies myocardial I/R injury by exacerbating the impairment of autophagic flux. Activation of FGF21 or Irgm1 may serve as a promising therapeutic strategy for myocardial I/R injury.
J Cardiovasc Transl Res
· 2025 Dec · PMID 41032190
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Investigated the role and possible mechanisms of SMILR in angiogenesis among chronic heart failure (CHF) patients to establish novel biomarkers for the clinical assessment of CHF. qPCR was employed to assess the levels o...Investigated the role and possible mechanisms of SMILR in angiogenesis among chronic heart failure (CHF) patients to establish novel biomarkers for the clinical assessment of CHF. qPCR was employed to assess the levels of serum SMILR and miR-10b-3p. ROC analysis and logistic regression were utilized to evaluate the diagnostic and predictive value of SMILR. Pearson correlation analysis was conducted to explore the relationship between serum SMILR and myocardial injury markers, as well as cardiac function indicators. In CHF patients, serum SMILR was up-regulated, while miR-10b-3p was down-regulated. In a hypoxic injury model, SMILR silencing restored both the function and oxidative stress levels of hCMECs, and promoted the secretion of pro-angiogenic factors. Inhibition of miR-10b-3p prevented the angiogenic enhancement associated with the knockdown of SMILR. SMILR influences angiogenesis and CHF progression via miR-10b-3p. SMILR is a promising candidate for early detection and subsequent therapy in CHF.
Tzvi-Minker E, Dittmann S, Rickert C
… +2 more, Keck A, Schulze-Bahr E
J Cardiovasc Transl Res
· 2025 Oct · PMID 41028332
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Myocardial repolarization and QT duration are crucial markers for diagnosis and monitoring of congenital long QT syndrome (LQTS). Here we present a novel algorithm to automatically estimate the QT interval based on Lepes...Myocardial repolarization and QT duration are crucial markers for diagnosis and monitoring of congenital long QT syndrome (LQTS). Here we present a novel algorithm to automatically estimate the QT interval based on Lepeschkin's tangent method, as well as parameters underlying T-wave morphology in digital electrocardiograms (ECGs) of 466 patients with LQTS. The algorithm's performance was validated using ECG data from 40 healthy controls. The results were compared against expert measurement of the QT interval, as well as against the results of the ECG device MUSE™ system. Applying an optimizable Support Vector Machine classifier on the algorithm's outcomes achieved an accuracy of 78.1% and area under the curve of 0.85 in classifying LQTS patients with a prolonged QTc interval (upon QT_GS) from those with a normal QTc interval. The presented MATLAB®-based algorithm offers a transparent and reproducible approach to automatic QT interval estimation and QTc calculation in LQTS patients, potentially improving automatized screening, diagnostic precision and patient management.
J Cardiovasc Transl Res
· 2025 Dec · PMID 41023336
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The American Statistical Association (ASA) has cautioned against overreliance on p-values, noting that rigid thresholds (e.g., p < 0.05) can obscure statistical uncertainty and clinical meaning. This study illustrates ho...The American Statistical Association (ASA) has cautioned against overreliance on p-values, noting that rigid thresholds (e.g., p < 0.05) can obscure statistical uncertainty and clinical meaning. This study illustrates how Bayesian methods can enrich trial interpretation by estimating the probability of treatment benefit. We reanalyzed all-cause mortality outcomes from two randomized trials-EMPULSE (empagliflozin in acute heart failure) and DanGer Shock (microaxial flow pump in cardiogenic shock)-using Bayesian hierarchical random-effects models with reference and data-derived priors. For EMPULSE, posterior probabilities of mortality benefit were high (RR < 1: 90%-99%; RR < 0.85: 72%-86%). In DanGer Shock, they were lower and more uncertain (RR < 1: 76%-98%; RR < 0.85: 15%-72%). Although both trials had similar frequentist p-values (0.04 and 0.05), Bayesian analysis revealed differing levels of certainty. These results highlight the value of Bayesian approaches in providing more nuanced, decision-relevant insights, particularly when trial results lie near conventional significance thresholds.
J Cardiovasc Transl Res
· 2025 Dec · PMID 40996589
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Sarcoidosis is a heterogenous, multi-systemic granulomatous disease with highly variable incidence (5-40/100,000) and a disproportionate mortality burden in those presented with pulmonary fibrosis or cardiac involvement....Sarcoidosis is a heterogenous, multi-systemic granulomatous disease with highly variable incidence (5-40/100,000) and a disproportionate mortality burden in those presented with pulmonary fibrosis or cardiac involvement. Yet, current management strategies are symptom-targeting, not always effective and come with significant side effects. Preclinical murine models of sarcoidosis have shown that aberrant mTORC1 activation promotes macrophage-driven inflammation and disrupts autophagic clearance, sustaining granuloma formation. Sirolimus, a selective mTORC1 inhibitor, restores autophagy and macrophage function, offering a targeted therapeutic approach. Herein, we present the first comprehensive review of all known clinical cases of sirolimus use in different forms of sarcoidosis. All studies reviewed suggest that sirolimus may be an effective, yet safe, mechanism-targeting therapy for patients with sarcoidosis not responding to conventional pharmacological interventions.
J Cardiovasc Transl Res
· 2025 Oct · PMID 40986231
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Fumarate is increasingly recognized as a metabolic signal with dual effects in cardiovascular disease. Pharmacologic doses of dimethyl fumarate (DMF) and its metabolite monomethyl fumarate (MMF) transiently activate Nrf2...Fumarate is increasingly recognized as a metabolic signal with dual effects in cardiovascular disease. Pharmacologic doses of dimethyl fumarate (DMF) and its metabolite monomethyl fumarate (MMF) transiently activate Nrf2 and HCAR2 pathways, offering antioxidant, anti-inflammatory, and antifibrotic benefits. These include reduced endothelial activation, macrophage foam cell formation, and vascular remodeling in atherosclerosis, ischemia-reperfusion injury, hypertension, and diabetic cardiomyopathy. In contrast, sustained fumarate accumulation-due to fumarate hydratase 1 (FH1) loss-drives protein succination, cGAS-STING activation, HIF-1α stabilization, and epigenetic enzyme inhibition, promoting oxidative stress, inflammation, and cellular senescence. FH1 insufficiency is associated with plaque destabilization, renal dysfunction, and galectin-3-driven fibrosis. Despite promising preclinical results, human data remain limited: FH1 mutation syndromes rarely present with cardiovascular phenotypes, and DMF clinical trials have not evaluated major cardiovascular endpoints. Future studies should define a therapeutic window, develop succination biomarkers, and assess long-term effects to safely harness fumarate's hormetic potential in cardiovascular medicine.
Cui X, Hu Y, Xu Y
… +6 more, Yang L, Chatterjee E, Li G, Cretoiu D, Wang L, Xiao J
J Cardiovasc Transl Res
· 2025 Dec · PMID 40982203
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Heart failure with preserved ejection fraction (HFpEF) is a complex multisystem syndrome with increasing prevalence in aging and metabolically compromised populations. In addition to diastolic dysfunction, HFpEF involves...Heart failure with preserved ejection fraction (HFpEF) is a complex multisystem syndrome with increasing prevalence in aging and metabolically compromised populations. In addition to diastolic dysfunction, HFpEF involves metabolic abnormalities, chronic inflammation, and oxidative stress across kidney, lung, liver, adipose tissue, and skeletal muscle. Interorgan crosstalk plays a key role in disease progression. Current treatments including SGLT2 inhibitors, GLP-1 receptor agonists, combined with lifestyle interventions like exercise and diet, offer potential benefits for specific subgroups, but broader efficacy remains limited. In this review, we summarized the pathophysiological characteristics of HFpEF from a multi-organ perspective, encompassing intrinsic cardiac mechanisms, cardio-renal and cardio-hepatic interactions, pulmonary and skeletal muscle abnormalities, regional adiposity, and endothelial dysfunction. Future strategies emphasizing multi-organ integration to develop individualized, mechanism-based therapies for the precision treatment and comprehensive management of HFpEF were further discussed.
Ali I, Muhammad S, Wei L
… +4 more, Naqvi SSZH, Mehmood A, Abbas M, Shah W
J Cardiovasc Transl Res
· 2025 Oct · PMID 40971046
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Chronic social stress is increasingly recognized as a significant contributor to endothelial dysfunction, a key precursor to various cardiovascular diseases. This review endeavors to explain the intricate molecular pathw...Chronic social stress is increasingly recognized as a significant contributor to endothelial dysfunction, a key precursor to various cardiovascular diseases. This review endeavors to explain the intricate molecular pathways underlying endothelial dysfunction triggered by chronic social stress and to explore its implications for treatment. We summarize the roles of neurotransmitters, neuromodulators, and immune factors in mediating stress-induced vascular changes. We examine recent advances in pharmacology aimed at targeting these pathways, presenting potential avenues for therapeutic intervention. Understanding these molecular mechanisms not only enhances our comprehension of stress-related vascular disorders but also offers the potential for developing targeted therapies to alleviate their adverse effects on cardiovascular health. This review underlines the importance of unraveling molecular pathways and highlights therapeutic opportunities for managing endothelial dysfunction resulting from chronic social stress.
Kotikhina E, Karchkov D, Moskalenko V
… +3 more, Nikolskiy A, Osipov G, Smirnov L
J Cardiovasc Transl Res
· 2025 Dec · PMID 40965593
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The article presents the results of applying artificial intelligence algorithms to analyze multichannel electrograms of bioelectrical activity registered by microelectrode arrays from myocardium of isolated rat hearts un...The article presents the results of applying artificial intelligence algorithms to analyze multichannel electrograms of bioelectrical activity registered by microelectrode arrays from myocardium of isolated rat hearts under the influence of L-carnitine and adrenaline. Localization of activation times on electrograms was performed using a new neural network model based on the U-Net architecture adapted for one-dimensional signal segmentation. In the organism, L-carnitine is necessary for the oxidation of fatty acids. But the effects of its supplemental intake on the cardiovascular system are still poorly understood. A decrease in heart rate, myocardial excitation conduction velocity, intensity of coronary blood flow and physiologic cardiac response to adrenaline action ex vivo caused by L-carnitine were shown. The methodological approach, applying a neural network to analyze data from microelectrode arrays, tested in this research can be translated into clinical practice for electrograms obtained by electrophysiology study of human heart.
Jiang J, Zheng Z, Jiang C
… +5 more, Wu T, Shi W, Liu M, Fan Q, Cui G
J Cardiovasc Transl Res
· 2025 Oct · PMID 40928570
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Atherosclerosis remains a leading cause of cardiovascular disease and mortality worldwide, despite advancements in statin therapies. Here, we aimed to identify potential anti-atherosclerosis drugs by an integrated approa...Atherosclerosis remains a leading cause of cardiovascular disease and mortality worldwide, despite advancements in statin therapies. Here, we aimed to identify potential anti-atherosclerosis drugs by an integrated approach combining network medicine-based prediction with empirical validation. Among the top drugs predicted by the preferred algorithm, mesalazine─a drug traditionally used to treat inflammatory bowel disease, was selected for in vivo validation in ApoE mouse model of atherosclerosis. After an 8-week treatment period, mesalazine significantly inhibited atherosclerosis progression by reducing total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels, while increasing high-density lipoprotein cholesterol (HDL-C) levels. Additionally, it decreased the plaque area and hepatic steatosis. Gene expression analysis via RT-qPCR revealed that mesalazine downregulated key genes associated with atherosclerosis. These findings highlight the potential of mesalazine as a repurposed anti-atherosclerosis drug and offer novel insights into drug screening for atherosclerosis treatment.
Saemann L, Wächter K, Großkopf A
… +7 more, Pohl S, Georgevici AI, Hoorn F, Korkmaz-Icöz S, Karck M, Simm A, Szabó G
J Cardiovasc Transl Res
· 2025 Oct · PMID 40921935
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We compared the effects of ex-vivo machine perfusion (EVMP) of hearts donated after circulatory death (DCD) with the single-shot solutions HTK-N and Del Nido cardioplegia (DNC) on left-ventricular (LV) contractility and...We compared the effects of ex-vivo machine perfusion (EVMP) of hearts donated after circulatory death (DCD) with the single-shot solutions HTK-N and Del Nido cardioplegia (DNC) on left-ventricular (LV) contractility and myocardial microcirculation. In a DCD pig model, hearts were maintained by EVMP with hypothermic, oxygenated HTK-N (DCD-HTK-N; N = 8) or DNC (DCD-DNC; N = 8) followed by reperfusion with blood, including assessment of contractility and microcirculation with Laser-Doppler-Flow (LDF). We performed transcriptomics using microarrays. In DCD-HTK-N, the ESP, dp/dt and dp/dt were significantly higher (p < 0.05) compared to DCD-DNC. Relative LDF was higher in DCD-HTK-N vs. DCD-DNC. Pathways related to inflammatory mediators, cAMP, ion channels, intracellular signaling, and cell death were regulated differently. In DCD-HTK-N, longevity-associated pathways were up-, and ageing-associated pathways were downregulated. EVMP of DCD hearts with HTK-N results in a superior LV function, microcirculation, and regulation of pathways with short- and long-term relevance compared to DNC.
J Cardiovasc Transl Res
· 2025 Oct · PMID 40920282
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Myocardial ischemia/reperfusion injury (MIRI) worsens ischemic damage, with ferroptosis as a key mediator of this iron-dependent cell death. Lactylation, a novel epigenetic modification, remains poorly understood in MIRI...Myocardial ischemia/reperfusion injury (MIRI) worsens ischemic damage, with ferroptosis as a key mediator of this iron-dependent cell death. Lactylation, a novel epigenetic modification, remains poorly understood in MIRI-associated ferroptosis. This study aimed to elucidate the mechanistic link between lactylation and ferroptosis in MIRI. Experimental results demonstrated that hypoxia/reoxygenation (H/R) induction combined with lactate (LA) treatment significantly enhanced the protein expression levels, lactylation status, and protein stability of acyl-CoA synthetase long-chain family member 4 (ACSL4). Site-specific analysis identified lysine 83 (K83) as the critical lactylation modification site on ACSL4. Functional studies revealed that LDHA knockdown-mediated suppression of lactate levels attenuated ferroptosis in H/R-treated cells, an effect that was reversed by ACSL4 overexpression. In vivo validation confirmed that LDHA depletion ameliorated ferroptosis-related damage and mitigated MIRI-induced cardiac dysfunction. Collectively, these findings establish that lactylation-regulated ACSL4 ferroptosis exacerbates MIRI pathogenesis, suggesting that targeting the lactylation-ACSL4 axis represents a promising therapeutic strategy for MIRI.
Akhtar S, Sagar K, Hote MP
… +3 more, Roy A, Yadav S, Sharma A
J Cardiovasc Transl Res
· 2025 Oct · PMID 40913144
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Diagnostic potential of sialin in identifying endothelial dysfunction is explored. 50 CAD patients, 50 young (20-35 years) dyslipidemic individuals (DLP), and 50 healthy controls (HC) were included in the study. HUVECs w...Diagnostic potential of sialin in identifying endothelial dysfunction is explored. 50 CAD patients, 50 young (20-35 years) dyslipidemic individuals (DLP), and 50 healthy controls (HC) were included in the study. HUVECs were stimulated with either TNFα or AT-2. RNA isolation, Real-time PCR, ELISA, and immunofluorescence staining were performed. In silico analysis was performed. ROC curves were constructed. Stimulated ECs showed increased sialin mRNA expression. Sialin mRNA peaked in the supernatant at 1-6 h, decreasing by 24 h. Serum sialin mRNA was significantly higher in DLP patients than in HC and CAD patients, whereas CXCL14 mRNA was elevated in CAD patients. Sialin mRNA had high sensitivity/specificity for predicting endothelial dysfunction. In silico analysis revealed the binding of translational repressor RNPs to the 5'UTR of sialin mRNA. This is the first study highlighting circulating sialin mRNA as a novel biomarker for endothelial activation.
Huertas-Nieto S, Moraga-Yébenes A, Zamora-Pérez L
… +9 more, Moreno G, Maneiro-Melón N, Sarnago-Cebada F, Kadir BF, Medina A, García-Martín RM, Lizasoain I, Bueno H, on belhaf of the NET-AMI team
J Cardiovasc Transl Res
· 2025 Oct · PMID 40900282
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Neutrophil extracellular traps (NETs) are implicated in thrombosis and inflammation during acute myocardial infarction (AMI), but their kinetics, local distribution, and clinical relevance remain unclear. We conducted a...Neutrophil extracellular traps (NETs) are implicated in thrombosis and inflammation during acute myocardial infarction (AMI), but their kinetics, local distribution, and clinical relevance remain unclear. We conducted a prospective study in 144 patients with ST-segment elevation (STEMI) and non-ST-segment elevation AMI (NSTEMI) undergoing coronary angioplasty (PCI), quantifying double-stranded DNA (dsDNA), myeloperoxidase (MPO), and neutrophil elastase (NE) in the infarct-related artery (IRA), contralateral coronary artery (CCA), and peripheral blood. Coronary thrombi and DNASE1 Q222R were also analysed. NET markers were elevated in the IRA, and NE and dsDNA increased peripherally after PCI. IRA NE levels independently predicted cardiovascular events (HR, 1.76; 95%CI: 1.24 - 2.51). Thrombi with higher NE and citrullinated histone H3 content were associated with suboptimal PCI results. dsDNA levels were significantly higher in patients with the GG DNASE1 genotype. These findings indicate a compartmentalized NET response in AMI and support a potential prognostic impact of NETs.
Bellon Quinones N, Belluomo R, Juni RP
… +1 more, Boon RA
J Cardiovasc Transl Res
· 2025 Dec · PMID 40900281
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Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality worldwide, necessitating innovative therapeutic strategies. Long non-coding RNAs (lncRNAs) have emerged as regulators of gene expression, i...Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality worldwide, necessitating innovative therapeutic strategies. Long non-coding RNAs (lncRNAs) have emerged as regulators of gene expression, influencing various cellular processes involved in cardiovascular health and disease. This review explores the functional roles of lncRNAs in CVD pathogenesis, highlighting their involvement in processes such as hypertrophy, fibrosis, inflammation, and vascular remodeling. We discuss their potential as diagnostic biomarkers and therapeutic targets, alongside recent advancements in gene therapy approaches. While no lncRNA-based therapies have yet reached clinical trials, emerging RNA-targeting technologies, including antisense oligonucleotides, siRNAs, and CRISPR-based interventions, offer promising avenues for future therapeutic applications. Additionally, we examine the challenges associated with delivering lncRNA-based therapies, evaluating both viral and non-viral delivery methods, and their potential to revolutionize cardiovascular medicine. Ultimately, a deeper understanding of lncRNA biology and improvements in delivery strategies will be crucial in translating these findings into clinical treatments.
Gjermeni D, Vetter H, Szabó S
… +9 more, Anfang V, Juelch C, Leggewie S, Hesselbarth D, Jäckel M, Duerschmied D, Trenk D, Westermann D, Olivier CB
J Cardiovasc Transl Res
· 2025 Oct · PMID 40866669
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Platelet reactivity (PR) in clopidogrel-treated patients undergoing percutaneous coronary syndrome (PCI) associates with ischemic and bleeding risk. The aim was to investigate the association of PR and global hemostasis...Platelet reactivity (PR) in clopidogrel-treated patients undergoing percutaneous coronary syndrome (PCI) associates with ischemic and bleeding risk. The aim was to investigate the association of PR and global hemostasis with this risk in patients with atrial fibrillation (AF) undergoing PCI. TEG was performed on day 1-3 after PCI. 168 patients were included. Mean age was 79 years (IQR 72-82). 101 (60%) patients had high platelet reactivity (HPR). HPR was not associated with the composite outcome of MACE (HR 1.23 [ CI 95% 0.43-3.49], p = 0.700). 33(19.6%) patients had HPR and increased platelet-fibrin clot strength and showed a trend for association with higher ischemic risk (HR 2.83 [CI 95% 0.70-8.06], p = 0.078). Rates of HPR in patients with AF undergoing PCI were high. Neither HPR nor LPR predicted ischemic or bleeding risks. Patients with HPR and increased platelet-fibrin clot strength may be at higher risk for ischemic events.
Zhou Q, Jiang N, Li S
… +6 more, Li S, Liu J, Yu L, Liu G, Xia H, Li M
J Cardiovasc Transl Res
· 2025 Oct · PMID 40864376
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Myocardial fibrosis (MF) severely impairs the heart structure and function post-myocardial infarction. The study investigated the effectiveness and mechanism of diammonium glycyrrhizinate (DG) on ISO-induced MF. ISO-stim...Myocardial fibrosis (MF) severely impairs the heart structure and function post-myocardial infarction. The study investigated the effectiveness and mechanism of diammonium glycyrrhizinate (DG) on ISO-induced MF. ISO-stimulated mouse cardiac fibroblasts (CFs) were treated with DG to assess the proliferation, inflammation, and fibrosis markers (α-SMA, collagen, TGF-β1, Smad3). The MF model was induced in mice by administering ISO, followed by a 4-week treatment with DG (60 mg/kg/day). Cardiac function was measured using echocardiography, and histology and molecular analyses were performed. DG significantly suppressed the CF proliferation and reduced the expression of fibrotic markers. In ISO-treated mice, DG improved the cardiac function and attenuated the upregulated fibrosis markers. Molecular analysis revealed DG suppressed the TGF-β1/Smad3 pathway activation. The antifibrotic effect was enhanced when combined with STAT3 inhibition. DG effectively alleviates ISO-induced myocardial fibrosis dysfunction by inhibiting the STAT3/Smad3 signaling pathway, demonstrating its potential as a treatment for cardiac fibrosis.
Sia DCS, Mufti H, Yap WH
… +2 more, Wong WF, Looi CY
J Cardiovasc Transl Res
· 2025 Oct · PMID 40853432
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Acute myocardial infarction (AMI) remains a leading cause of mortality worldwide, highlighting the need for improved diagnostic approaches. While cardiac troponins are the current gold standard, their reliability in earl...Acute myocardial infarction (AMI) remains a leading cause of mortality worldwide, highlighting the need for improved diagnostic approaches. While cardiac troponins are the current gold standard, their reliability in early detection and in patients with comorbidities is limited. This review evaluates conventional AMI biomarkers and highlights emerging candidates including non-coding RNAs, cell-free DNA, exosomes, proteins, and metabolites. It also explores the potential of non-invasive samples such as saliva and urine for early detection. After reviewing recent advances in biomarker discovery and detection technologies, this article presents a comprehensive overview of evolving AMI diagnostics. Identifying sensitive and specific biomarker detectable in non-invasive samples has important clinical relevance for improving early diagnosis and guiding prompt treatment. Future efforts should focus on multi-marker strategies, patient-specific diagnostic thresholds, and the clinical validation of novel non-invasive biomarkers.