Cardiac Injury Biomarkers Research Articles

Patients with chronic heart failure and predominant left atrial versus left ventricular myopathy

BackgroundLeft atrial (LA) and ventricular (LV) functional impairment often co-exist in patients with heart failure (HF). However, some patients with HF have a disproportionate LA or LV dysfunction. We aimed to characterize patients with predominant LA and LV myopathy in a cohort of patients with chronic HF across the spectrum of LV ejection fraction (LVEF).MethodsFrom a nationwide, prospective, multi-center, observational HF cohort, transthoracic echocardiographic examination was performed on each patient. LA reservoir strain and LV global longitudinal strain (LVGLS) were measured using dedicated software of the two-dimensional speckle tracking analysis to evaluate LA and LV function and to define the myopathy.ResultsA total of 374 patients with chronic HF (mean age 58.9±11.5 years, 20% female, mean LVEF 39±17%) were included. By calculating the residuals from the linear regression between LA reservoir and LVGLS, we identified 47 patients with predominant LA myopathy, 271 patients with balanced LA/LV and 56 patients with predominant LV myopathy. Patients with predominant LA myopathy were older, had a higher prevalence of atrial fibrillation (AF), diabetes, higher plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), Growth differential factor 15(GDF15), high sensitivity Troponin T (hs-TNT) as well as more dilated left and right atria, and worse right atrial function compared to other groups (all p-values < 0.05). Using multivariable logistic regression adjusted for LVEF and LA size, independent predictors of predominant LA myopathy were the presence of AF, diabetes, and higher GDF15, whereas absence of diabetes independently predicted predominant LV myopathy. Patients with predominant LA myopathy group had a lower probability of survival than the other groups (Log rank p-value = 0.01).ConclusionWhile most patients with HF have balanced LA/LV myopathy, those with predominant LA myopathy are characterized by older age, more AF, more diabetes, higher circulating biomarkers of cardiac stress and injury, and worse outcomes.

From bench to bedside: elucidating VEGF(R) inhibitor-related heart failure in cancer treatment

BackgroundVascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors play a pivotal role in treating various tumors; however, the clinical characteristics and molecular mechanisms of their associated heart failure (HF) remain incompletely understood.MethodsWe investigated the epidemiological characteristics of VEGF or VEGFR inhibitors [VEGF(R)i]-related heart failure (VirHF) using the global pharmacovigilance database Vigibase. The phenotypic features and molecular mechanisms of VirHF were characterized using VEGF(R)i-treated mouse models through a combination of echocardiography, histopathological analysis, and transcriptome sequencing. Furthermore, we performed a retrospective analysis of cardiac function parameters in patients undergoing VEGF(R)i treatment at local hospitals.ResultsIn the analysis of 1871 VirHF cases, elderly patients (≥ 65 years) and female subjects demonstrated an elevated risk of occurrence. Experimental studies in mice revealed that both acute and chronic VEGF(R)i administration resulted in reduced left ventricular EF, cardiomyocyte hypertrophy, and myocardial fibrosis. Transcriptomic analysis identified significant dysregulation of multiple key signaling pathways, including DNA repair (R = 0.46), mitochondrial ATP synthesis (R = 0.39), glycogen metabolism regulation (R = 0.45), and proteasome-mediated protein degradation (R = 0.45). Moreover, significant upregulation was observed in inflammatory pathways, specifically those involving IL-1, IL-6, TNF-α, and IRF3/IRF7-mediated immune responses. Clinical cohort analyses demonstrated significant elevations in both cardiac injury biomarkers (NT-proBNP, CK-MB, cTnT) and inflammatory mediators (CRP) following VEGF(R)i administration.ConclusionsOur findings present the first comprehensive characterization of VirHF clinical features and elucidate its underlying molecular mechanisms, thereby providing a theoretical framework for optimizing the clinical safety of VEGF(R)i therapy.

2-[18F]Fluoropropionic Acid PET Imaging of Doxorubicin-Induced Cardiotoxicity.

Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[18F]fluoropropionic acid ([18F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin. Cardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24mg/kg) administered over 14days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [18F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations. Significantly higher cardiac [18F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 to 120min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [18F]FPA in tissues other than the heart. Co-administration of [18F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity. [18F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.

Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy.

Septic cardiomyopathy (SCM) is a severe cardiac complication of sepsis, characterized by cardiac dysfunction with limited effective treatments. This study aimed to identify repurposable drugs for SCM by integrated multi-omics and network analyses. We generated a mouse model of SCM induced by lipopolysaccharide (LPS) and then obtained comprehensive metabolic and genetic data from SCM mouse hearts using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and RNA sequencing (RNA-seq). Using network proximity analysis, we screened for FDA-approved drugs that interact with SCM-associated pathways. Additionally, we tested the cardioprotective effects of two drug candidates in the SCM mouse model and explored their mechanism-of-action in H9c2 cells. Network analysis identified 129 drugs associated with SCM, which were refined to 14 drug candidates based on strong network predictions, proven anti-infective effects, suitability for ICU use, and minimal side effects. Among them, acetaminophen and pyridoxal phosphate significantly improved cardiac function in SCM moues, as demonstrated by the increased ejection fraction (EF) and fractional shortening (FS), and the reduced levels of cardiac injury biomarkers: B-type natriuretic peptide (BNP) and cardiac troponin I (cTn-I). In vitro assays revealed that acetaminophen inhibited prostaglandin synthesis, reducing inflammation, while pyridoxal phosphate restored amino acid balance, supporting cellular function. These findings suggest that both drugs possess protective effects against SCM. This study provides a robust platform for drug repurposing in SCM, identifying acetaminophen and pyridoxal phosphate as promising candidates for clinical translation, with the potential to improve treatment outcomes in septic patients with cardiac complications.

Tianxiangdan (TXD) alleviates myocardial ischemia reperfusion-induced ferroptosis through the activation of estrogen receptor alpha (ERα).

Tianxiangdan (TXD), a traditional Chinese herbal remedy, demonstrates efficacy in mitigating myocardial ischemia-reperfusion (I/R)-induced damage. This study employed network pharmacology to evaluate the therapeutic targets and mechanisms of TXD in treating I/R. High-performance liquid chromatography-mass spectrometry (HPLC-MS) identified 86 compounds in TXD. Network pharmacological analysis predicted potential target genes and their modes of action. Cardiac function, ischaemic ST changes, lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, myocardial fiber, and infarct size were assessed using in vivo and in vitro I/R injury models. Estrogen receptor alpha (ERα) protein expression and estradiol (E2) levels were measured to confirm TXD's impact on estrogen levels and ERα expression. To examine if TXD reduces I/R injury through ERα, an AZD group (300 nmol·L-1 AZD9496 and 15% TXD serum) was compared to a TXD group (15% TXD serum). The study hypothesized that TXD upregulates the ERα-mediated iron metamorphosis pathway. I/R injury-induced ferroptosis was identified using a Fer-1 group (1.0 μmol·L-1 Fer-1 and 15% TXD serum) to elucidate the potential association between ferroptosis and ERα proteins. A DCFH-DA probe detected reactive oxygen species (ROS) and Fe2+, while Western blotting assessed target protein expression. Both in vitro and in vivo experiments demonstrated that TXD attenuated I/R injury by reducing elevated ST-segment levels, improving cardiac injury biomarkers (LDH, MDA, and SOD), alleviating pathological features, and preventing I/R-induced loss of cell viability in vitro. The effects and mechanisms of TXD on I/R injury-associated ferroptosis were investigated using I/R-induced H9c2 cells. The TXD group showed significantly decreased ROS and Fe2+ levels, while the AZ group (treated with AZD9496) exhibited increased levels. The TXD group demonstrated enhanced expression of ERα and glutathione peroxidase 4 (GPX4), with reduced levels of P53 protein and ferritin-heavy polypeptide 1 (FTH1). The AZ group exhibited contrasting effects on these expression levels. The literature indicated a novel connection between ERα and ferroptosis. TXD activates the ERα signaling pathway, promoting protection against I/R-induced myocardial cell ferroptosis. This study provides evidence supporting TXD use for myocardial ischemia treatment, particularly in older female patients who may benefit from its therapeutic outcomes.

Potential cardioprotective effect of paroxetine against ventricular remodeling in an animal model of myocardial infarction: a comparative study

BackgroundPost-myocardial infarction (MI) remodeling involves various structural and functional changes, such as inflammation and fibrosis. Upregulation of G protein-coupled receptor kinase 2 (GRK2) is linked to the progression of cardiovascular diseases, including myocardial infarction. The inhibitory effects of paroxetine on GRK2 are recognized, yet its protective effect on post-MI remodeling has not been elucidated. Here, we investigated the cardioprotective effect of paroxetine in an animal model of MI, focusing on post-MI cardiac remodeling and comparing its effect to a β-blocker and an angiotensin receptor antagonist.MethodsAlbino Wistar rats were divided into five groups (control; untreated MI; and MI pre-treated with either paroxetine, metoprolol, or irbesartan). MI was induced using isoproterenol (100 mg.kg−1) on days 16 and 17. Cardioprotective effects were determined by assessing markers of cardiac injury, histopathology, inflammation, oxidative stress, and fibrosis. Statistical analysis performed using a one-way analysis of variance, followed by an appropriate post hoc test, the differences between the groups were considered significant when the (P < 0.05).ResultsParoxetine significantly attenuated cardiac injury biomarkers including serum Tn-I and CK-MB levels. In terms of cardiac remodeling, paroxetine significantly reduced the relative HW/BW index and the plasms FGF23 level. Furthermore, it modulated markers of fibrosis, inflammation, and oxidative stress.ConclusionThe current findings suggest that pre-treatment with paroxetine may exert a beneficial effect that protects against post-MI remodeling, including modulating fibrotic, inflammatory, and angiogenesis-related factors. Therefore, the current findings show the promising role of paroxetine as a cardioprotective that attenuates post-MI remodeling processes.

Hypoxia Microenvironment Preconditioning Attenuated Myocardial Ischemia-Reperfusion Injury via Stc1-Mediating Cardiomyocyte Self-Protection and Neutrophil Polarization.

Ischemic preconditioning (IPC) therapy application to attenuate myocardial ischemia-reperfusion (MI/R) injury in clinical practice remains challenging. The secretome, derived from hypoxia-preconditioned cardiomyocytes (SHPC), potentially mimics the IPC microenvironment and facilitates IPC clinical translation. This study aims to determine whether SHPC can be a feasible alternative to IPC for attenuating MI/R injury, and to identify the functional factor of SHPC. The ultrafiltration technique is applied to generate an SHPC formulation that is intramyocardially injected before reperfusion in a murine MI/R model. The effects of SHPC on cardiomyocyte apoptosis, pyroptosis, and neutrophil polarization are evaluated. Secretomics, neutralizing antibodies, and recombinant proteins are employed to identify the functional factor in SHPC. Co-immunoprecipitation assays, RNA sequencing, and site-directed mutagenesis are conducted to investigate the underlying mechanism. Additionally, a recombinant functional factor-encapsulated hydrogel is developed for intrapericardial injections (iPC). An intramyocardial SHPC injection in MI/R-injured mice strikingly reduces infarct size and the expression of cardiac injury biomarker while improving cardiac function. SHPC eliminated mitochondrial reactive oxygen species and triggered neutrophil polarization to reduce cardiomyocyte apoptosis/pyroptosis upon hypoxia/reoxygenation injury. Stanniocalcin 1 (Stc1) is identified as the functional factor in SHPC, mediating hypoxic microenvironment. Mechanistically, hypoxia-preconditioned cardiomyocytes secrete Stc1 into the microenvironment and activate calcium-sensing receptor (CaSR) that increases Stat3 phosphorylation at Ser727 via nitric oxide synthase 2 (NOS2)-mediated S-nitrosylation, thereby decreasing cardiomyocyte apoptosis/pyroptosis in an autocrine mechanism. Simultaneously, Stc1 facilitates cardiomyocyte-neutrophil crosstalk, thereby triggering neutrophil polarization to reduce inflammatory damage via the CaSR/NOS2/Stat3 axis in a paracrine mechanism. Pericardial delivery of a recombinant rStc1-encapsulated hydrogel has extended the therapeutic time window of rStc1, improving long-term cardiac function. The hypoxia microenvironment preconditioning, which mimicked by SHPC, attenuated MI/R injury via Stc1-mediated cardiomyocyte self-protection and neutrophil polarization. This study suggests that SHPC, with hypoxia preconditioning factor Stc1, represents a clinically feasible alternative to IPC for attenuating MI/R injury.

Unveiling Key Biomarkers and Mechanisms in Septic Cardiomyopathy: A Comprehensive Transcriptome Analysis.

Septic cardiomyopathy (SCM) is a significant global public health concern characterized by substantial morbidity and mortality, which has not been improved for decades due to lack of early diagnosis and effective therapies. This study aimed to identify hub biomarkers in SCM and explore their potential mechanisms. We utilized the GSE53007 and GSE207363 datasets for transcriptome analysis of normal and SCM mice. Hub biomarkers were identified through a protein-protein interaction (PPI) network and validated using LPS-treated C57/BL6 mice. Functional enrichment analysis was performed to uncover relevant signaling pathways, while single-cell RNA sequencing was used to examine key genes and regulatory mechanisms associated with SCM. A total of 374 differentially expressed genes (DEGs) were identified, with 268 genes up-regulated and 106 genes down-regulated. Functional enrichment highlighted chemokine activity and receptor binding, with KEGG pathways revealing significant involvement of the TNF and IL-7 signaling pathways. Deterioration of cardiac function, elevated inflammatory markers such as IL-1β, IL-6, and increased cardiac injury biomarkers such as cTnI indicated the successful establishment of our SCM model. Subsequently, qPCR was conducted to validate the expression of the top 10 genes, through which we identified Cd40, Tlr2, Cxcl10, Ccl5, Cxcl1, Cd14, Gbp2, Ifit2, and Vegfa as key biomarkers. Single-cell sequencing indicated increased neutrophil and macrophage populations, with decreased B cells and cardiomyocytes. Additionally, transcription regulators Irf1 and Stat1 were found to potentially regulate the expression of Gbp2, Cxcl10, Ccl5, and Cd40, linking SCM to immune response, ferroptosis, pyroptosis, cuproptosis, and m6A RNA methylation modification. This study identified nine hub biomarkers and two transcription regulators associated with SCM. Exploring the connections between SCM and immunity, ferroptosis, pyroptosis, cuproptosis, and m6A RNA methylation might provide insights into the underlying mechanisms. These findings enhanced our understanding of SCM's underlying mechanisms and might pave the way for novel therapeutic strategies to improve clinical outcomes.

Andrographolide Attenuates Myocardial Ischemia-Reperfusion Injury in Mice by Up-Regulating PPAR-α.

Andrographolide (AGP), a bioactive diterpene lactone, is an active constituent extracted from Andrographis paniculata. It has many biological activities, such as antioxidant, antitumor, antivirus, anti-inflammation, hepatoprotection, and cardioprotection. The aim of the present study is to investigate the cardioprotective effects of AGP in a mouse model of myocardial ischemia-reperfusion injury (MIRI). Adult male C57BL/6J mice were pre-treated orally with AGP (25mg/kg) for six days. After 30min of the left anterior descending coronary artery occlusion followed by 24h of reperfusion, mice received an additional dose of AGP. The results showed that: (i) AGP pretreatment significantly reduced myocardial infarct size and cardiac injury biomarkers in MIRI mice and improved left ventricular ejection fraction (EF) and fractional shortening (FS); (ii) AGP pretreatment attenuated MIRI-induced oxidative stress imbalance in MIRI mice by increasing total antioxidant capacity (T-AOC) and reducing the levels of hydrogen peroxide (H2O2), nitric oxide (NO), malondialdehyde (MDA), and dihydroethidium (DHE); (iii) AGP pretreatment increased Bcl-2 expression and decreased caspase-3 and Bax expression in ischemic myocardial tissue, along with a reduction in TUNEL-positive cells. Further analysis showed that stimulation by I/R decreased peroxisome proliferator-activated receptor-α (PPAR-α) expression in ischemic cardiac tissue, which was prevented by AGP administration. Moreover, administration of the PPAR-α antagonist GW6471 (1mg/kg) abolished the protective effect of AGP on oxidative stress and apoptosis in the ischemic heart tissue of mice stimulated by ischemia-reperfusion. Taken together, these results suggest that AGP attenuates MIRI-induced cardiac injury by up-regulating PPAR-α expression, thereby preventing oxidative stress and cellular apoptosis.

Residual post-infarct myocardial inflammation detected by 68Ga-DOTATATE PET/MRI predicts long-term adverse cardiac remodelling

Abstract Background Maladaptive inflammatory responses are associated with adverse cardiac remodelling after myocardial infarction (MI), but clinical methods for detecting residual myocardial inflammation post-MI are lacking. Purpose To investigate somatostatin receptor subtype 2 (SST2) positron emission tomography (PET)/magnetic resonance imaging (MRI) using 68Ga-DOTATATE after MI. Methods In a prospective observational cohort study, infarct-related myocardial inflammation detected by 68Ga-DOTATATE PET at 2wk and 3mo post-MI was compared with MRI characteristics including left ventricular (LV) volumetric changes at 1yr, as well circulating immune cell phenotyping and serum proteomic markers. Patients with a prior history of MI or heart failure were excluded. Histological SST2 expression was assessed in myocardial biopsies. Results 38 participants (mean age 60 [SD 9] years; 84% male) with recent MI were enrolled, of whom 58% had an ST-segment elevation MI. Mean peak Troponin I was 16,665 (range 408 to &amp;gt;25,000) ng/L and mean post-infarct LV ejection fraction was 51 (SD 9) %. 68Ga-DOTATATE maximum standardized uptake values (SUVmax) at 10 (SD 4) days accurately localised infarcted myocardial segments defined by late-gadolinium enhancement MRI (LGE; Fig. 1); were 14.2% higher in akinetic/hypokinetic vs. normo-kinetic segments (p&amp;lt;0.0001); and were correlated both with peak segmental strain (r=0.47, p=0.003) and segmental T1 values (r=0.51, p=0.02). Mean infarct SUVmax was 19.7% lower on repeat PET/MRI after a mean 102 (SD 22) days (p&amp;lt;0.0001), and this change was in keeping with parallel reductions in T2-weighted oedema signal on MRI and serum biomarkers of cardiac injury and systemic inflammation. Residual inflammation assessed by mean infarct SUVmax at 3mo was correlated with ΔLV indexed end-diastolic volume at 369 (SD 14) days, after adjustment for baseline infarct size and other clinical variables (p=0.038). The 3mo:2wk ratio of mean infarct SUVmax was an even stronger predictor of adverse myocardial remodelling (p=0.0025). Circulating SST2+ classical monocytes were correlated with infarct 68Ga-DOTATATE signal (r=0.47, p=0.02), and SST2 was co-expressed with CD68+ macrophages in inflamed myocardial specimens of patients with recent MI and ischaemic heart failure. After statistical feature selection and multiple comparisons adjustments, among the blood markers associated with 3mo:2wk infarct SUVmax was CCL25, a chemokine involved in macrophage recruitment which has been implicated in adverse cardiac remodelling. Conclusions Here, in the first prospective clinical study of serial SST2 PET/MRI after MI, we show that 68Ga-DOTATATE can identify and track resolving infarct-related myocardial inflammation. Moreover, residual inflammation detected by 68Ga-DOTATATE is associated with long-term adverse myocardial remodelling and could provide a potential future imaging biomarker to help stratify high-risk patients for emerging immunomodulatory therapies.Figure 1.68Ga-DOTATATE PET-MRI after MI

Dexmedetomidine Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming.

Myocardial ischemia-reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK-MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex-treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1)phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI.

2-[18F]Fluoropropionic Acid PET Imaging of Doxorubicin-induced Cardiotoxicity.

Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[18F]fluoropropionic acid ([18F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin. Procedures: Cardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24 mg/kg) administered over 14 days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [18F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations. Significantly higher cardiac [18F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 min to 120 min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [18F]FPA in tissues other than the heart. Co-administration of [18F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity. [18F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.

Unleashing the cardioprotective potential of Ezetimibe against Doxorubicin-induced cardiotoxicity in Wistar rats: Targeting oxidative stress and NF-κB-mediated inflammation

Background Doxorubicin (DOX) is a potent antineoplastic agent used in treating various adult and pediatric cancers, but it tends to provoke dose-dependent cardiotoxicity. Ezetimibe (EZE), a cholesterol-lowering drug, has been reported to possess defensive actions against oxidative stress and inflammation, which are two of the main proposed mechanisms underlying the development of DOX-induced cardiotoxicity (DIC), hence, we aimed to inspect the possible protective effect of EZE against DIC in rats. Methods 24 adult male Wistar rats were allocated into four groups of six: control, DOX, 10 mg/kg EZE plus DOX and 20 mg/kg EZE plus DOX. At the end of the study, the experimental rats were anesthetized and blood samples were collected for biochemical analysis, after which the hearts were excised and heart tissue samples were obtained for biochemical and gene expression analyses. Results Pretreatment with EZE at a dose of 10 or 20 mg/kg alleviated cardiac damage induced by DOX, as EZE blunted the rise in serum levels of cardiac injury biomarkers, including cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Additionally, pretreating rats with EZE at either dose mitigated DOX-induced oxidative stress by elevating the levels of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), with consequent reduction in the lipid peroxidation biomarker malondialdehyde (MDA) in cardiac tissues. Furthermore, pretreatment with either dose of EZE hindered DOX-mediated inflammation, where EZE suppressed cardiac nuclear factor-kappa B (NF-κB) signaling and negatively regulated the gene expression of its downstream proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) with either dose and interleukin-1 beta (IL-1β) with the higher one. Conclusions Our findings indicate that EZE exhibited cardioprotection against DIC in rats, which makes EZE an interesting area for further investigations, animal- and human-wise, that can pave the way for a potential clinical application in preventing DIC in the future.

Predicting troponin biomarker elevation from electrocardiograms using a deep neural network.

Elevated troponin levels are a sensitive biomarker for cardiac injury. The quick and reliable prediction of troponin elevation for patients with chest pain from readily available ECGs may pose a valuable time-saving diagnostic tool during decision-making concerning this patient population. The data used included 15 856 ECGs from patients presenting to the emergency rooms with chest pain or dyspnoea at two centres in Sweden from 2015 to June 2023. All patients had high-sensitivity troponin test results within 6 hours after 12-lead ECG. Both troponin I (TnI) and TnT were used, with biomarker-specific cut-offs and sex-specific cut-offs for TnI. On this dataset, a residual convolutional neural network (ResNet) was trained 10 times, each on a unique split of the data. The final model achieved an average area under the curve for the receiver operating characteristic curve of 0.7717 (95% CI±0.0052), calibration curve analysis revealed a mean slope of 1.243 (95% CI±0.075) and intercept of -0.073 (95% CI±0.034), indicating a good correlation between prediction and ground truth. Post-classification, tuned for F1 score, accuracy was 71.43% (95% CI±1.28), with an F1 score of 0.5642 (95% CI±0.0052) and a negative predictive value of 0.8660 (95% CI±0.0048), respectively. The ResNet displayed comparable or surpassing metrics to prior presented models. The model exhibited clinically meaningful performance, notably its high negative predictive accuracy. Therefore, clinical use of comparable neural networks in first-line, quick-response triage of patients with chest pain or dyspnoea appears as a valuable option in future medical practice.

Association Between High Sensitivity Troponin I and NTproBNP With Rejection and Graft Loss in Pediatric Heart Transplant Recipients.

Troponin I is a blood biomarker of cardiac injury and levels measured using a high-sensitivity assay after pediatric heart transplantation (HT) have not been described. We sought to assess the association between high-sensitivity troponin I (hsTnI) and N-terminal pro-B-type natriuretic peptide (NTproBNP) with treated acute rejection (AR) and graft loss in pediatric heart transplant (HT) recipients. Serum was collected and banked from pediatric HT recipients prior to cardiac catheterization. Patients with samples drawn within 365 days post-HT were included and followed for up to 5 years. Generalized linear mixed-effect models examined the association between hsTnI and treated AR using a random intercept per patient. Cox proportional hazards models tested the association between maximal hsTnI and NT-proBNP and death/graft loss. HsTnI and NTproBNP values decline in the weeks following HT, after which these biomarkers stabilize. HsTnI was higher in AR versus no AR (6.2 vs. 3.5 ng/L, p < 0.001); doubling of hsTnI increased the odds of AR by 33% (p = 0.004). HsTnI showed moderate discrimination for AR with an AUC of 0.811 (95% CI 0.76, 0.87) and a NPV of 96.4% (95% CI 93.0, 98.1). Elevation in NT-proBNP was not associated with AR. In multivariable Cox modeling, a doubling of maximal NT-proBNP was associated with graft loss (HR 8.96, p = 0.014). In this pediatric HT cohort, HsTnI was moderately discriminative for AR and higher maximal NT-proBNP was associated with graft loss. HsTnI may add value in pediatric HT non-invasive AR surveillance, and elevated NTproBNP could suggest an increased risk of graft loss.

Preconditioning with Ginsenoside Rg3 mitigates cardiac injury induced by high-altitude hypobaric hypoxia exposure in mice by suppressing ferroptosis through inhibition of the RhoA/ROCK signaling pathway

Ethnopharmacological relevanceGinseng has historically been utilized as a conventional herbal remedy and dietary supplement to enhance physical stamina and alleviate fatigue. The primary active component of Ginseng, Ginsenoside Rg3 (GS-Rg3), possesses diverse pharmacological properties including immune modulation and anti-inflammatory effects. Furthermore, GS-Rg3 has demonstrated efficacy in mitigating tissue and organ damage associated with metabolic disorders such as hypertension, hyperglycemia, and hyperlipidemia. Nevertheless, its potential impact on high-altitude cardiac injury (HACI) remains insufficiently explored. Aim of the studyThe aim of this study was to examine the potential cardioprotective effects of Ginsenoside Rg3, and to investigate how Ginsenoside Rg3 preconditioning can enhance high-altitude cardiac injury by inhibiting the RhoA/ROCK pathway and ferroptosis in cardiac tissue. The findings of this study may contribute to the development of novel therapeutic strategies using traditional Chinese medicine for high-altitude cardiac injury, based on experimental evidence. Materials and methodsA hypobaric hypoxia chamber was employed to simulate hypobaric hypoxia conditions equivalent to an altitude of 6000 m. Through a randomization process, groups of six male mice were assigned to receive either saline, Ginsenoside Rg3 at doses of 15 mg/kg or 30 mg/kg, or lysophosphatidic acid (LPA) at 1 mg/kg. The impact of Ginsenoside Rg3 on high altitude-induced arrhythmias was evaluated using electrocardiography. Cardiac pathology sections stained with hematoxylin and eosin were evaluated for damage, with the extent of cardiomyocyte damage observed via transmission electron microscopy. The impact of Ginsenoside Rg3 on high-altitude cardiac injury was investigated through analysis of serum biomarkers for cardiac injury (CK-MB, BNP), inflammatory cytokines (TNF, IL-6, IL-1β), reactive oxygen species (ROS) and glutathione (GSH). The expression levels of hypoxia and hypoxia-related proteins in myocardial tissues from each experimental group were assessed using Western blot analysis. Following a review of the existing literature, the traditional regulatory mechanisms of ferroptosis were examined. Immunofluorescence staining of cardiac tissues and Western blotting techniques were utilized to investigate the impact of Ginsenoside Rg3 on cardiomyocyte ferroptosis through the RhoA/ROCK signaling pathway under conditions of hypobaric hypoxia exposure. ResultsPre-treatment with Ginsenoside Rg3 improved high altitude-induced arrhythmias, reduced cardiomyocyte damage, decreased cardiac injury biomarkers and inflammatory cytokines, and lowered the expression of hypoxia-related proteins in myocardial tissues. Both Western blotting and immunofluorescence staining of cardiac tissues demonstrated that exposure to high-altitude hypobaric hypoxia results in elevated expression of ferroptosis and proteins related to the RhoA/ROCK pathway. Experimental validation corroborated that the role of the RhoA/ROCK signaling pathway in mediating ferroptosis. ConclusionsThe findings of our study suggest that preconditioning with Ginsenoside Rg3 may attenuate cardiac injury caused by high-altitude hypobaric hypoxia exposure in mice by inhibiting ferroptosis through the suppression of the RhoA/ROCK signaling pathway. These findings contribute to the current knowledge of Ginsenoside Rg3 and high-altitude cardiac injury, suggesting that Ginsenoside Rg3 shows potential as a therapeutic agent for high-altitude cardiac injury.

Potential mechanisms underlying podophyllotoxin-induced cardiotoxicity in male rats: toxicological evidence chain (TEC) concept.

Podophyllotoxin (PPT) is a high-content and high-activity compound extracted from the traditional Chinese medicinal plant Dysosma versipellis (DV) which exhibits various biological activities. However, its severe toxicity limits its use. In clinical settings, patients with DV poisoning often experience adverse reactions when taking large doses in a short period. The heart is an important toxic target organ, so it is necessary to conduct 24-h acute cardiac toxicity studies on PPT to understand its underlying toxicity mechanism. Based on the concept of the toxicological evidence chain (TEC), we utilized targeted metabolomic and transcriptomic analyses to reveal the mechanism of the acute cardiotoxicity of PPT. The manifestation of toxicity in Sprague-Dawley rats, including changes in weight and behavior, served as Injury Phenotype Evidence (IPE). To determine Adverse Outcomes Evidence (AOE), the hearts of the rats were evaluated through histopathological examination and by measuring myocardial enzyme and cardiac injury markers levels. Additionally, transcriptome analysis, metabolome analysis, myocardial enzymes, and cardiac injury markers were integrated to obtain Toxic Event Evidence (TEE) using correlation analysis. The experiment showed significant epistaxis, hypokinesia, and hunched posture in PPT group rats within 24h after exposure to 120mg/kg PPT. It is found that PPT induced cardiac injury in rats within 24h, as evidenced by increased serum myocardial enzyme levels, elevated concentrations of cardiac injury biomarkers, and altered cardiac cell morphology, all indicating some degree of cardiac toxicity. Transcriptome analysis revealed that primary altered metabolic pathway was arachidonic acid metabolism after PPT exposure. Cyp2e1, Aldob were positively correlated with differential metabolites, while DHA showed positive correlation with differential genes Fmo2 and Timd2, as well as with heart injury markers BNP and Mb. This study comprehensively evaluated cardiac toxicity of PPT and initially revealed the mechanism of PPT-induced acute cardiotoxicity, which involved oxidative stress, apoptosis, inflammatory response, and energy metabolism disorder.

Role of Circulating Biomarkers in Diabetic Cardiomyopathy.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that has alarmingly increased in incidence in recent decades. One of the most serious complications of T2DM is diabetic cardiomyopathy (DCM), an often underrecognized yet severe condition that is a leading cause of mortality among diabetic patients. In the early stages of DCM, patients typically show no symptoms and maintain normal systolic and diastolic left ventricle function, making early detection challenging. Currently available clinical markers are often not specific enough to detect the early stage of DCM. Conventional biomarkers of cardiac mechanical stress and injury, such as natriuretic peptides (NPs) and cardiac troponin I (cTnI), have shown limited predictive value for patients with T2DM. NPs have proven efficacy in detecting diastolic dysfunction in diabetic patients when used alongside 2D echocardiography, but their utility as biomarkers is limited to symptomatic individuals. While cTnI is a reliable indicator of general cardiac damage, it is not specific to cardiac injury caused by high glucose levels or T2DM. This underscores the need for research into biomarkers that can enable early diagnosis and management of DCM to reduce mortality rates. Promising novel biomarkers that showed good performance in detecting diastolic dysfunction or heart failure in diabetic patients include galectin-3, ST2, FGF-21, IGFBP-7, GDF-15, and TGF-β. This review summarizes the current understanding of DCM biomarkers, aiming to generate new ideas for the early recognition and treatment of DCM by exploring related pathophysiological mechanisms.

Aminopeptidasic Enzymes as Early Biomarkers of Cardiac Surgery-Associated Acute Kidney Injury and Long-Term Events.

Diagnosis of acute kidney injury (AKI) relies on serum creatinine (SCr) changes. This study investigated if urinary aminopeptidases are early and predictive biomarkers of cardiac surgery-associated AKI (CSA-AKI). Glutamyl aminopeptidase (GluAp), alanyl aminopeptidase (AlaAp), dipeptidyl peptidase-4 (DPP4), proteinuria, albuminuria, N-acetyl-β-D-glucosaminidase (NAG), and neutrophile gelatinase-associated lipocalin (NGAL) were measured in urine samples from 44 patients at arrival in the intensive care unit (ICU) after cardiac surgery. Sensitivity, specificity, and positive and negative predictive value for diagnosis of stages 1, 2, and 3 of AKI were analyzed for the highest quartile of each marker. We also studied the relationship with SCr after surgery, 6- and 12-month glomerular filtration rates (GFRs), and other long-term events over the next 5 years. GluAp diagnosed the maximal number of patients that developed stage 2 or 3 of AKI, increasing diagnostic sensitivity from 0% to 75%. In addition, GluAp and DPP4 were related to the decrease in GFR at 6 or 12 months after surgery. Urinary aminopeptidases are a potential tool for the early diagnosis of CSA-AKI, with GluAp being the most effective marker for diagnosing stage 2 or 3 of AKI at ICU admission. GluAp and DPP4 serve as predictive biomarkers for a decrease in GFR.

Allicin and L-carnitine as Preventive Agents Against Doxorubicin-induced Cardiac Damage in Rats

Background: Doxorubicin (DOX) is a potent anthracycline chemotherapy agent widely employed to treat various malignancies, such as cancers and this study sought to determine how allicin (ALC) and or L-carnitine (LC) affect DOX-induced cardiotoxicity in rats.Methods: In this study, the possible alleviative role of ALC (20 mg/kg/day orally (PO)) or LC (100 mg/kg/day PO) or the combined treatment of both ALC and LC (with the previously mentioned dosages) was evaluated against the cardiotoxic effect of a widely used chemotherapeutic agent, DOX (20 mg DOX /kg intraperitoneal injection (IP) as a single dose) in rats in 30 days experiment. Results: The results revealed that ALC and LC significantly suppressed the DOX-induced increment in serum levels of cardiac damage biomarkers, such as lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase-megabyte (CK-MB). Moreover, DOX-associated oxidative stress, including the elevation in malondialdehyde (MDA) level and reduced activity of antioxidant enzymes, such as catalase (CAT) and superoxide dismutase (SOD) and the level of reduced glutathione (GSH) was corrected in ALC and or LC treated groups. Furthermore, DOX-induced cardiomyopathy showed significant pathological changes, including myocyte degeneration, vacuolization, interstitial edema, and focal necrosis. Nevertheless, the histopathological lesions were corrected in the treated groups mostly in the combined treatment with ALC plus LC. Compared to ALC and LC, ALC plus LC was more effective at restoring the cardiac injury biomarkers, inhibiting cardiac oxidative damage and preserving the cardiac architecture. Conclusions: Conclusively, the study results evidenced the beneficial role of the combined treatment with ALC plus LC in mitigating DOX-induced cardiotoxicity.