Search Results (2,579)

Septic cardiomyopathy is recognized as an acute, transient, and reversible condition. However, septic insult may induce latent changes characteristic of cardiac remodeling, with future consequences. Therefore, the present study aimed to evaluate the morphological and functional cardiac changes in the acute and subacute phases (with 7-day follow-up) in male Wistar rats subjected to experimental sepsis using a cecal ligation and puncture (CLP) model. In the acute phase, the animals underwent echocardiographic assessment at baseline and 48 h after the induction of sepsis. In the subacute 7 days follow-up, animals were allocated in control and sepsis groups. After this period, the animals underwent echocardiographic assessment, followed by euthanasia, papillary muscle testing, and subsequent morphometric and biochemical analyses. Fecal samples from six animals per group were collected at baseline and after 7 days for microbiota analysis. In the acute phase, echocardiographic assessment revealed that, following sepsis, animals exhibited reduced systolic function. In the subacute 7 days follow-up, both echocardiogram and papillary muscles revealed cardiac dysfunction in the sepsis group. Cardiomyocyte cross-sectional area and collagen content were significantly greater in the sepsis group compared with that in the control group. Analysis of maximal enzymatic activities involved in cardiac energy metabolism and oxidative stress biomarkers revealed no significant differences between groups. Considering microbiota assessment, beta diversity analysis revealed significant differences between septic animals and controls. In conclusion, sepsis was associated with persistent systolic/diastolic dysfunction, cardiomyocyte hypertrophy, and fibrosis after 7 days. These data suggest that septic cardiomyopathy should not be considered merely an acute, transient, and reversible condition in this experimental context. Full article

Heart failure is a leading cause of global morbidity and mortality, often developing as a consequence of acute myocardial infarction. Current management focuses on timely reperfusion via percutaneous coronary intervention. Yet, this approach fails to prevent the molecular cascades that drive the death of viable yet stressed cardiomyocytes within the infarct and peri-infarct zone. Effective antifibrotic therapies remain limited, highlighting a critical gap in current management strategies. This review aims to integrate current understanding of the molecular mechanisms underpinning post-infarct fibrosis and potential interventions for therapeutic development. This emphasis on molecular death signal activation and cell elimination highlights the redundancy of interconnecting fibrosis pathways. Anti-inflammatory and cell-targeted therapies focussing on oxidative stress and haemodynamic load have demonstrated strong preclinical promise. Yet, these approaches have largely failed to translate into clinical benefit. Overall, these limitations emphasise a narrow therapeutic window for intervention. As such, current therapies often fail to preserve metabolically vulnerable myocardium that remains potentially salvageable. Therefore, emerging approaches including RNA-based therapies, cardiac reprogramming, and targeted delivery systems offer new opportunities to improve therapeutic precision. Collectively, these findings support a shift toward early, cell-targeted intervention strategies. This approach aims to prevent progression to heart failure and increases patient quality of life. Full article

Cardiovascular diseases remain the leading cause of mortality in developed countries. Among these conditions, acute myocardial infarction (AMI) is associated with particularly high rates of cardiac morbidity and mortality. Cardiac development in mammals is primarily dependent on cardiomyocyte (CM) proliferation during embryonic and early postnatal stages. However, following birth, the proliferative capacity of CMs declines markedly, with only limited cellular renewal occurring during adult life in response to pathological injury. Consequently, the irreversible loss of functional cardiomyocytes and the subsequent formation of fibrotic scar tissue frequently lead to persistent cardiac dysfunction and progressive impairment of cardiac physiology. Cardiomyocyte self-renewal is a tightly regulated process involving multiple molecular pathways. Among factors implicated in this regulation, microRNAs (miRNAs) have emerged as key modulators coordinating both cardiac development and tissue repair mechanisms. In this context, extracellular vesicles (EVs) have attracted considerable interest as potential modulators of these regenerative processes. In particular, mesenchymal stromal cells (MSCs) represent a promising therapeutic platform due to their immunomodulatory and anti-fibrotic properties demonstrated across multiple in vitro and in vivo models. Furthermore, the therapeutic potential of MSC-derived EVs can be enhanced through bioengineering approaches aimed at improving targeted molecular delivery. In this review, we summarize recent advances in the development and application of EV-based therapeutic strategies, with particular emphasis on their potential use as advanced therapy medicinal products (ATMPs) for cardiovascular regeneration and repair. Full article

Gestational diabetes mellitus (GDM) exposes the fetus to chronic hyperglycemia, promoting early cardiac remodeling and increasing the risk of diabetic cardiomyopathy later in life. Epigenetic regulators such as p53 tumor suppressor gene (p53), microRNA-34a (miR-34a), and the sirtuins 1 and 7 (SIRT1/SIRT7) may contribute to this programming process; however, their temporal dynamics during postnatal cardiac development remain unclear. This study aimed to characterize structural and molecular alterations in the hearts of offspring exposed to GDM and to determine the involvement of the p53–miR-34a–SIRT1/SIRT7 axis in early cardiac remodeling. Cardiac morphometry was assessed at birth (newborn [NB]) and at 8, 15, 25, and 35 days. Left ventricles were examined through hematoxylin/eosin staining. SIRT1, SIRT7, Bcl-2, and Bax were evaluated by immunofluorescence, while p53 and miR-34a were evaluated by RT-PCR. Molecular interactions were integrated using IPA software, version 159584291. Offspring exposed to GDM exhibited a reduced cardiac area and ventricular lumen, along with increased left ventricular wall thickness and fibrosis during early postnatal stages. The cardiomyocyte area was elevated at all ages. The level of miR-34a increased early, preceding p53 upregulation. SIRT1 presences decreased from NB to 35 days, whereas SIRT7 expression remained consistently elevated. These findings suggest that GDM induces early and sustained cardiac remodeling associated with dysregulation of the p53–miR-34a–SIRT1/SIRT7 axis, a pattern that could increase susceptibility to diabetic cardiomyopathy. Full article

During donation after circulatory death (DCD), circulating levels of mitochondrial damage-associated molecular patterns (mtDAMPs) may increase, thereby exposing donor hearts to mtDAMPs prior to procurement and during machine perfusion. Mitochondrial DNA (mtDNA) is a pro-inflammatory mtDAMP that may stimulate several intracellular cascades including that of toll-like receptor 9 (TLR9). We administered mtDNA or ODN2088 (TLR9 antagonist) to hearts at reperfusion onset using an isolated rat heart model of DCD transplantation to investigate their effects. Four experimental groups were compared: (1) no ischemia; (2) ischemia; (3) ischemia + mtDNA; (4) ischemia + ODN2088. During reperfusion, cardiac power in ischemic hearts was significantly reduced compared to non-ischemic hearts (p < 0.01), and was further decreased with mtDNA (p < 0.05), but remained unchanged with ODN2088. Reduced ventricular recovery in mtDNA-treated hearts likely resulted from lower recovery of oxidative metabolism, demonstrated by reduced oxygen efficiency (p < 0.05) and a strong tendency for increased cytochrome c release (p < 0.06),indicating mitochondrial dysfunction and disruption, respectively. ODN2088 phosphorylated IκBα (NF-κB inhibitor alpha) and appeared to decrease cardiomyocyte death compared to ischemic hearts. Given the detrimental effects of circulating mtDNA on cardiac functional and metabolic recovery, circulating mtDAMPs, and particularly mtDNA, are of clinical relevance as potential therapeutic targets for optimizing graft quality and post-transplant outcomes. Full article

Background and Objectives: Sevoflurane, a widely used volatile anesthetic, can induce oxidative stress and apoptosis, but the underlying mechanisms in human cardiomyocytes remain unclear. This study investigated the role of transient receptor potential vanilloid 1 (TRPV1) channels in sevoflurane-induced cardiotoxicity and the potential mitigating effect of ascorbic acid. Materials and Methods: Human cardiomyocytes were exposed to sevoflurane (5.1%, 6 h) and/or ascorbic acid (1 mM, 30 min), with or without the TRPV1 channel antagonist capsazepine and with the TRPV1 channel agonist Capsaicin. Intracellular calcium, reactive oxygen species (ROS), apoptosis, mitochondrial membrane potential, and caspase-3/9 activities were assessed. Results: Sevoflurane significantly increased intracellular calcium levels, ROS production, mitochondrial depolarization, apoptosis, and caspase-3/9 activity compared with controls (p < 0.001). These effects were attenuated by capsazepine, suggesting a role for TRPV1 involvement. Ascorbic acid pretreatment significantly reduced sevoflurane-induced elevations in all parameters (p < 0.001). Combined ascorbic acid and capsazepine treatment yielded further reductions in calcium, ROS, apoptosis, and caspase activities compared to ascorbic acid alone (p < 0.05). Conclusions: Sevoflurane induces apoptosis in human cardiomyocytes via ROS-mediated activation of the TRPV1 channel, leading to calcium overload, mitochondrial dysfunction, and caspase-dependent cell death. Ascorbic acid exerts mitigating effects by reducing oxidative stress and modulating TRPV1 channel activity, suggesting a potential therapeutic strategy for myocardial protection during sevoflurane anesthesia. Full article

Heart failure (HF) and myocardial infarction (MI) are interconnected syndromes with overlapping pathogenic pathways, including ischemia, neurohormonal activation, and maladaptive remodeling. Hypoxia-response genes, lipid-handling genes, and extracellular matrix (ECM) genes each influence these processes. Understanding their integrated roles can uncover biomarkers and targets. A systematic literature search was conducted (PubMed, Web of Science, and Scopus; 2000–2026; English-only, following PRISMA guidelines) to identify studies on key genes in hypoxia signaling, lipid metabolism, and ECM remodeling in MI/HF. Acute hypoxia (via HIFs) orchestrates metabolic adaptation and inflammation, but chronic HIF activation drives fibrosis and dysfunction. In parallel, genes controlling triglyceride and cholesterol handling (e.g., LPL, APOC3) influence energy supply and vascular risk. Variants in these genes modulate plasma lipids and MI/HF risk. For example, genetic loss-of-function in APOC3 lowers triglycerides and reduces coronary risk. ECM-related genes (e.g., COL4A1, LRP1) govern fibrosis and vascular integrity. Mutations in COL4A1 cause cardiomyocyte hypertrophy and severe fibrosis, while LRP1 regulates matrix remodeling and is upregulated in ischemic myocardium. Throughout, gene functions span acute repair versus chronic maladaptation. Findings derive from mixed sources: rodent models and cell studies demonstrate mechanistic links, while human genetics and cohorts link gene variants to HF/MI outcomes. Many promising biomarkers (e.g., circulating ITGA1) are preliminary, lacking large prospective validation. Not all cited therapeutic ideas have been tested in the treatment of human cardiac disease. The literature mix of species, models, and patient cohorts introduces heterogeneity. Full article

Type-1 ryanodine receptor (RyR1) is essential for skeletal muscle contraction. This Ca²⁺ release channel is expressed in cardiac myocytes; however, its function remains elusive. Cardiac-specific RyR1 overexpression (OE) mice were generated under the cardiac-specific Myh6 promoter. Cardiac hypertrophy (CH), cardiac functions, and mechanistic changes in RyR1 OE and control (wildtype, WT) mice were assessed using hematoxylin and eosin staining, echocardiography, electrocardiogram, quantitative RT-PCR, Western blotting, [³H]-ryanodine binding assay, confocal microscope, ROS dye Amplex Red and 2′,7′-dichlorofluorescein diacetate. RyR1 OE mice had increased whole heart, left ventricular weight, and left ventricular wall thickness, but decreased cardiac output and stroke volume, thereby presenting CH and heart failure (HF). CH markers like ANF, BNF, and aSKA mRNAs were increased in RyR1 OE heart. RyR1, but not RyR2 or RyR3, expression was increased in the RyR1 OE mouse heart. Similar results were found in mice with TAC-induced CH. RyR1, but not RyR2 mRNA, was increased in cardiac muscle from dogs and humans with CH and/or HF. Maximum [³H]-ryanodine binding was increased, whereas the binding dissociation constant decreased in left ventricular cardiomyocytes from RyR1 OE mice. RyR2-dependent Ca²⁺ sparks were increased, which was blocked by riluzole, a small molecule known to inhibit RyR2. Consistently, ROS was remarkably increased in RyR1 OE cardiac cells. We first generated cardiac-specific RyR1 OE mice; these mice had CH, HF, and increased RyR1 expression with no RyR2 or RyR3 alteration. Similar changes were observed in mice, dogs, and humans with CH and HF. Increased mitochondrial ROS-dependent RyR2 Ca²⁺ release was essential for RyR1-induced CH and HF. Full article

Background and Objectives: Green tea is known for its powerful antioxidant properties. However, the effects of green tea consumption during pregnancy on neonatal development and the mechanisms of these effects are not fully understood. The aim of this study was to investigate potential damage to atrial cardiomyocytes of newborn rat pups whose mothers received green tea during pregnancy and to elucidate the apoptotic mechanisms underlying this possible damage. Materials and Methods: Wistar albino rats (weighing 200–220 g, 10 weeks old) were used in this study. Following the confirmation of pregnancy, rats were randomly assigned to groups, and the experimental group was administered green tea by oral gavage at a dose of 50 mg/kg per day for 21 days. Atrial cardiomyocytes and mitral valve cells from newborn pups (postnatal day 1) were obtained and evaluated immunohistochemically for cytochrome c, caspase-9, and caspase-3 expression. Results: TUNEL analysis revealed a significant increase in DNA fragmentation in the green tea group, with the median number of apoptotic cells per region of interest (ROI) rising from 5.5 to 24.5 in atrial cardiomyocytes (p < 0.001), and from 2.0 to 10.0 in mitral valve cells (p < 0.05). Immunohistochemically, the control group showed faint-to-weak basal immunoreactivity of cytochrome c and caspase-3, and weak-to-moderate expression of caspase-9. In the green tea group, caspase-3 immunoreactivity was moderate, while cytochrome c and caspase-9 immunoreactivity were significantly higher. Quantitative HSCORE analysis confirmed significant elevations in atrial cardiomyocytes for cytochrome c (from 65.0 to 210.0; p < 0.001), caspase-9 (from 85.0 to 140.0; p < 0.001), and caspase-3 (from 60.0 to 120.5; p < 0.001). Similar statistically significant increases were observed across all corresponding markers in the mitral valve cells (p < 0.05). Overall, the induction of apoptosis was notably more pronounced in atrial cardiomyocytes than in mitral valve cells. Conclusions: Our findings suggest that the mechanism of potential damage in atrial cardiomyocytes of newborn rat pups is associated with mitochondria-mediated apoptosis, potentially triggered by activation of the cytochrome c, caspase-9 and caspase-3 axis. These results highlight the importance of exercising caution regarding the consumption of green tea supplements during pregnancy. Further studies are needed to correlate these preliminary neonatal observations with clinical outcomes. Full article

Postnatal loss of cardiac regenerative capacity coincides with profound remodeling of signaling, structural, and metabolic programs in the developing heart. Here, we profiled Insulin growth factor (IGF)/Fibrobrast growth factor (FGF)/insulin receptors (InsR), Ras/Raf/MEK/ERK pathway components, cytoskeletal markers, and cell-cycle/metabolic proteins in mouse whole-heart tissue at P3, P7, P14, P28, and adulthood. IGF-1R- and IGF-2R-associated signals declined sharply during maturation, whereas InsR changed more modestly. FGFR1-derived immunoreactive species showed a transient early postnatal increase before marked reduction at later stages. These receptor-associated changes paralleled strong decreases in B-Raf, MEK1, and MEK2, together with pronounced loss of MEK1/2 activation-loop phosphorylation. MEK1 Thr292 phosphorylation also declined markedly, identifying a previously unrecognized developmental phosphorylation pattern. Structural maturation was accompanied by stable Actn2 expression, downregulation of immature cytoskeletal markers, increased cytochrome c and myoglobin, and significant loss of Aurora B and phospho-histone H3 in adult hearts. Together, these findings describe a coordinated postnatal maturation program in which signaling, cytoskeletal remodeling, metabolism, and proliferative withdrawal change in parallel. These data are consistent with reduced MAPK pathway activity during maturation and highlighting this signaling as node associated with closure of the neonatal regenerative window. Full article

Sorafenib is a first-line tyrosine kinase inhibitor for malignant tumor treatment, yet its clinical application is greatly restricted by unavoidable cardiotoxicity. Astragaloside IV is a natural compound with prominent cardiovascular protective effects. We first carried out modeling studies including network pharmacology, human proteome microarray screening, molecular docking, and molecular dynamics simulation. Network pharmacology highlighted the hypoxia-inducible factor-1 signaling pathway as a key route; the integrated approach further identified signal transducer and activator of transcription 3 as a novel direct binding target of astragaloside IV with high binding stability. In a mouse model of chronic sorafenib-induced cardiotoxicity, astragaloside IV significantly improved cardiac function, and attenuated myocardial fibrosis, oxidative damage, and cardiomyocyte apoptosis. Mechanistically, astragaloside IV reduced the expression of signal transducer and activator of transcription 3 and hypoxia-inducible transcription factor-1α, and elevated the expression of B-cell lymphoma 2. In cellular experiments, astragaloside IV protected HL-1 cardiomyocytes against sorafenib-induced cytotoxicity and apoptosis through the same signaling pathway. This study confirms that astragaloside IV alleviates sorafenib-induced cardiotoxicity by inhibiting cardiomyocyte apoptosis via targeting the signal transducer and activator of transcription 3/hypoxia-inducible transcription factor-1α/B-cell lymphoma 2 pathway, providing a promising strategy for clinical prevention of chemotherapy-related cardiac injury. Full article

Arrhythmogenic cardiomyopathy (ACM) is a genetic myocardial disorder marked by progressive cardiomyocyte loss, fibro-fatty replacement, ventricular arrhythmias, and risk of sudden cardiac death. Traditionally considered a structural and electrical disease driven by desmosomal dysfunction, emerging evidence redefines ACM as an inflammatory cardiomyopathy in which immune activation plays a central role. This review integrates genetic, molecular, experimental, and clinical data to highlight inflammation as a unifying feature of ACM. Desmosomal gene variants impair cell adhesion and also activate cardiomyocyte-intrinsic inflammatory pathways, including nuclear factor of kappa B (NFκB) and glycogen synthase kinase 3β (GSK3β) signaling, promoting cytokine release, immune cell recruitment, and fibrotic remodeling. Preclinical studies suggest inflammation precedes structural changes, indicating it may be an initiating event rather than a secondary response. Clinical and pathological findings support this model, with inflammatory infiltrates, circulating cytokines, and autoantibodies observed across disease stages. These processes often present as episodic “hot phases” resembling myocarditis, thus complicating diagnosis. The inflammatory landscape involves both innate and adaptive immunity, along with stromal and neuronal remodeling, contributing to arrhythmogenesis through gap junction disruption, calcium-handling abnormalities, and fibrosis. Environmental factors such as exercise, stress, and metabolic disturbances further modulate inflammatory pathways and disease expression. Therapeutically, this evolving perspective supports immunomodulatory approaches, including inhibition of NFκB, GSK3β, and cytokine signaling. Early clinical data on immunosuppressive and cytokine-directed therapies are promising, especially during active inflammatory phases, while gene-based strategies specifically address the underlying genetic defects. In conclusion, ACM should be recognized as an inflammatory cardiomyopathy shaped by interactions between genetic susceptibility and immune dysregulation. Integrating genetic and immunologic profiling may improve diagnosis, risk stratification, and treatment, ultimately leading to refined personalized therapeutic strategies. Full article

Cardiovascular diseases (CVDs) remain a leading cause of death worldwide. Mitochondria, essential organelles within cells, play a crucial role in maintaining cardiovascular health by producing energy through ATP synthesis. The heart’s high energy demand makes it particularly sensitive to mitochondrial function. In CVDs, mitochondrial adaptability is compromised, resulting in dysfunction characterized by impaired respiratory chain activity, decreased ATP production, oxidative stress, and structural damage. This review consolidates current research on mitochondrial roles in CVD development, focusing on mitochondrial respiration, ATP synthesis, and the processes involved in maintaining mitochondrial quality, such as mitophagy. It discusses the challenges in developing therapies aimed at restoring mitochondrial function, including drug delivery issues and targeting specificity. The assessment includes analysis of mitochondrial anomalies associated with cardiac disease progression and potential therapeutic strategies. Mitochondrial dysfunction contributes to the progression of various CVDs by reducing energy output and increasing oxidative stress, leading to cardiomyocyte injury and death. Damaged mitochondria produce excessive reactive oxygen species (ROS), exacerbating cellular damage. Repairing mitochondrial components, especially the respiratory chain and ATP synthesis pathways, has shown potential in mitigating cellular injury and improving cardiac function. Restoring mitochondrial function is vital for preventing and treating CVDs. Targeted therapies that repair mitochondrial respiratory activity and enhance ATP production may reduce cellular damage, promote cardiomyocyte survival, and improve clinical outcomes. Understanding mitochondrial dynamics offers promising avenues for innovative interventions in cardiovascular health management. Full article

Isovitexin (ISOV) is an active component identified in the traditional Tibetan medicine Tsantan Sumtang, which is commonly used for treating myocardial ischemia. Although previous studies have suggested the protective effect of ISOV on cardiomyocytes, the in vivo anti-ischemic efficacy and underlying mechanisms of ISOV remain unclear. This study aimed to systematically evaluate the therapeutic effects of ISOV on myocardial ischemia in rats and to elucidate its molecular mechanism of action. An acute myocardial infarction model was established in rats by ligating the left anterior descending branch (LADL) of the coronary artery. The protective effects of ISOV were assessed by measuring infarct size, serum cardiac injury biomarkers, and oxidative stress levels. Chemical proteomics using photoaffinity magnetic beads was employed to identify potential target proteins of ISOV. Molecular docking, pull-down western blotting, and cellular thermal shift assay (CETSA) western blotting were applied to validate the interaction between ISOV and target. Knockdown of the target was used to verify the mechanism of ISOV on anti-myocardial ischemia effect. ISOV treatment significantly reduced myocardial infarct size, decreased serum levels of lactate dehydrogenase (LDH), creatine kinase isoenzymes (CK-MB), malondialdehyde (MDA), and enhanced superoxide dismutase (SOD) activity in myocardial ischemia rats. Furthermore, ISOV improved mitochondrial function, as evidenced by increased ATP content and enhanced activities of mitochondrial complexes I and IV. Chemical proteomics and bioinformatic analysis identified SLC25A4 as a direct target of ISOV. Molecular docking revealed a high-affinity binding (binding energy: −8.3 kcal/mol), which was further confirmed by pull-down assays and CETSA. In SLC25A4-knockdown H9c2 cells under hypoxic conditions, ISOV upregulated SLC25A4 expression, promoted the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and upregulated the expression of proliferator-activated receptor gamma coactivator-1$\alpha$ (PGC-1$\alpha$). ISOV exerts cardioprotective effects against myocardial ischemia by directly binding to SLC25A4 and activating the AMPK/PGC-1$\alpha$ pathway, highlighting its potential as a therapeutic agent for myocardial ischemia. Full article

Myocardial edema is associated with cardiac electrical instability, but the cellular mechanisms linking osmotic cell swelling to arrhythmias remain unclear. Hypoosmotic conditions are hypothesized to drive transitions between dynamical regimes (e.g., spiral waves and multiple wavelets), producing distinct calcium oscillatory dynamics that act as markers of the underlying electrophysiological state. This study presents an integrated computational framework combining analysis of optical mapping data with mechanistic mathematical modeling to investigate calcium dynamics in cardiomyocyte monolayers under varying extracellular osmolality conditions. We developed an enhanced signal processing pipeline that reconstructs dynamic baselines from local minima using piecewise linear interpolation, enabling robust detection and characterization of calcium transients in highly heterogeneous and aperiodic signals. The computational workflow incorporated peak detection algorithms adapted for irregular oscillatory patterns, extraction of calcium transient features (amplitude, time to peak, decay durations at 30%, 50%, and 80% of peak amplitude) across spatial regions corresponding to different excitation regimes, and mathematical modeling to investigate the effects of hypoosmotic swelling at a cellular level. The parameters of the Gattoni (2016) rat ventricular cardiomyocyte model were modified to match experimental observations of the calcium transients. Simulation suggests that hypoosmotic swelling increases sarcolemmal calcium pump activity and elevates cytosolic concentrations of calmodulin and troponin, promoting alternans and delayed afterdepolarizations. Full article