Search Results (2,444)

Cocaine-related deaths present significant diagnostic challenges due to the nonspecific nature of cardiac histopathology and the limited reliability of postmortem toxicology, often affected by redistribution phenomena. This study investigated the postmortem heart expression and distribution of an anti-cocaine monoclonal antibody, aiming to evaluate immunohistochemistry (IHC) as a potential complementary tool for diagnosing cocaine-related fatalities. Fifteen cases of acute cocaine-related death, with toxicological data exclusively positive for cocaine, were examined and compared to ten cases negative for drug abuse. Cardiac samples from the lateral left ventricular wall and interventricular septum underwent IHC using an experimentally optimized protocol. All cocaine-related cases demonstrated clear and widespread immunopositivity, with varying staining intensities across a semi-quantitative scale. Immunostaining localized consistently to nuclear and myofibrillar compartments and showed no association with postmortem interval (mean PMI 72.33 h; range 30–144). Control samples exhibited no staining. Positive immunostaining also highlighted cardiomyocyte alterations related to cocaine toxicity, particularly hypercontracted fibers with myofibrillar rhexis and contraction band necrosis. While these findings align with the established cocaine-induced myocardial injury, the intense nuclear staining observed may further reflect oxidative DNA damage associated with cocaine exposure. This study provides novel evidence supporting the applicability of anti-cocaine IHC in postmortem investigations. The technique may serve as a valuable adjunct in detecting cocaine distribution within cardiac tissue, particularly when toxicological data are inconclusive or unavailable. Full article

Epicardial adipose tissue (EAT) function may influence the heart, given its metabolic actions and proximity to the heart. We hypothesized that diabetes mellitus (DM) alters miRNA expression across adipose tissue types, and that modifications in EAT may have critical implications for cardiac physiology. To test this, we compared EAT and subcutaneous adipose tissue (SAT) miRNA profiles between patients with and without DM and across tissues within each disease group. Paired biopsies from patients with (n = 18) and without DM (n = 46) undergoing cardiac surgery were analyzed using miRNA profiling and bioinformatics. Among 680 miRNAs screened, 34 were uniquely expressed in EAT, confirming a distinct molecular signature in this fat depot. Notably, miR-155-5p was significantly elevated in EAT from patients with DM, indicating a localized metabolic effect. In SAT, miR-93-3p and miR-223-3p were upregulated in patients with DM and consistently higher than in EAT, regardless of DM status, indicating tissue-specific regulation. miR-324-5p was more expressed in SAT of patients in the NDM group, reflecting combined effects of tissue type and DM. These patterns remained consistent across cardiac disease stratifications. Pathway analysis revealed that miRNAs enriched in EAT target genes involved in cardiomyocyte growth and differentiation. Overall, the findings highlight the unique miRNA profile of epicardial fat and its altered response to DM, supporting its relevance in cardiac physiology. Full article

Background/Objectives: Metabolic syndrome (MetS) conditions lead to structural and functional alterations in cardiomyocytes, microvasculature, and extracellular matrix (ECM), leading to myocardial fibrosis and impaired diastolic function. Cardiac lymphatic vessels (LVs) are increasingly recognized as key regulators of myocardial homeostasis, yet their response to MetS remains poorly understood. Therefore, we aimed to investigate transcriptional changes in cardiac lymphatic endothelial cells (LECs) in db/db mice, a well-established model of MetS. Methods: Using flow cytometry-sorted LECs and RT-PCR, we analyzed mRNA expression of genes involved in lymphangiogenesis, metabolism, mechanotransduction, immune cell trafficking, and ECM interactions. Results: Our findings show the transcriptional plasticity of cardiac LECs in response to MetS. Conclusions: Although our study is limited by the lack of protein-level validation and functional assays, our approach provides a broader interpretative framework and identifies potential directions for future research, including functional studies and pathway-specific investigations of the identified genes to assess their impact on lymphatic flow and cardiac function. Understanding LEC responses to metabolic stress may uncover novel therapeutic targets for heart failure associated with MetS. Full article

Regular exercise enhances heart function and metabolism. The N6-methyladenosine (m⁶A) RNA modification is related to myocardial homeostasis, with the demethylase fat mass and obesity-associated protein (FTO) crucial for myocardial remodeling. However, its role in exercise-induced heart protection is unclear. We analyzed m⁶A levels and methylation enzymes to evaluate FTO changes in transverse aortic constriction (TAC) mice hearts after six weeks of treadmill exercise. Further in vivo experiments explored the effect of FTO. High-throughput sequencing identified the target gene enoyl-CoA delta isomerase 1 (Eci1). Cardiac-specific Eci1 knockout mice were used to assess the role of Eci1. The influence of FTO on Eci1 expression was explored by eliminating demethylase activity. The results showed that exercise increased FTO expression in TAC mice hearts. Reducing FTO in the heart diminishes exercise benefits. The differential m⁶A-modified genes in TAC mice hearts were enriched in fatty acid metabolism, with increased methylation of Eci1 m⁶A and decreased protein levels, leading to abnormal lipid accumulation. Exercise could reverse these effects. Eci1 knockout partially weakened exercise benefits. FTO regulated Eci1 expression via m⁶A modification, and inhibiting FTO demethylase activity blunted its protective effects on hypertrophic cardiomyocytes. Thus, FTO modulates Eci1 expression through m⁶A-dependent mechanisms, facilitates fatty acid metabolism and mitigates pressure overload-induced heart failure during exercise. Full article

Human adult cardiomyocytes (CMs) have limited regenerative capacity, posing a significant challenge in restoring cardiac function following substantial CM loss due to an acute ischemic event or chronic hemodynamic overload. Nearly half of patients show no improvement in left ventricular ejection fraction during recovery from acute myocardial infarction. At baseline, both humans and mice exhibit low but continuous cell turnover originating from the existing CMs. Moreover, myocardial infarction can induce endogenous CM cell cycling. Consequently, research has focused on identifying drivers of CM rejuvenation and proliferation from pre-existing CMs. High-throughput screening has facilitated the discovery of novel pro-proliferative targets through small molecules, microRNAs, and pathway-specific interventions. More recently, omics-based approaches such as single-nucleus RNA sequencing and spatial transcriptomics have expanded our understanding of cardiac cellular heterogeneity. The big-data strategies provide critical insights into why only a subset of CMs re-enter the cell cycle while most remain quiescent. In this review, we compare several high-throughput screening strategies used to identify novel targets for CM proliferation. We also summarize the benefits and limitations of various screening models—including zebrafish embryos, rodent CMs, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and cardiac organoids—underscoring the importance of integrating multiple systems to uncover new regenerative mechanisms. Further work is needed to identify translatable and safe targets capable of inducing functional CM expansion in clinical settings. By integrating high-throughput screening findings with insights into CM heterogeneity, this review provides a comprehensive framework for advancing cardiac regeneration research and guiding future therapeutic development. Full article

Cardiac hypertrophy is an important risk factor for heart failure and is often accompanied by contractile dysfunction. While hypertrophic growth contributes to disease progression, the underlying molecular mechanisms remain incompletely understood. A proposed contributor is a metabolic shift toward glucose uptake, suggesting that kinases regulating this process, such as protein kinase D1 (PKD1) and downstream target phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), might be effective targets to mitigate cardiac hypertrophy-induced contractile dysfunction. We investigated whether PI4KIIIβ inhibition downregulates enhanced glucose uptake in hypertrophic cardiomyocytes and thereby treats cardiac hypertrophy-induced contractile dysfunction. Hypertrophy was induced in cultured adult rat cardiomyocytes and human stem cell-derived cardiomyocytes using either phenylephrine (PE) or adenoviral PKD1 overexpression. PE-induced hypertrophy was associated with increased mRNA expression of BNP, activation of hypertrophic signaling, morphological alterations, enhanced protein synthesis and glucose uptake, and impaired contractile function. Treatment with the PI4KIIIβ inhibitor MI14 prevented and reversed PE-stimulated glucose uptake and contractile dysfunction, while hypertrophic signaling, cell size, and protein synthesis remained unaffected. Similar effects on glucose uptake were observed in the PKD1 overexpression model. These findings suggest that targeting myocardial substrate metabolism via the PI4KIIIβ pathway, rather than hypertrophic growth itself, could be a promising strategy to treat hypertrophy-induced contractile dysfunction. Full article

The cardiac extracellular matrix (ECM) is a dynamic, tissue-specific scaffold essential for cardiovascular development, homeostasis, and disease. Once considered a passive structural framework, the ECM is now recognized as an active regulator of mechanical, electrical, and biochemical signaling in the heart. Its composition evolves from embryogenesis through adulthood, coordinating cardiomyocyte maturation, chamber formation, and postnatal remodeling. In pathological states, diverse stimuli—including ischemia, pressure or volume overload, metabolic dysfunction, and aging—disrupt ECM homeostasis, triggering fibroblast activation, myofibroblast transformation, and maladaptive collagen deposition. These processes underpin myocardial fibrosis, a key driver of impaired contractility, diastolic dysfunction, arrhythmogenesis, and heart failure across ischemic and non-ischemic cardiac diseases. ECM alterations also exhibit age- and sex-specific patterns that influence susceptibility to cardiovascular pathology. Advances in imaging and circulating biomarkers have improved fibrosis assessment, though limitations persist. Therapeutic strategies targeting ECM remodeling, including modulation of profibrotic signaling pathways, non-coding RNAs, cellular therapies, and nano-delivery systems, show promise but remain largely experimental. Collectively, expanding knowledge of ECM biology highlights its central role in cardiovascular physiology and pathology and underscores the need for targeted diagnostic and therapeutic innovations. Full article

Cardiomyopathies represent a heterogeneous group of myocardial diseases that share overlapping clinical and genetic profiles but distinct morphological and molecular signatures. Advances in molecular genetics and next-generation sequencing have revolutionized the diagnostic landscape, revealing that up to 60% of cardiomyopathies have an identifiable genetic basis. From a pathologist’s perspective, integrating histopathological findings with molecular data is crucial for understanding genotype–phenotype correlations and for guiding precision medicine. This review provides an updated overview of the molecular pathology of major cardiomyopathy subtypes, including dilated, hypertrophic, restrictive, arrhythmogenic, and non-compaction forms. For each entity, we discuss morphologic hallmarks, genetic mechanisms, and their impact on disease progression and sudden cardiac death. Special emphasis is placed on the role of desmosomal, sarcomeric, and cytoskeletal proteins in myocardial structure and function, and on how their mutations disrupt cardiomyocyte integrity and signaling pathways. Furthermore, we address the emerging role of molecular autopsy in unexplained sudden cardiac death, underscoring the importance of multidisciplinary collaboration among pathologists, geneticists, and clinicians. Finally, we highlight future directions in molecular diagnostics and targeted therapies, which are reshaping the classification and management of cardiomyopathies. Full article

Background: Sepsis-induced myocardial dysfunction (SIMD) is a life-threatening complication with limited therapeutic options. Jaceosidin (JAC), a natural flavonoid from Folium Artemisiae Argyi, shows potential in cardiovascular diseases, but its role and mechanism in SIMD remain unclear. This study aims to investigate the protective effects of JAC against SIMD and explore the underlying molecular mechanisms. Methods: In vitro, AC16 human cardiomyocytes were stimulated with TNF-α and treated with JAC. Cell viability and apoptosis were assessed using CCK−8 and flow cytometry, respectively. Transcriptomic and metabolomic analyses were performed to identify altered pathways. Molecular docking evaluated JAC’s interaction with SIRT2. The SIRT2 inhibitor AGK2 was used to validate its role. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) determined H3K18la enrichment on target gene promoters. In vivo, a murine SIMD model was established via LPS injection, and cardiac function was evaluated by echocardiography. Serum markers (cTnT, CK−MB) and myocardial lactylation levels were measured. Results: JAC significantly attenuated TNF-α−induced injury in AC16 cells by enhancing viability and reducing apoptosis. Multi-omics analyses revealed JAC suppressed glycolysis and lactate production. JAC specifically inhibited histone H3K18 lactylation (H3K18la), and molecular docking indicated strong binding affinity with SIRT2. AGK2 treatment reversed JAC-mediated suppression of H3K18la. ChIP-qPCR confirmed H3K18la directly regulates IL-6, BAX, and BCL-2 expression. In vivo, JAC improved cardiac function (LVEF, LVFS, LVDd, LVDs), reduced serum cTnT and CK−MB levels, and decreased myocardial H3K18la in LPS−treated mice. Conclusions: JAC alleviates SIMD by activating SIRT2, which inhibits H3K18la, thereby modulating inflammatory and apoptotic pathways. This study identifies JAC as a novel metabolic-epigenetic therapeutic agent for SIMD. Full article

Mitochondrial dysfunction plays a central role in cardiac aging. Damaged mitochondria release excessive free radicals from the electron transport chain (ETC), leading to an increased production of reactive oxygen species (ROS). The accumulation of ROS, together with impaired ROS clearance mechanisms, results in oxidative stress, further disrupts mitochondrial dynamics, and diminishes bioenergetic capacity. Furthermore, the dysfunctional mitochondria exhibit an impaired endogenous antioxidant system, exacerbating this imbalance. These alterations drive the structural and functional deterioration of the aging heart, positioning mitochondria at the center of mechanisms underlying age-associated cardiovascular decline. In this review, we summarize the current evidence on how mitochondrial oxidative stress, mutations on mitochondrial DNA (mtDNA), and disruptions in the fission—fusion balance contribute to cardiomyocyte aging. This review also explores ways to mitigate oxidative stress, particularly with mitochondria-targeted antioxidants, and discusses the emerging potential of mitochondrial transplantation to replace dysfunctional mitochondria. Full article

Human induced pluripotent stem cells (hiPSCs) offer significant potential for differentiation and research applications in cardiovascular diseases. When induced differentiated hiPSC-derived cardiomyocytes (hiPSC-CMs) are transplanted into the infarcted myocardial region, they exhibit extremely low survival rates and unsatisfactory therapeutic effects due to ischemia, hypoxia, and immune inflammation in the surrounding environment. To address this issue, we used Panax notoginseng saponin R1 (NGR1), which has demonstrated significant protective effects in prior research, to pretreat hiPSC-CMs before transplantation. Utilizing an in vitro H₂O₂ oxidative stress model and a nude mouse myocardial infarction (MI) model, we investigated the mechanism through which NGR1 pretreatment enhances the therapeutic efficacy of hiPSC-CM transplantation. The results revealed that the hiPSC-CMs expressed cTnT. NGR1 did not promote the proliferation of hiPSC-CMs but instead induced elevated levels of p-Akt protein in these cells. Compared to hiPSC-CM transplantation alone, transplantation of hiPSC-CMs pretreated with NGR1 exhibited higher ejection fraction (EF) and fractional shortening (FS) values, along with reduced infarct size and collagen deposition. Additionally, there were more HNA-positive cardiomyocytes in the cardiac tissue, fewer TUNEL-positive signals, and increased VWF-positive and Lyve1-positive signals. Furthermore, the gene expression levels of VEGFC, IGF-1, and SDF-1 were higher. Therefore, NGR1 pretreatment improves the survival of transplanted hiPSC-CMs in tissues, reduces myocardial apoptosis, enhances cardiac function, decreases infarct size and collagen deposition, promotes angiogenesis and lymphangiogenesis, and stimulates paracrine secretion. Full article

Background/Objectives: Necroptosis is a critical process in the pathogenesis of myocardial ischemia–reperfusion injury (MIRI). Tilianin (Til), a natural flavonoid glycoside derived from Dracocephalum moldavica L., exhibits significant therapeutic potential in cardiovascular diseases. However, its efficacy and mechanisms in mitigating necroptosis-induced MIRI remain incompletely understood. This study aimed to elucidate the molecular mechanisms by which Til regulates cardiomyocyte necroptosis to alleviate MIRI. Methods: A rat model of MIRI was established by ligating the left anterior descending coronary artery. Necroptosis in H9c2 cardiomyocytes was induced by oxygen–glucose deprivation/reoxygenation (H/R) combined with Z-VAD-FMK. Myocardial infarct size was assessed using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Histopathological injury in cardiac tissue was examined by hematoxylin–eosin (HE) staining. Fluorescent probes were used to detect reactive oxygen species (ROS) and mitochondria. The molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) method was used to predict the binding energy between Til and RIP3. Furthermore, RIP3 overexpression and knockdown, along with inhibition of the downstream protein CaMKII, were used to further investigate the mechanism. Results: Til treatment significantly reduced MIRI in rats, decreased myocardial infarct size, histopathological injury, and regulated myocardial enzyme levels. Til pretreatment effectively inhibited necroptosis in H9c2 cells induced by H/R and Z-VAD-FMK, as evidenced by reduced necroptosis rates, decreased inflammatory cytokine release, improved mitochondrial function, and suppressed phosphorylation of the necroptosis marker MLKL. Molecular docking and dynamics simulation demonstrated stable binding of Til to RIP3, which was verified through Western blot. The protective effects of Til on necroptosis were reversed by RIP3 overexpression. Furthermore, the CaMKII inhibitor KN93 abolished Til’s effect on mitochondria. Conclusions: Til alleviates MIRI by targeting RIP3 to inhibit the necroptosis pathway and mPTP opening. These findings provide a new therapeutic strategy for MIRI and necroptosis-related diseases. Full article

Acute myocardial infarction (AMI) is a significant factor leading to the death of patients with coronary heart disease. Both AMI and reperfusion therapy after AMI cause myocardial cell death, which plays a significant role in heart failure. Following the restoration of blood flow during reperfusion, myocardial cells generate a large amount of oxygen free radicals, causing various forms of myocardial ischemia–reperfusion (IR) injury (IRI), ultimately leading to multiple types of myocardial cell death, among which apoptosis and necroptosis are the two major types. Given the extremely limited regenerative capacity of myocardium, inhibiting myocardial cell apoptosis and necroptosis is a key strategy for reducing mortality in patients with AMI. Both apoptosis and necroptosis are regulated by the BCL2 family of proteins, which were modulated by multiple signaling pathways, converging at BAK/BAX-mediated mitochondrial outer membrane permeabilization (MOMP), as well as mitochondrial inner membrane permeabilization (MIMP). BAK/BAX double knock out (DKO) mice showed reduced cell apoptosis, necroptosis, and infarct size in AMI animal models compared to wild type. This review describes the role of BCL2 family proteins in regulating apoptotic and necroptotic myocardial cell death during AMI and IR, explores the upstream pathways modulating apoptosis and necroptosis, and summarizes the recent advances in targeting BAK and/or BAX for cardiac protection. In addition, targeted delivery of BAK/BAX inhibitors to cardiomyocytes during AMI or myocardial IR has the potential to reduce myocardial cell death and therefore lower the mortality and enhance long-term prognosis for myocardial infarction patients. Full article

Background: Parvovirus B19 (B19V; Erythroparvovirus primate 1) is now the most commonly detected virus in human endomyocardial biopsies from patients with myocarditis or dilated cardiomyopathy; however, its true causal role remains uncertain. By contrast, Protoparvovirus carnivoran 1, also known as canine parvovirus type 2 (CPV-2), is an apparent cause of myocarditis in neonatal puppies, where it replicates in cardiomyocytes, induces extensive cell death, and often leaves fibrotic scars in survivors. Conclusions: This review compares B19V and CPV-2 from basic biology to clinical expression. Divergent tropism and replication kinetics produce distinct injury patterns: predominantly endothelial and microvascular dysfunction with immune-mediated damage in adult human B19V infection versus direct, age-restricted cardiomyocyte lysis in neonatal CPV-2 infection, often followed by fibrosis. Because parvoviral DNA can persist in cardiac tissue, detection alone does not prove causality. We advocate an “evidence bundle” integrating viral load by quantitative polymerase chain reaction (qPCR), detection of viral transcripts and/or proteins when feasible, spatial co-localization with histological injury, and concordant clinical markers (cardiac troponins and advanced imaging, including cardiac magnetic resonance imaging [CMR]) to support etiologic attribution and guide management in human and veterinary cardiology. Full article

Microfluidic technologies have ushered in a new era in cardiac tissue engineering, providing more predictive in vitro models compared to two-dimensional culture studies. This review examines Organ-on-a-Chip (OoC) and Lab-on-a-Chip (LoC) platforms, with a specific focus on cardiovascular applications. OoCs, and particularly Heart-on-a-Chip systems, have advanced biomimicry to a higher level by recreating complex 3D cardiac microenvironments in vitro and dynamic fluid flow. These platforms employ induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), engineered extracellular matrices, and dynamic mechanical and electrical stimulation to reproduce the structural and functional features of myocardial tissue. LoCs have introduced miniaturization and integration of analytical functions into compact devices, enabling high-throughput screening, advanced diagnostics, and efficient pharmacological testing. They enable the investigation of pathophysiological mechanisms, the assessment of cardiotoxicity, and the development of precision medicine approaches. Furthermore, progress in multi-organ systems expands the potential of microfluidic technologies to simulate heart–liver, heart–kidney, and heart–tumor interactions, providing more comprehensive predictive models. However, challenges remain, including the immaturity of iPSC-derived cells, the lack of standardization, and scalability issues. In general, microfluidic platforms represent strategic tools for advancing cardiovascular research in translation and accelerating therapeutic innovation within precision medicine. Full article