Cardiomyocytes Research Articles

AN EFFICIENT FRACTAL CARDIO DISEASES ANALYSIS USING OPTIMIZED DEEP LEARNING MODEL IN CLOUD OF THING CONTINUUM ARCHITECTURE

Exercise has long been known to improve cardiovascular health, energy metabolism, and well-being. However, myocardial cell responses to exercise are complex and multifaceted due to their molecular pathways. To understand cardiac physiology and path physiology, one must understand these pathways, including energy autophagy. In recent years, deep learning techniques, IoT devices, and cloud computing infrastructure have enabled real-time, large-scale biological data analysis. The objective of this work is to extract and analyze autophagy properties in exercise-induced cardiac cells in a cloud-IoT context using deep learning, more especially an autoencoder. The Shanghai University of Sport Ethics Committee for Science Research gave its approval for the data collection, which involved 150 male Sprague–Dawley (SD) rats that were eight weeks old and in good health. The [Formula: see text]-score normalization method was used to standardize the data. Fractal optimization methods could be applied to these algorithms. For example, fractal-inspired optimization techniques might be used to analyze deep learning with Autoencoder, the autography energy of exercise myocardial cells within a cloud-IoT. To capture the intricate myocardial energy autophagy during exercise, we introduced the DMO-GCNN-Autoencoder, a Dwarf Mongoose Optimized Graph Convolutional Neural Network. The results showed that the proposed network’s performance matches that of the existing methods.

Differential Effects of Four Canonical Notch-Activating Ligands on c-Kit+ Cardiac Progenitor Cells.

Notch signaling, an important signaling pathway in cardiac development, has been shown to mediate the reparative functions of c-kit+ progenitor cells (CPCs). However, it is unclear how each of the four canonical Notch-activating ligands affects intracellular processes in c-kit+ cells when used as an external stimulus. Neonatal c-kit+ CPCs were stimulated using four different chimeric Notch-activating ligands tethered to Dynabeads, and the resulting changes were assessed using TaqMan gene expression arrays, with subsequent analysis by principal component analysis (PCA). Additionally, functional outcomes were measured using an endothelial cell tube formation assay and MSC migration assay to assess the paracrine capacity to stimulate new vessel formation and recruit other reparative cell types to the site of injury. Gene expression data showed that stimulation with Jagged-1 is associated with the greatest pro-angiogenic gene response, including the expression of VEGF and basement membrane proteins, while the other canonical ligands, Jagged-2, Dll-1, and Dll-4, are more associated with regulatory and epigenetic changes. The functional assay showed differential responses to the four ligands in terms of angiogenesis, while none of the ligands produced a robust change in migration. These data demonstrate how the four Notch-activating ligands differentially regulate CPC gene expression and function.

A recombinant fragment antigen-binding (Fab) of trastuzumab displays low cytotoxic profile in adult human cardiomyocytes: first evidence and the key implication of FcγRIIA receptor.

Fragment crystallizable gamma receptors (FcγRs) mediate various cellular responses with significant cardiovascular implications. They contribute to the anticancer activity of trastuzumab (TRZ), a recombinant humanized monoclonal antibody that interferes with human epidermal growth factor receptor 2 (HER2), thereby blocking its physiological function in cardiac cells. This is responsible for cardiac complications that hamper TRZ clinical application. In this study we investigated the involvement of FcγRs in the TRZ cardiotoxicity. We used a recombinant antigen-binding fragment (Fab) of TRZ (rFab-HER2) to examine whether the absence of the Fc region resulted in fewer cardiomyocyte toxicity while preserving TRZ's ability to inhibit HER2. When exposed to rFab-HER2, AC16 human adult ventricular cardiomyocytes were less vulnerable to damage and death, than to TRZ. Specifically, TRZ exhibited cytotoxicity at a lower concentration (150 µg/mL, corresponding to ~1 µM) compared to rFab-HER2 (250 µg/mL, corresponding to ~5 µM). Like TRZ, rFab-HER2 negatively modulated HER2 levels in cardiomyocyte (without inducing cytotoxic activity in BJ human fibroblast cells that either did not express or express very low levels of HER2) and inhibited the downstream ERK/AKT cascades. But rFab-HER2 did not alter cardiomyocyte mitochondrial dynamic balance, and affect apoptosis and inflammation, while it limited cytosolic and mitochondrial ROS indicators. On contrary, the Fc region (50-250 μg/mL) exerted direct cytotoxic action on cardiomyocytes (but not on human fibroblasts that lacked Fc receptors). TRZ (150 μg/mL) markedly upregulated the expression level of FcγRIIA (a FcγRs strongly involved in TRZ-induced antibody-dependent cellular toxicity) in cardiomyocytes, whereas the Fab fragment (150 μg/mL) had no effect. Our results demonstrate that Fc region plays an important pathogenic role in TRZ-induced cardiomyocyte toxicity. In addition, targeting FcγRIIA might contribute to the off-target effects of TRZ therapy.

Neutrophil N1 polarization induced by cardiomyocyte-derived extracellular vesicle miR-9-5p aggravates myocardial ischemia/reperfusion injury

Neutrophil polarization contributes to inflammation and its resolution, but the role of neutrophil polarization in myocardial ischemia/reperfusion (I/R) injury remains unknown. Cardiomyocytes (CMs) participate in cardiac inflammation by secreting extracellular vesicles (EVs). Therefore, we investigated the role of neutrophil polarization in myocardial I/R injury and the mechanism by which CM-derived EVs regulated neutrophil polarization. In the present study, our data showed that N1 neutrophil polarization enlarged cardiac infarct size and exacerbated cardiac dysfunction at the early stage of myocardial I/R. Further, CM-EV-derived miR-9-5p was identified as a mediator inducing neutrophils to the N1 phenotype. Mechanistically, miR-9-5p directly suppressed SOCS5 and SIRT1 expression, resulting in activating JAK2/STAT3 and NF-κB signaling pathways in neutrophils. Importantly, we confirmed that serum EV-derived miR-9-5p levels were independently associated with cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. These findings suggest neutrophil polarization is a promising therapeutic target against myocardial I/R-induced inflammation and injury, and serum EV-derived miR-9-5p is a promising prognostic biomarker for cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.Graphical

TRAITER: Transformer-guided diagnosis and prognosis of heart failure using cell nuclear morphology and DNA damage marker.

Heart failure (HF), a major cause of morbidity and mortality, necessitates precise diagnostic and prognostic methods. This study presents a novel deep learning approach, Transformer-based Analysis of Images of Tissue for Effective Remedy (TRAITER), for HF diagnosis and prognosis. Employing image segmentation techniques and a Vision Transformer, TRAITER predicts HF likelihood from cardiac tissue cell nuclear morphology images and the potential for left ventricular reverse remodeling (LVRR) from dual-stained images with cell nuclei and DNA damage markers. In HF prediction using 31,158 images from 9 patients, TRAITER achieved 83.1% accuracy. For LVRR prediction with 231,840 images from 46 patients, TRAITER attained 84.2% accuracy for individual images and 92.9% for individual patients. TRAITER outperformed other neural network models in terms of receiver operating characteristics, and precision-recall curves. Our method promises to advance personalized HF medicine decision-making. The source code and data are available at the following link: Https://github.com/HamanoLaboratory/predict-of-HF-and-LVRR. Supplementary data are available at Bioinformatics online.

Investigating the Impact of Microgravity on Stem Cells for Cardiovascular Disease Treatment

Cardiovascular disease is a widespread cause of physical disability, and while treatment options result in reduced mortality, they are still limited in their capabilities for cardiac repair. Since their discovery, the regenerative capacities of stem cells have been hypothesized to one day reverse countless diseases. Current stem cell research in cardiovascular disease has delineated the regenerative capabilities of bone marrow–derived mesenchymal stem cells, induced pluripotent stem cells, and cardiac stem cells, but has its limitations. Additionally, current therapies reduce mortality rates and the risk of recurrent myocardial infarctions and damage, but they do not address the apparently irreversible remodeling of myocardial tissue, which is linked to frequent hospitalizations and a diminished quality of life. As researchers continue to investigate the most efficacious growth mediums for stem cells, microgravity appears to be a supportive environment for stem cell growth. Thus, this review aims to catalogue existing research on microgravity’s differing effects on various stem cell lineages and what implications it may have on the treatment of cardiovascular diseases. Cells grown under these conditions have increased expression of cardioprotective proteins and improved proliferative capacities but may have elevated tumorigenic potential and hypertrophic pathways. Additionally, the results of microgravity’s effects on stem cells are mixed. Nonetheless, microgravity’s impact on the cytoskeleton, overexpression of electrical contraction receptors, and increased proliferative and pluripotent effects make these cells promising avenues for potential improved clinical treatment options.

Cardiac Matrix-Derived Granular Hydrogel Enhances Cell Function in 3D Culture.

Hydrogels derived from decellularized porcine myocardial matrix have demonstrated significant potential as therapeutic delivery platforms for promoting cardiac repair after injury. Our previous study developed a fibrin-enriched cardiac matrix hydrogel to enhance its angiogenic capacities. However, the bulk hydrogel structure may limit their full potential in cell delivery. Recently, granular hydrogels have emerged as a promising class of biomaterials, offering unique features such as a highly interconnected porous structure that facilitates nutrient diffusion and enhances cell viability. Several techniques have been developed for fabricating various types of granular hydrogels, among which extrusion fragmentation is particularly appealing due to its adaptability to many types of hydrogels, low cost, and high scalability. In this study, we first confirmed the effects of the bulk cardiac matrix hydrogel on the viability of encapsulated human umbilical vein endothelial cells and human mesenchymal stem cells. We then tested the feasibility of producing granular hydrogels from both cardiac matrix and fibrin-enriched cardiac matrix through cellular cross-linking of microgels fabricated by extrusion fragmentation. Afterward, we examined the roles of the produced granular hydrogels in the embedded cells and cell spheroids. Our in vitro data demonstrate that cardiac matrix-derived granular hydrogels support optimal viability of encapsulated cells and promote sprouting of human mesenchymal stem cell spheroids. Additionally, granular hydrogel derived from fibrin-enriched cardiac matrix accelerates angiogenic sprouting of embedded human mesenchymal stem cell spheroids. The results obtained from this study lay an important foundation for the future exploration of using cardiac matrix-derived granular hydrogels for cardiac cell therapy.

Transient Inhibition of Translation Improves Cardiac Function After Ischemia/Reperfusion by Attenuating the Inflammatory Response.

The myocardium adapts to ischemia/reperfusion (I/R) by changes in gene expression, determining the cardiac response to reperfusion. mRNA translation is a key component of gene expression. It is largely unknown how regulation of mRNA translation contributes to cardiac gene expression and inflammation in response to reperfusion and whether it can be targeted to mitigate I/R injury. To examine translation and its impact on gene expression in response to I/R, we measured protein synthesis after reperfusion in vitro and in vivo. Underlying mechanisms of translational control were examined by pharmacological and genetic targeting of translation initiation in mice. Cell type-specific ribosome profiling was performed in mice that had been subjected to I/R to determine the impact of mRNA translation on the regulation of gene expression in cardiomyocytes. Translational regulation of inflammation was studied by quantification of immune cell infiltration, inflammatory gene expression, and cardiac function after short-term inhibition of translation initiation. Reperfusion induced a rapid recovery of translational activity that exceeds baseline levels in the infarct and border zone and is mediated by translation initiation through the mTORC1 (mechanistic target of rapamycin complex 1)-4EBP1 (eIF4E-binding protein 1)-eIF (eukaryotic initiation factor) 4F axis. Cardiomyocyte-specific ribosome profiling identified that I/R increased translation of mRNA networks associated with cardiac inflammation and cell infiltration. Short-term inhibition of the mTORC1-4EBP1-eIF4F axis decreased the expression of proinflammatory cytokines such as Ccl2 (C-C motif chemokine ligand 2) of border zone cardiomyocytes, thereby attenuating Ly6Chi monocyte infiltration and myocardial inflammation. In addition, we identified a systemic immunosuppressive effect of eIF4F translation inhibitors on circulating monocytes, directly inhibiting monocyte infiltration. Short-term pharmacological inhibition of eIF4F complex formation by 4EGI-1 or rapamycin attenuated translation, reduced infarct size, and improved cardiac function after myocardial infarction. Global protein synthesis is inhibited during ischemia and shortly after reperfusion, followed by a recovery of protein synthesis that exceeds baseline levels in the border and infarct zones. Activation of mRNA translation after reperfusion is driven by mTORC1/eIF4F-mediated regulation of initiation and mediates an mRNA network that controls inflammation and monocyte infiltration to the myocardium. Transient inhibition of the mTORC1-/eIF4F axis inhibits translation and attenuates Ly6Chi monocyte infiltration by inhibiting a proinflammatory response at the site of injury and of circulating monocytes.

The Potential Health Risks of Catha edulis Forsk (Khat) Consumption on Some Vital Organs

Abstract Introduction/Objective Introduction: Catha edulis Forsk (Khat) leaves are widely chewed by adults in the Arabian Peninsula and the Horn of Africa for their mild stimulating properties. Objectives To investigate the impact of an aqueous extract of Catha edulis Forsk leaves on the proper functioning of vital organs. Methods/Case Report Methods: Materials and methods: Twenty-five female albino rats were divided into two groups: a control group and a treated group which received a daily gavage of 1 ml of aqueous Khat extract with a concentration of 700 mg/kg body weight for four weeks. The effects of this treatment on selected organs, including the brain, hippocampus, heart, and ovaries, were assessed using various measurements and analyses. Results (if a Case Study enter NA) Results: Results: The antioxidant evaluation showed a significant increase in MDA levels in the khat group and a significant decrease in GSH, SOD, and CAT levels compared to the control group. There was a significant decrease in IL-4 and a significant increase in TNF-α and TGF-β1 compared to the control group. In contrast, the cardiac enzymes; Troponin, CK, CPK, and GOT showed a significant increase compared to the control group. The results of the hormonal assay indicated a significant increase in LH, FSH, and testosterone levels, along with a significant decrease in estrogen in the khat group compared to the control group. Furthermore, the histological investigations revealed significant changes in tissue architecture in the studied organs. In the heart, the treated group exhibited an intact, thick pericardium, along with markedly apoptotic cardiac muscle fibers and others with pyknotic nuclei and mildly congested blood vessels and capillaries. The examination of brain tissues in the treated group showed thick meninges with mild inflammatory infiltrate, marked astrogliosis with degenerated neurons in the cerebral cortex, inflammatory infiltrate with abscess formation and mildly congested blood vessels and eosinophilic plaque-like area in the deep cortex, and scattered degenerated neurons and some neurons with nuclear vacuoles and average glial cells in the white matter. In the ovaries, sections showed primary, secondary, and antral follicles, scattered cystically dilated follicles with atrophied lining, and multiple corpora lutea in the edematous stroma with scattered apoptotic stromal cells. Conclusion Based on these findings, long-term use of khat as a chewing material may harm vital organs.

Causes and consequences of DNA double-stranded breaks in cardiovascular disease.

The genome, whose stability is essential for survival, is incessantly exposed to internal and external stressors, which introduce an estimated 104 to 105 lesions, such as oxidation, in the nuclear genome of each mammalian cell each day. A delicate homeostatic balance between the generation and repair of DNA lesions maintains genomic stability. To initiate transcription, DNA strands unwind to form a transcription bubble and provide a template for the RNA polymerase II (RNAPII) complex to synthesize nascent RNA. The process generates DNA supercoils and introduces torsional stress. To enable RNAPII processing, the supercoils are released by topoisomerases by introducing strand breaks, including double-stranded breaks (DSBs). Thus, DSBs are intrinsic genomic features of gene expression. The breaks are quickly repaired upon processing of the transcription. DNA lesions and damaged proteins involved in transcription could impede the integrity and efficiency of RNAPII processing. The impediment, which is referred to as transcription stress, not only could lead to the generation of aberrant RNA species but also the accumulation of DSBs. The latter is particularly the case when topoisomerase processing and/or the repair mechanisms are compromised. The DSBs activate the DNA damage response (DDR) pathways to repair the damaged DNA and/or impose cell cycle arrest and cell death. In addition, the release of DSBs into the cytosol activates the cytosolic DNA-sensing proteins (CDSPs), which along with the nuclear DDR pathways induce the expression of senescence-associated secretory phenotype (SASP), cell cycle arrest, senescence, cell death, inflammation, and aging. The primary stimulus in hereditary cardiomyopathies is a mutation(s) in genes encoding the protein constituents of cardiac myocytes; however, the phenotype is the consequence of intertwined complex interactions among numerous stressors and the causal mutation(s). Increased internal DNA stressors, such as oxidation, alkylation, and cross-linking, are expected to be common in pathological conditions, including in hereditary cardiomyopathies. In addition, dysregulation of gene expression also imposes transcriptional stress and collectively with other stressors provokes the generation of DSBs. In addition, the depletion of nicotinamide adenine dinucleotide (NAD), which occurs in pathological conditions, impairs the repair mechanism and further facilitates the accumulation of DSBs. Because DSBs activate the DDR pathways, they are expected to contribute to the pathogenesis of cardiomyopathies. Thus, interventions to reduce the generation of DSBs, enhance their repair, and block the deleterious DDR pathways would be expected to impart salubrious effects not only in pathological states, as in hereditary cardiomyopathies but also aging.

Case of Bone Morphogenetic Protein Receptor Type 2 (BMPR2) Mutation Complicated by Pulmonary Hypertension Encountered at Autopsy

Abstract Introduction/Objective Bone morphogenetic protein receptor type 2 is a protein encoded by the BMPR2 gene which regulates cell division and apoptosis. BMPR2 mutations result in monoclonal plexiform lesions of proliferating endothelial cells in pulmonary arterioles, which leads to elevated pulmonary artery pressures, right ventricular failure, and death. Here, we present the case of a 12-year-old male with a known history of pulmonary hypertension secondary to BMPR2 mutation referred for medical autopsy after suffering cardiac arrest and passing away. Methods/Case Report This 12-year-old male was diagnosed with pulmonary hypertension in December 2022 after suffering a syncopal episode while running at recess. Genetic testing was obtained, and he was found to have a BMPR2 mutation. His father was tested and also harbored this mutation, but did not clinically have pulmonary hypertension. The decedent was initiated on ambrisentan, tadalafil, and spironolactone, but continued to present to the Emergency Department periodically for syncopal episodes. In April 2024, he presented to the Medical University of South Carolina in cardiac arrest which began while playing outside. A complete autopsy was performed, including gross and microscopic examination of tissues and postmortem vitreous electrolyte analysis. Gross examination revealed the decedent’s heart was enlarged to 350 grams (normal mean for age = 181 grams). Both cardiac ventricles were dilated and the right ventricle was markedly hypertrophic with a thickness of 1.2 cm. Microscopic sections are pending but will presumptively show significant cardiac myocyte hypertrophy and pulmonary arteriole thickening. Cause of death is pending certification but is presumed to be sudden cardiac death resulting from BMPR2 mutation- related pulmonary hypertension. Results (if a Case Study enter NA) NA Conclusion This case highlights a common genetic presentation of pulmonary arterial hypertension, with approximately 80% of familial cases of pulmonary arterial hypertension harboring BMPR2 mutations. Further research should be done to investigate treatment options and management of this genetic presentation.

Magnitude of cardiac abnormality and its associated factors among hyperthyroidism patients on follow-up at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia

BackgroundThyroid hormones have an effect on every organ system, in particular, the heart responds to minimal changes in serum thyroid hormone level. Thyroid hormone causes a lot of changes in the cardiovascular system, such as increased heart rate, contractility, systolic hypertension, changes in peripheral vascular resistance, atrial fibrillation (AF), and hypercoagulability from the direct effect of thyroid hormone on cardiac myocyte and /or due to increased metabolic state. However, the magnitude of such heart abnormalities and its associated factors were not well studied in Ethiopia.ObjectiveTo determine the magnitude of cardiac abnormality and its associated factors among hyperthyroidism patients on follow-up at Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia, 2022.MethodsAn institution-based cross-sectional study was carried out among 318 hyperthyroid patients who were on follow-up at the endocrine clinic of TASH, Addis Ababa, Ethiopia from June to October 2022. The data were collected using a pretested structured interviewer administered questionnaire. The data were entered into the computer using EpiData version 3.1 and analyzed using SPSS version 25 software. Bivariable and multivariable logistic regression models were fitted to determine the association between the independent and dependent variables. Adjusted odds ratio with its 95% confidence interval and p-value < 0.05 were used to declare the presence and strength of statistically significant associations.ResultIn this study a total of 318 hyperthyroid patients were participated, most (90.9%) of them were females. The overall prevalence of heart failure among hyperthyroid patients was 17.0% (95% CI = 13.0, 21.6). More than half (52.7%) and one third (33.2%) of the participants showed abnormal electrocardiographic and echocardiographic findings respectively. Marital status (not married) [AOR = 2.37, 95% CI (1.03, 5.44)], pattern of hyperthyroidism [AOR = 13.09, 95% CI (4.70, 36.41)], being Asthmatic [AOR = 7.63, 95% CI (1.55, 37.52)], type of medication [AOR = 3.49, 95% CI (1.11, 11.02)] and duration of treatment [AOR = 4.95, 95% CI (2.05,11.99)] were significantly associated with cardiac abnormality.ConclusionA significant portion of hyperthyroid patients overburdened by cardiac abnormalities. Being unmarried, overt hyperthyroid, Asthmatic, long stay on treatment and type of treatment were significantly associated with cardiac abnormality. Hence, attention should be given for cardiac abnormalities while treating hyperthyroid patients.

Formulation, Optimization, and Evaluation of Solid-lipid Formulation for Bioavailability Enhancement Utilizing Diltiazem Hydrochloride

Background: Cardiac arrhythmia is a health concern, requiring effective medication for proper treatment. Diltiazem hydrochloride (DTZ.HCL), a class IV anti-arrhythmic calcium channel blocker, was used as a model drug due to its ability to block Ca++ channels in the SA and AV nodes, reducing calcium entry into cardiac cells and subsequently decreasing the force of contraction and oxygen consumption by the heart. Despite its good oral absorption, DTZ.HCL bioavailability is reduced to approximately 40% due to extensive first-pass metabolism. A nano-enabled drug delivery system has the advantage of incorporating both lipophilic and hydrophilic drugs with improved physical stability and enhanced bioavailability. Objective: The objective of this study was to develop a solid-lipid formulation utilizing diltiazem hydrochloride and evaluate it for its bioavailability enhancement. Method: In the experimental study, SLNs were prepared using the microemulsion technique. A blend ratio (1:1) of lipid (stearic acid: compritol 888 ATO), span 80, PEG 200, and water was selected based on the microemulsion region obtained from the Triplot (4.1) ternary phase diagram. The hydrophilic drug diltiazem hydrochloride was incorporated into the lipid blend, and a preheated Smix was maintained at 80°C to obtain a transparent microemulsion, which then crystallized to form SLNs upon subsequent dispersion in cold water (1:25). Critical process parameters, including magnetic stirring speed, homogenizer speed, and probe sonication cycle, were optimized using Design Expert 10 software to achieve the desired particle size diameter, PDI, and entrapment efficiency. Results: The results revealed that the particle size and PDI were significantly influenced by the span 80 and PEG 200. An increase in the concentration of the lipid blend resulted in large particle sizes. The optimized formulation showed a particle size of 415.4±0.2 nm, PDI of 0.184±0.01, and zeta potential of -24.19±0.12 mV. These results were corroborated by DSC thermograms, which indicated reduced enthalpy associated with the reduced particle size of SLNs. Given that diltiazem hydrochloride is a hydrophilic drug with high water solubility, the entrapment efficiency was relatively 30.6% ±0.45. In vitro release studies demonstrated an initial burst release, followed by a sustained release of 85% over 24 hours. The optimized SLNs followed the Higuchi matrix model, with a coefficient of correlation (R²) value of 0.9369. Conclusion: Results concluded successful development of SLNs with improved bioavailability when compared by way of in-vitro method with marketed preparations.

FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy.

Fibroblast growth factor (FGF) 23 is a bone-derived hormone that promotes renal phosphate excretion. Serum FGF23 is increased in chronic kidney disease (CKD) and contributes to pathologic cardiac hypertrophy by activating FGF receptor (FGFR) 4 on cardiac myocytes, which might lead to the high cardiovascular mortality in CKD patients. Increases in serum FGF23 levels have also been observed following endurance exercise and in pregnancy, which are scenarios of physiologic cardiac hypertrophy as an adaptive response of the heart to increased demand. To determine whether FGF23/FGFR4 contributes to physiologic cardiac hypertrophy, we studied FGFR4 knockout mice (FGFR4-/-) during late pregnancy. In comparison to virgin littermates, pregnant wild-type and FGFR4-/- mice showed increases in serum FGF23 levels and heart weight; however, the elevation in myocyte area observed in pregnant wild-type mice was abrogated in pregnant FGFR4-/- mice. This outcome was supported by treatments of cultured cardiac myocytes with serum from fed Burmese pythons, another model of physiologic hypertrophy, where the co-treatment with an FGFR4-specific inhibitor abrogated the serum-induced increase in cell area. Interestingly, we found that in pregnant mice, the heart, and not the bone, shows elevated FGF23 expression, and that increases in serum FGF23 are not accompanied by changes in phosphate metabolism. Our study suggests that in physiologic cardiac hypertrophy, the heart produces FGF23 that contributes to hypertrophic growth of cardiac myocytes in a paracrine and FGFR4-dependent manner, and that the kidney does not respond to heart-derived FGF23.

Extracellular vesicles from human cardiac stromal cells up-regulate cardiomyocyte protective responses to hypoxia

BackgroundCell therapy can protect cardiomyocytes from hypoxia, primarily via paracrine secretions, including extracellular vesicles (EVs). Since EVs fulfil specific biological functions based on their cellular origin, we hypothesised that EVs from human cardiac stromal cells (CMSCLCs) obtained from coronary artery bypass surgery may have cardioprotective properties.ObjectivesThis study characterises CMSCLC EVs (C_EVs), miRNA cargo, cardioprotective efficacy and transcriptomic modulation of hypoxic human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). C_EVs are compared to bone marrow mesenchymal stromal cell EVs (B_EVs) which are a known therapeutic EV type.MethodsCells were characterised for surface markers, gene expression and differentiation potential. EVs were compared for yield, phenotype, and ability to protect hiPSC-CMs from hypoxia/reoxygenation injury. EV dose was normalised by both protein concentration and particle count, allowing direct comparison. C_EV and B_EV miRNA cargo was profiled and RNA-seq was performed on EV-treated hypoxic hiPSC-CMs, then data were integrated by multi-omics. Confirmatory experiments were carried out using miRNA mimics.ResultsAt the same dose, C_EVs were more effective than B_EVs at protecting CM integrity, reducing apoptotic markers, and cell death during hypoxia. While C_EVs and B_EVs shared 70–77% similarity in miRNA content, C_EVs contained unique miRNAs, including miR-202-5p, miR-451a and miR-142-3p. Delivering miRNA mimics confirmed that miR-1260a and miR-202/451a/142 were cardioprotective, and the latter upregulated protective pathways similar to whole C_EVs.ConclusionsThis study demonstrates the potential of cardiac tissues, routinely discarded following surgery, as a valuable source of EVs for myocardial infarction therapy. We also identify miR-1260a as protective of CM hypoxia.

Mitochondrial Dysfunction as a Potential Mechanism Mediating Cardiac Comorbidities in Parkinson’s Disease

Individuals diagnosed with Parkinson’s disease (PD) often exhibit heightened susceptibility to cardiac dysfunction, reflecting a complex interaction between these conditions. The involvement of mitochondrial dysfunction in the development and progression of cardiac dysfunction and PD suggests a plausible commonality in some aspects of their molecular pathogenesis, potentially contributing to the prevalence of cardiac issues in PD. Mitochondria, crucial organelles responsible for energy production and cellular regulation, play important roles in tissues with high energetic demands, such as neurons and cardiac cells. Mitochondrial dysfunction can occur in different and non-mutually exclusive ways; however, some mechanisms include alterations in mitochondrial dynamics, compromised bioenergetics, biogenesis deficits, oxidative stress, impaired mitophagy, and disrupted calcium balance. It is plausible that these factors contribute to the increased prevalence of cardiac dysfunction in PD, suggesting mitochondrial health as a potential target for therapeutic intervention. This review provides an overview of the physiological mechanisms underlying mitochondrial quality control systems. It summarises the diverse roles of mitochondria in brain and heart function, highlighting shared pathways potentially exhibiting dysfunction and driving cardiac comorbidities in PD. By highlighting strategies to mitigate dysfunction associated with mitochondrial impairment in cardiac and neural tissues, our review aims to provide new perspectives on therapeutic approaches.

HDAC7 promotes cardiomyocyte proliferation by suppressing Myocyte Enhancer Factor 2.

Postnatal mammalian cardiomyocytes (CMs) rapidly lose proliferative capacity and exit the cell cycle and undergo further differentiation and maturation. Cell cycle activation has been a major strategy to stimulate postnatal CM proliferation, albeit achieving modest effects. One impediment is that postnatal CMs may need to undergo dedifferentiation before proliferation, if not simultaneously. Here, we report that overexpression of Hdac7 in neonatal mouse CMs results in significant CM dedifferentiation and proliferation. Mechanistically, we show that HDAC7-mediated CM proliferation is contingent on dedifferentiation, which is accomplished through suppressing MEF2. Hdac7 overexpression in CM shifts the chromatin state from binding MEF2, which favors the differentiation transcriptional program to AP-1, which favors the proliferative transcriptional program. Further, we found that HDAC7 interacts with minichromosome maintenance complex (MCM) components to initiate cell cycle progression. Our findings reveal that HDAC7 promotes CM proliferation by its dual action on CM dedifferentiation and proliferation, uncovering a potential new strategy for heart regeneration/repair.

Shaping cardiac destiny: the role of post-translational modifications on endoplasmic reticulum - mitochondria crosstalk in cardiac remodeling.

Cardiac remodeling is a shared pathological change in most cardiovascular diseases. Encompassing both adaptive physiological responses and decompensated pathological changes. Anatomically, atrial remodeling is primarily caused by atrial fibrillation, whereas ventricular remodeling is typically induced by myocardial infarction, hypertension, or cardiomyopathy. Mitochondria, the powerhouse of cardiomyocytes, collaborate with other organelles such as the endoplasmic reticulum to control a variety of pathophysiological processes such as calcium signaling, lipid transfer, mitochondrial dynamics, biogenesis, and mitophagy. This mechanism is proven to be essential for cardiac remodeling. Post-translational modifications can regulate intracellular signaling pathways, gene expression, and cellular stress responses in cardiac cells by modulating protein function, stability, and interactions, consequently shaping the myocardial response to injury and stress. These modifications, in particular phosphorylation, acetylation, and ubiquitination, are essential for the regulation of the complex molecular pathways that underlie cardiac remodeling. This review provides a comprehensive overview of the crosstalk between the endoplasmic reticulum and mitochondria during cardiac remodeling, focusing on the regulatory effects of various post-translational modifications on these interactions.

SnRNA-seq reveals differential functional transcriptional pathway alterations in three mutant types of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, characterized by ventricular dilation, thinning of the ventricular walls, and systolic dysfunction in either the left or both ventricles, often accompanied by fibrosis. Human cardiac tissue is composed of various cell types, including cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), macrophages, lymphocytes and so on. In DCM patients, these cells frequently undergo functional and phenotypic changes, contributing to contractile dysfunction, inflammation, fibrosis, and cell death, thereby increasing the risk of heart failure. This study focuses on DCM patients with mutations (LMNA, RBM20, and TTN) and analyzes functional changes in subpopulations of four cardiac cell types. The study involves functional annotation of subpopulations within each cell type and explores the association between gene mutations and specific functions and pathways. Additionally, the SCENIC method is employed of a particular cell subpopulation with significant functional importance, aiming to identify key transcriptional regulators in specific cell states. By analyzing the expression levels of ligand-receptor pairs in vCM4, vFB2, EC5.0, T cells, and NK cells across the DCM mutant genotypes, we predicted their signaling pathways and communications. This research provides insights into the molecular mechanisms of DCM and potential therapeutic targets.

Cdk1 Deficiency Extends the Postnatal Window of Cardiomyocyte Proliferation and Restores Cardiac Function after Myocardial Infarction.

Cyclin-dependent kinase 1 (Cdk1) is a master regulator of the G2-M transition between DNA replication and cell division. This study investigates the regulation of cardiomyocyte (CM) proliferation during the early neonatal period and following ischemic injury in adult mice. We analyzed cell cycle dynamics with the assessment of DNA synthesis, and cytokinesis in murine hearts during the first 15 days after birth. A distinct proliferative block was observed at 1 day, followed by a second wave of DNA synthesis at 4 days, leading to CM binucleation (CMBN) by day 5. Genome-wide mRNA profiling revealed the differential expression of cell cycle regulatory genes during this period, with a downregulation of factors involved in cell division and mitosis. The loss of Cdk1 impaired CMBN but extended the neonatal CM proliferation window until day 10 post-birth. In adult hearts, the cardiac-specific ablation of Cdk1 triggered CM proliferation post-myocardial-infarction (MI) in specific zones, driven by the activation of EGFR1 signaling and suppression of the anti-proliferative p38 and p53 signaling. This was accompanied by restoration of fractional shortening, mitochondrial function, and decreased reactive oxygen species. Additionally, cardiac hypertrophy was mitigated, and survival rates post-MI were increased in Cdk1-knockout mice. These findings reveal a novel role of Cdk1 in regulating cell cycle exit and re-entry in differentiated CMs and offer insights into potential strategies for cardiac repair.