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Congenital heart disease (CHD) represents a spectrum of inborn heart defects influenced by genetic and environmental factors. This study advances the field by analyzing gene expression profiles in 21,034 cardiac fibroblasts, 73,296 cardiomyocytes, and 35,673 endothelial cells, utilizing single-cell level analysis and machine learning techniques. Six CHD conditions: dilated cardiomyopathy (DCM), donor hearts (used as healthy controls), hypertrophic cardiomyopathy (HCM), heart failure with hypoplastic left heart syndrome (HF_HLHS), Neonatal Hypoplastic Left Heart Syndrome (Neo_HLHS), and Tetralogy of Fallot (TOF), were investigated for each cardiac cell type. Each cell sample was represented by 29,266 gene features. These features were first analyzed by six feature-ranking algorithms, resulting in several feature lists. Then, these lists were fed into incremental feature selection, containing two classification algorithms, to extract essential gene features and classification rules and build efficient classifiers. The identified essential genes can be potential CHD markers in different cardiac cell types. For instance, the LASSO identified key genes specific to various heart cell types in CHD subtypes. FOXO3 was found to be up-regulated in cardiac fibroblasts for both Dilated and hypertrophic cardiomyopathy. In cardiomyocytes, distinct genes such as TMTC1, ART3, ARHGAP24, SHROOM3, and XIST were linked to dilated cardiomyopathy, Neo-Hypoplastic Left Heart Syndrome, hypertrophic cardiomyopathy, HF-Hypoplastic Left Heart Syndrome, and Tetralogy of Fallot, respectively. Endothelial cell analysis further revealed COL25A1, NFIB, and KLF7 as significant genes for dilated cardiomyopathy, hypertrophic cardiomyopathy, and Tetralogy of Fallot. LightGBM, Catboost, MCFS, RF, and XGBoost further delineated key genes for specific CHD subtypes, demonstrating the efficacy of machine learning in identifying CHD-specific genes. Additionally, this study developed quantitative rules for representing the gene expression patterns related to CHDs. This research underscores the potential of machine learning in unraveling the molecular complexities of CHD and establishes a foundation for future mechanism-based studies. [ABSTRACT FROM AUTHOR]

The T-box family transcription factor 18 (Tbx18) has been found to play a critical role in regulating the development of the mammalian heart during the primary stages of embryonic development while the cellular heterogeneity and landscape of Tbx18-positive (Tbx18+) cardiac cells remain incompletely characterized. Here, we analyzed prior published single-cell RNA sequencing (scRNA-seq) mouse heart data to explore the heterogeneity of Tbx18+ cardiac cell subpopulations and provide a comprehensive transcriptional landscape of Tbx18+ cardiac cells during their development. Bioinformatic analysis methods were utilized to identify the heterogeneity between cell groups. Based on the gene expression characteristics, Tbx18+ cardiac cells can be classified into a minimum of two distinct cell populations, namely fibroblast-like cells and cardiomyocytes. In terms of temporal heterogeneity, these cells exhibit three developmental stages, namely the MEM stage, ML_P0 stage, and P stage Tbx18+ cardiac cells. Furthermore, Tbx18+ cardiac cells encompass several cell types, including cardiac progenitor-like cells, cardiomyocytes, and epicardial/stromal cells, as determined by specific transcriptional regulatory networks. The scRNA-seq results revealed the involvement of extracellular matrix (ECM) signals and epicardial epithelial-to-mesenchymal transition (EMT) in the development of Tbx18+ cardiac cells. The utilization of a lineage-tracing model served to validate the crucial function of Tbx18 in the differentiation of cardiac cells. Consequently, these findings offer a comprehensive depiction of the cellular heterogeneity within Tbx18+ cardiac cells. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) represents a spectrum of inborn heart defects influenced by genetic and environmental factors. This study advances the field by analyzing gene expression profiles in 21,034 cardiac fibroblasts, 73,296 cardiomyocytes, and 35,673 endothelial cells, utilizing single-cell level analysis and machine learning techniques. Six CHD conditions: dilated cardiomyopathy (DCM), donor hearts (used as healthy controls), hypertrophic cardiomyopathy (HCM), heart failure with hypoplastic left heart syndrome (HF_HLHS), Neonatal Hypoplastic Left Heart Syndrome (Neo_HLHS), and Tetralogy of Fallot (TOF), were investigated for each cardiac cell type. Each cell sample was represented by 29,266 gene features. These features were first analyzed by six feature-ranking algorithms, resulting in several feature lists. Then, these lists were fed into incremental feature selection, containing two classification algorithms, to extract essential gene features and classification rules and build efficient classifiers. The identified essential genes can be potential CHD markers in different cardiac cell types. For instance, the LASSO identified key genes specific to various heart cell types in CHD subtypes. FOXO3 was found to be up-regulated in cardiac fibroblasts for both Dilated and hypertrophic cardiomyopathy. In cardiomyocytes, distinct genes such as TMTC1, ART3, ARHGAP24, SHROOM3, and XIST were linked to dilated cardiomyopathy, Neo-Hypoplastic Left Heart Syndrome, hypertrophic cardiomyopathy, HF-Hypoplastic Left Heart Syndrome, and Tetralogy of Fallot, respectively. Endothelial cell analysis further revealed COL25A1, NFIB, and KLF7 as significant genes for dilated cardiomyopathy, hypertrophic cardiomyopathy, and Tetralogy of Fallot. LightGBM, Catboost, MCFS, RF, and XGBoost further delineated key genes for specific CHD subtypes, demonstrating the efficacy of machine learning in identifying CHD-specific genes. Additionally, this study developed quantitative rules for representing the gene expression patterns related to CHDs. This research underscores the potential of machine learning in unraveling the molecular complexities of CHD and establishes a foundation for future mechanism-based studies.

Objective: This research aims to increase the level and quality of the information acquired from 90 previously conducted studies regarding zebrafish heart regeneration and to summarize the best and latest information as well as the methods gleaned from those studies, which will allow us to determine the best ways to rebuild cardiac tissue in zebrafish. Methods: This study was conducted under the PRISMA guidelines. The search for primary research articles was conducted using PubMed, Web of science, and Mendeley. We used the latest update of Microsoft office Excel, Of the total 1158 results, 1066 were dropped according to the criteria for exclusion. The selected results included previously published and unpublished studies on cardiac cell regeneration in zebrafish from 2012 to 2022. Results: 90 studies met the inclusion criteria. Out of these, 43 used the AR method, 36 used cryoinjury, and 16 used genetic amputation. All methods used were based on selected heart sections, not the whole heart. The primary evaluation technique used in the included studies was histology, either alone or in combination with other methods. Acid Fuchsin Orange G (AFOG), Masson's Trichrome (MT), Hematoxylin/Eosin (HE), immunofluorescence (IF), and in situ hybridization (ISH) were the main histological techniques employed to assess heart regrowth and regeneration. Conclusion: This study may have a risk of bias due to the qualitative and quantitative data that was selected. Further research can help understand and utilize zebrafish regeneration genes in humans. [ABSTRACT FROM AUTHOR]

Calcium (Ca2+) sparks are the elementary events of excitation–contraction coupling, yet they are not explicitly represented in human ventricular myocyte models. A stochastic ventricular cardiomyocyte human model that adapts to intracellular Ca2+ ([Ca2+]i) dynamics, spark regulation, and frequency-dependent changes in the form of locally controlled Ca2+ release was developed. The 20,000 CRUs in this model are composed of 9 individual LCCs and 49 RyRs that function as couplons. The simulated action potential duration at 1 Hz steady-state pacing is ~0.280 s similar to human ventricular cell recordings. Rate-dependence experiments reveal that APD shortening mechanisms are largely contributed by the L-type calcium channel inactivation, RyR open fraction, and [Ca2+]myo concentrations. The dynamic slow-rapid-slow pacing protocol shows that RyR open probability during high pacing frequency (2.5 Hz) switches to an adapted "nonconducting" form of Ca2+-dependent transition state. The predicted force was also observed to be increased in high pacing, but the SR Ca2+ fractional release was lower due to the smaller difference between diastolic and systolic [Ca2+]SR. Restitution analysis through the S1S2 protocol and increased LCC Ca2+-dependent activation rate show that the duration of LCC opening helps modulate its effects on the APD restitution at different diastolic intervals. Ultimately, a longer duration of calcium sparks was observed in relation to the SR Ca2+ loading at high pacing rates. Overall, this study demonstrates the spontaneous Ca2+ release events and ion channel responses throughout various stimuli. [ABSTRACT FROM AUTHOR]

In this study, we have investigated how new composite material (magnetic polyurethane (PU) nanofibers) influences the culture and maturation of cardiomyocyte cells. Magnetic iron (II, III) oxide nanoparticles (Fe3O4, MNPs) were incorporated into the nanofiber structure using the solution blow spinning (SBS) method, resulting in composite magnetic nanofiber mats. These mats were characterized by physicochemical, optical (Young's modulus, wettability, surface zeta potential, autofluorescence), and magnetic properties. It was found that adding MNPs provided magnetic functionality and significantly reduced the autofluorescence properties of nanofiber mats. High viability of Human Cardiomyocytes (HCM) cells was obtained for magnetic nanofibrous mats. The results showed that the presence of MNPs increased the viability of HCM cells by 70% (p

Advances in electron microscopy (EM) such as electron tomography and focused ion-beam scanning electron microscopy provide unprecedented, three-dimensional views of cardiac ultrastructures within sample volumes ranging from hundreds of nanometres to hundreds of micrometres. The datasets from these samples are typically large, with file sizes ranging from gigabytes to terabytes and the number of image slices within the three-dimensional stack in the hundreds. A significant bottleneck with these large datasets is the time taken to extract and statistically analyse three-dimensional changes in cardiac ultrastructures. This is because of the inherently low contrast and the significant amount of structural detail that is present in EM images. These datasets often require manual annotation, which needs substantial person-hours and may result in only partial segmentation that makes quantitative analysis of the three-dimensional volumes infeasible. We present CardioVinci, a deep learning workflow to automatically segment and statistically quantify the morphologies and spatial assembly of mitochondria, myofibrils and Z-discs with minimal manual annotation. The workflow encodes a probabilistic model of the three-dimensional cardiomyocyte using a generative adversarial network. This generative model can be used to create new models of cardiomyocyte architecture that reflect variations in morphologies and cell architecture found in EM datasets. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'. [ABSTRACT FROM AUTHOR]

Calcium (Ca2+) sparks are the elementary events of excitation–contraction coupling, yet they are not explicitly represented in human ventricular myocyte models. A stochastic ventricular cardiomyocyte human model that adapts to intracellular Ca2+ ([Ca2+]i) dynamics, spark regulation, and frequency-dependent changes in the form of locally controlled Ca2+ release was developed. The 20,000 CRUs in this model are composed of 9 individual LCCs and 49 RyRs that function as couplons. The simulated action potential duration at 1 Hz steady-state pacing is ~0.280 s similar to human ventricular cell recordings. Rate-dependence experiments reveal that APD shortening mechanisms are largely contributed by the L-type calcium channel inactivation, RyR open fraction, and [Ca2+]myo concentrations. The dynamic slow-rapid-slow pacing protocol shows that RyR open probability during high pacing frequency (2.5 Hz) switches to an adapted “nonconducting” form of Ca2+-dependent transition state. The predicted force was also observed to be increased in high pacing, but the SR Ca2+ fractional release was lower due to the smaller difference between diastolic and systolic [Ca2+]SR. Restitution analysis through the S1S2 protocol and increased LCC Ca2+-dependent activation rate show that the duration of LCC opening helps modulate its effects on the APD restitution at different diastolic intervals. Ultimately, a longer duration of calcium sparks was observed in relation to the SR Ca2+ loading at high pacing rates. Overall, this study demonstrates the spontaneous Ca2+ release events and ion channel responses throughout various stimuli.

Abstract Background Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined. We sought to determine the consequences of HF neurohormonal activation in iron homeostasis and mitochondrial function in cardiac cells. Methods HF was induced in C57BL/6 mice by using isoproterenol osmotic pumps and embryonic rat heart-derived H9c2 cells were subsequently challenged with Angiotensin II and/or Norepinephrine. The expression of several genes and proteins related to intracellular iron metabolism were assessed by Real time-PCR and immunoblotting, respectively. The intracellular iron levels were also determined. Mitochondrial function was analyzed by studying the mitochondrial membrane potential, the accumulation of radical oxygen species (ROS) and the adenosine triphosphate (ATP) production. Results Hearts from isoproterenol-stimulated mice showed a decreased in both mRNA and protein levels of iron regulatory proteins, transferrin receptor 1, ferroportin 1 and hepcidin compared to control mice. Furthermore, mitoferrin 2 and mitochondrial ferritin were also downregulated in the hearts from HF mice. Similar data regarding these key iron regulatory molecules were found in the H9c2 cells challenged with neurohormonal stimuli. Accordingly, a depletion of intracellular iron levels was found in the stimulated cells compared to non-stimulated cells, as well as in the hearts from the isoproterenol-induced HF mice. Finally, neurohormonal activation impaired mitochondrial function as indicated by the accumulation of ROS, the impaired mitochondrial membrane potential and the decrease in the ATP levels in the cardiac cells. Conclusions HF characteristic neurohormonal activation induced changes in the regulation of key molecules involved in iron homeostasis, reduced intracellular iron levels and impaired mitochondrial function. The current results suggest that iron could be involved in the pathophysiology of HF.

Saeed Mohammadi Nasr,1 Navid Rabiee,2 Sakineh Hajebi,3,4 Sepideh Ahmadi,5 Yousef Fatahi,6– 8 Masoumehossadat Hosseini,9,10 Mojtaba Bagherzadeh,2 Amir Mohammad Ghadiri,2 Mohammad Rabiee,11 Vahid Jajarmi,12,13 Thomas J Webster14 1Faculty of Chemical Engineering, Sahand University of Technology, Tabriz, Iran; 2Department of Chemistry, Sharif University of Technology, Tehran, Iran; 3Faculty of Polymer Engineering, Sahand University of Technology, Tabriz, Iran; 4Institute of Polymeric Materials, Sahand University of Technology, Tabriz, Iran; 5Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 6Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 7Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 8Universal Scientific Education and Research Network (USERN), Tehran, Iran; 9Department of Chemistry, Faculty of Chemistry and Petroleum Sciences, Shahid Beheshti University, Tehran, Iran; 10Soroush Mana Pharmed, Pharmaceutical Holding, Golrang Industrial Group, Tehran, Iran; 11Biomaterial Group, Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran; 12Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 13Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 14Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United StatesCorrespondence: Thomas J Webster Email th.webster@neu.eduAbstract: Cardiovascular diseases are the number one cause of heart failure and death in the world, and the transplantation of the heart is an effective and viable choice for treatment despite presenting many disadvantages (most notably, transplant heart availability). To overcome this problem, cardiac tissue engineering is considered a promising approach by using implantable artificial blood vessels, injectable gels, and cardiac patches (to name a few) made from biodegradable polymers. Biodegradable polymers are classified into two main categories: natural and synthetic polymers. Natural biodegradable polymers have some distinct advantages such as biodegradability, abundant availability, and renewability but have some significant drawbacks such as rapid degradation, insufficient electrical conductivity, immunological reaction, and poor mechanical properties for cardiac tissue engineering. Synthetic biodegradable polymers have some advantages such as strong mechanical properties, controlled structure, great processing flexibility, and usually no immunological concerns; however, they have some drawbacks such as a lack of cell attachment and possible low biocompatibility. Some applications have combined the best of both and exciting new natural/synthetic composites have been utilized. Recently, the use of nanostructured polymers and polymer nanocomposites has revolutionized the field of cardiac tissue engineering due to their enhanced mechanical, electrical, and surface properties promoting tissue growth. In this review, recent research on the use of biodegradable natural/synthetic nanocomposite polymers in cardiac tissue engineering is presented with forward looking thoughts provided for what is needed for the field to mature.Keywords: biodegradable polymer, tissue engineering, cardiac cell, composite, natural, synthetic

Mitochondria fulfill the cell's energy demand and affect the intracellular calcium (Ca2+) dynamics via direct Ca2+ exchange, the redox effect of reactive oxygen species (ROS) on Ca2+ handling proteins, and other signaling pathways. Recent experimental evidence indicates that mitochondrial depolarization promotes arrhythmogenic delayed afterdepolarizations (DADs) in cardiac myocytes. However, the nonlinear interactions among the Ca2+ signaling pathways, ROS, and oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathways make it difficult to reveal the mechanisms. Here, we use a recently developed spatiotemporal ventricular myocyte computer model, which consists of a 3-dimensional network of Ca2+ release units (CRUs) intertwined with mitochondria and integrates mitochondrial Ca2+ signaling and other complex signaling pathways, to study the mitochondrial regulation of DADs. With a systematic investigation of the synergistic or competing factors that affect the occurrence of Ca2+ waves and DADs during mitochondrial depolarization, we find that the direct redox effect of ROS on ryanodine receptors (RyRs) plays a critical role in promoting Ca2+ waves and DADs under the acute effect of mitochondrial depolarization. Furthermore, the upregulation of mitochondrial Ca2+ uniporter can promote DADs through Ca2+-dependent opening of mitochondrial permeability transition pores (mPTPs). Also, due to much slower dynamics than Ca2+ cycling and ROS, oxidized CaMKII activation and the cytosolic ATP do not appear to significantly impact the genesis of DADs during the acute phase of mitochondrial depolarization. However, under chronic conditions, ATP depletion suppresses and enhanced CaMKII activation promotes Ca2+ waves and DADs. [ABSTRACT FROM AUTHOR]

Mitochondria fulfill the cell’s energy demand and affect the intracellular calcium (Ca2+) dynamics via direct Ca2+ exchange, the redox effect of reactive oxygen species (ROS) on Ca2+ handling proteins, and other signaling pathways. Recent experimental evidence indicates that mitochondrial depolarization promotes arrhythmogenic delayed afterdepolarizations (DADs) in cardiac myocytes. However, the nonlinear interactions among the Ca2+ signaling pathways, ROS, and oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathways make it difficult to reveal the mechanisms. Here, we use a recently developed spatiotemporal ventricular myocyte computer model, which consists of a 3-dimensional network of Ca2+ release units (CRUs) intertwined with mitochondria and integrates mitochondrial Ca2+ signaling and other complex signaling pathways, to study the mitochondrial regulation of DADs. With a systematic investigation of the synergistic or competing factors that affect the occurrence of Ca2+ waves and DADs during mitochondrial depolarization, we find that the direct redox effect of ROS on ryanodine receptors (RyRs) plays a critical role in promoting Ca2+ waves and DADs under the acute effect of mitochondrial depolarization. Furthermore, the upregulation of mitochondrial Ca2+ uniporter can promote DADs through Ca2+-dependent opening of mitochondrial permeability transition pores (mPTPs). Also, due to much slower dynamics than Ca2+ cycling and ROS, oxidized CaMKII activation and the cytosolic ATP do not appear to significantly impact the genesis of DADs during the acute phase of mitochondrial depolarization. However, under chronic conditions, ATP depletion suppresses and enhanced CaMKII activation promotes Ca2+ waves and DADs.

Background: Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined. We sought to determine the consequences of HF neurohormonal activation in iron homeostasis and mitochondrial function in cardiac cells. Methods: HF was induced in C57BL/6 mice by using isoproterenol osmotic pumps and embryonic rat heart-derived H9c2 cells were subsequently challenged with Angiotensin II and/or Norepinephrine. The expression of several genes and proteins related to intracellular iron metabolism were assessed by Real time-PCR and immunoblotting, respectively. The intracellular iron levels were also determined. Mitochondrial function was analyzed by studying the mitochondrial membrane potential, the accumulation of radical oxygen species (ROS) and the adenosine triphosphate (ATP) production. Results: Hearts from isoproterenol-stimulated mice showed a decreased in both mRNA and protein levels of iron regulatory proteins, transferrin receptor 1, ferroportin 1 and hepcidin compared to control mice. Furthermore, mitoferrin 2 and mitochondrial ferritin were also downregulated in the hearts from HF mice. Similar data regarding these key iron regulatory molecules were found in the H9c2 cells challenged with neurohormonal stimuli. Accordingly, a depletion of intracellular iron levels was found in the stimulated cells compared to non-stimulated cells, as well as in the hearts from the isoproterenol-induced HF mice. Finally, neurohormonal activation impaired mitochondrial function as indicated by the accumulation of ROS, the impaired mitochondrial membrane potential and the decrease in the ATP levels in the cardiac cells. Conclusions: HF characteristic neurohormonal activation induced changes in the regulation of key molecules involved in iron homeostasis, reduced intracellular iron levels and impaired mitochondrial function. The current results suggest that iron could be involved in the pathophysiology of HF. [ABSTRACT FROM AUTHOR]

This research aims at investigating the role of antioxidant of xanthone on 2-methoxyethanol (2-ME)-induced cardiac cell damage in mice. Forty mice were grouped into: (1) The control group (mice were given with distilled water), (2) the ME group (mice were given with 2-ME 200 mg/kg BW orally), and (3) the treatment group (mice were given of xanthone with doses 60 mg, 120 mg, 240 mg/kg BW orally and were also given 2-ME 200 mg/kg BW). Their blood samples were taken to measure the level of lactate dehydrogenase (LDH) and creatinine kinase-MB (CK-MB). Heart tissues were also taken to determine the malondialdehyde (MDA), histological findings of heart damage, and the immunohistochemical of the expression of superoxide dismutase (SOD) and glutathione peroxidase (GPx). The administration of 2-ME resulted in a significant increase level of the LDH, CK-MB, MDA, and a decrease in SOD and GPx expression were compared with the control group. The 2-ME also induced loss of the normal structure of heart cells and necrosis. However, treatment with the xanthone, only dose 240 mg/kg BW significantly decrease the level of LDH, CK-MB, MDA, and increase SOD, GPx expression. The xanthone 240 mg/kg BW also demonstrated significantly improved heart cell damage. From the results, it is concluded that the xanthone are a potent antioxidant in against 2-ME-induced cardiac toxicity in mice, through increasing SOD and GPx expression, and also inhibiting LDH, CK-MB and MDA.

Cardiac diseases are the leading cause of deaths worldwide; however, to date, there has been limited progress in the development of therapeutic options for these conditions. Animal models have been the most extensively studied methods to recapitulate a wide variety of cardiac diseases, but these models exhibit species-specific differences in physiology, metabolism and genetics, which lead to inaccurate and unpredictable drug safety and efficacy results, resulting in drug attrition. The development of human pluripotent stem cell (hPSC) technology in theory guarantees an unlimited source of human cardiac cells. These hPSC-derived cells are not only well suited for traditional two-dimensional (2-D) monoculture, but also applicable to more complex systems, such as three-dimensional (3-D) organoids, tissue engineering and heart on-a-chip. In this review, we discuss the application of hPSCs in heart disease modeling, cell therapy, and next-generation drug discovery. While the hPSC-related technologies still require optimization, their advances hold promise for revolutionizing cell-based therapies and drug discovery.

Recently, metabolism has been linked to the regulation of gene expression in cardiac cells with levels of several metabolites altered in response to physiological and pathological stresses in the heart. Keywords: cardiac cell; metabolism; vascular cells; heart; hypoxia EN cardiac cell metabolism vascular cells heart hypoxia 1 3 3 02/17/22 20220215 NES 220215 This Research Topic gathers a collection of five original and review articles that provide recent summaries and novel information regarding the role of metabolism in regulating cardiac and vascular cell function. Metabolism, heart, hypoxia, cardiac cell, vascular cells. [Extracted from the article]

In the ongoing quest for the “ideal” cell type for heart repair, pluripotent stem cells (PSC) derived from either embryonic or reprogrammed somatic cells have emerged as attractive candidates because of their unique ability to give rise to lineage-specific cells and to transplant them at the desired stage of differentiation. The technical obstacles which have initially hindered their clinical use have now been largely overcome and several trials are under way which encompass several different diseases, including heart failure. So far, there have been no safety warning but it is still too early to draw definite conclusions regarding efficacy. In parallel, mechanistic studies suggest that the primary objective of “remuscularizing” the heart with PSC-derived cardiac cells can be challenged by their alternate use as ex vivo sources of a biologically active extracellular vesicle-enriched secretome equally able to improve heart function through harnessing endogenous repair pathways. The exclusive use of this secretome would combine the advantages of a large-scale production more akin to that of a biological medication, the likely avoidance of cell-associated immune and tumorigenicity risks and the possibility of intravenous infusions compatible with repeated dosing.

Background/Aims: Diabetic cardiomyopathy is associated with increased apoptosis and suppressed autophagy in cardiac cells. The polyphenol resveratrol has shown beneficial effects in various cardiovascular diseases. This study investigated if resveratrol protected cardiac cells by modulating apoptosis and autophagy in the context of diabetes. Methods: H9c2 cardiac myoblast cells were exposed to high glucose combined with palmitate. Autophagy was evaluated by estimating LC3-II/I ratio, P62 protein levels, and LC3 fluorescent puncta. Apoptosis was assessed by using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), flow cytometry, and analysis of the protein expression of apoptotic markers (cleavage of caspase-3 and PARP). Results: High glucose and palmitate suppressed autophagic activity and exacerbated apoptotic cell death in cardiac myoblast cells. Resveratrol restored autophagy and attenuated apoptosis in cells upon diabetic stimuli. Moreover, resveratrol activated AMPK and JNK1, thereby suppressing mTOR and its downstream effectors p70S6K1 and 4EBP1, as well as disrupting the Beclin1–Bcl-2 complex. Conclusion: Resveratrol protects cardiac cells by regulating the switch between autophagy and apoptotic machinery under diabetic conditions, which is attributed by AMPK-mediated phosphorylation of mTORC1/p70S6K1/4EBP1 and JNK-mediated dissociation of Beclin1-Bcl-2. Our study suggests that autophagy may be an important target for resveratrol in the treatment of diabetic cardiomyopathy.

The Beeler–Reuter model is one of the oldest models of the cardiac ventricular cell. This model is used in many scientific studies that investigate the propagation of the action potential. In this paper, dynamical properties of Beeler–Reuter model with respect to the frequency and amplitude of the stimulus pulse with the shape of the half-sine period are being investigated. For this purpose bifurcation diagrams, the Fourier spectra, and the 0–1 test for chaos was applied. [ABSTRACT FROM AUTHOR]

Background/Aims: This study aimed to investigate whether exogenous hydrogen sulfide (H2S) confered cardiac protection against high glucose (HG)-induced injury by inhibiting NLRP3 inflammasome activation via a specific TLR4/NF-κB pathway. Methods: H9c2 cardiac cells were exposed to 33 mM glucose for 24 h to induce HG-induced cytotoxicity. The cells were pretreated with NaHS (a donor of H2S) before exposure to HG. Cell viability, cell apoptosis, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and TLR4, NF-κB, NLRP3 inflammasome, IL-1β, IL-18 and caspase-3 expression were measured by standard methods. Results: H2S attenuated HG-induced cell apoptosis, ROS expression and loss of MMP and reduced the expression of NLRP3, ASC, pro-caspase-1, caspase-1, IL-1β, IL-18 and caspase-3. In addition, H2S inhibited the HG-induced activation of TLR4 and NF-κB. Furthermore, NLRP3 inflammasome activation was regulated by the TLR4 and NF-κB pathway. Conclusion: The present study demonstrated for the first time that H2S appears to suppress HG-induced cardiomyocyte inflammation and apoptosis by inhibiting the TLR4/NF-κB pathway and its downstream NLRP3 inflammasome activation. Thus H2S might possess potential in the treatment of diabetic cardiomyopathy.

Abstract A growing number of epidemiological surveys show that PM 2.5 is an important promoter for the cardiovascular dysfunction induced by atmospheric pollution. PM 2.5 is a complex mixture of solid and liquid airborne particles and its components determine the health risk of PM 2.5 to a great extent. However, the individual cardiotoxicities of different PM 2.5 fractions are still unclear, especially in the cellular level. Here we used the neonatal rat cardiomyocytes (NRCMs) to evaluate the cardiac toxicity of PM 2.5 exposure. The cytotoxicities of Total-PM 2.5 , water soluble components of PM 2.5 (WS-PM 2.5) and water insoluble components of PM 2.5 (WIS-PM 2.5), which include the cell viability, cell membrane damage, reactive oxygen species (ROS) generation, were examined with NRCMs in vitro. The results indicated that Total-PM 2.5 or WIS-PM 2.5 exposure significantly decreased the cell viability, induced the cell membrane damage and increased the ROS level in NRCMs at concentrations above 50 µg/mL. However, WS-PM 2.5 exposure could induce the cytotoxicity on NRCMs until the concentration of WS-PM 2.5 was raised to a higher concentration (75 µg/mL). Furthermore, the DNA damage was detected in NRCMs after 48 h of exposure with Total-PM 2.5 , WS-PM 2.5 or WIS-PM 2.5 (75 µg/mL) and the adverse effects on mitochondrial function and action potentials of NRCMs were detected only both in the Total-PM 2.5 and WIS-PM 2.5 treatment group. In summary, our project not only estimates the risk of PM 2.5 on cardiac cells but also reveal that Total-PM 2.5 and WIS-PM 2.5 exposure were predominantly associated with the functional cardiotoxicities in NRCMs. Highlights • The amount of major chemical components in different PM 2.5 fractions were analyzed. • The cardiotoxicities of PM 2.5 were investigated on neonatal rat cardiomyocytes. • Different PM 2.5 fractions exposure significantly decreased the cell viability. • Water insoluble components of PM 2.5 contributed most to the cardiotoxicities. [ABSTRACT FROM AUTHOR]

In this study, we have investigated how new composite material (magnetic polyurethane (PU) nanofibers) influences the culture and maturation of cardiomyocyte cells. Magnetic iron (II, III) oxide nanoparticles (Fe 3 O 4 , MNPs) were incorporated into the nanofiber structure using the solution blow spinning (SBS) method, resulting in composite magnetic nanofiber mats. These mats were characterized by physicochemical, optical (Young's modulus, wettability, surface zeta potential, autofluorescence), and magnetic properties. It was found that adding MNPs provided magnetic functionality and significantly reduced the autofluorescence properties of nanofiber mats. High viability of Human Cardiomyocytes (HCM) cells was obtained for magnetic nanofibrous mats. The results showed that the presence of MNPs increased the viability of HCM cells by 70% (p < 0.05) compared to cultures on non-magnetic nanofibers. Moreover, AMF increased troponin T and MYH6 levels for ten days of culture on magnetic nanofibers. The results suggest that culturing cardiac cells on magnetic PU nanofibrous mats more effectively replicates in vivo conditions than cultures on non-magnetic nanofibers, which may benefit cardiovascular disease research. • Novel composite polurethane-based magnetic nanofibers. • Magnetic nanofibers enable structural and mechanical stimulation. • Mechanical stimulation on nanofibers increases the amount of proteins characteristic of mature heart cells. • The method of solution blow spinning allows the nanoparticles to be permanently bonded to the nanofibers. [ABSTRACT FROM AUTHOR]

Electrical and mechanical stimulations play a key role in cell biological processes, being essential in processes such as cardiac cell maturation, proliferation, migration, alignment, attachment, and organization of the contractile machinery. However, the mechanisms that trigger these processes are still elusive. The coupling of mechanical and electrical stimuli makes it difficult to abstract conclusions. In this sense, computational models can establish parametric assays with a low economic and time cost to determine the optimal conditions of in-vitro experiments. Here, a computational model has been developed, using the finite element method, to study cardiac cell maturation, proliferation, migration, alignment, and organization in 3D matrices, under mechano-electric stimulation. Different types of electric fields (continuous, pulsating, and alternating) in an intensity range of 50–350 Vm−1, and extracellular matrix with stiffnesses in the range of 10–40 kPa, are studied. In these experiments, the group’s morphology and cell orientation are compared to define the best conditions for cell culture. The obtained results are qualitatively consistent with the bibliography. The electric field orientates the cells and stimulates the formation of elongated groups. Group lengthening is observed when applying higher electric fields in lower stiffness extracellular matrix. Groups with higher aspect ratios can be obtained by electrical stimulation, with better results for alternating electric fields.

We have developed a computer model of human cardiac ventricular myocyte (CVM), including t-tubular and cleft spaces with the aim of evaluating the impact of accumulation-depletion of ions in restricted extracellular spaces on transmembrane ion transport and ionic homeostasis in human CVM. The model was based on available data from human CVMs. Under steady state, the effect of ion concentration changes in extracellular spaces on [Ca2+]i-transient was explored as a function of critical fractions of ion transporters in t-tubular membrane (not documented for human CVM). Depletion of Ca2+ and accumulation of K+ occurring in extracellular spaces slightly affected the transmembrane Ca2+ flux, but not the action potential duration (APD90). The [Ca2+]i-transient was reduced (by 2%–9%), depending on the stimulation frequency, the rate of ion exchange between t-tubules and clefts and fractions of ion-transfer proteins in the t-tubular membrane. Under non-steady state, the responses of the model to changes of stimulation frequency were analyzed. A sudden increase of frequency (1–2.5 Hz) caused a temporal decrease of [Ca2+] in both extracellular spaces, a reduction of [Ca2+]i-transient (by 15%) and APD90 (by 13 ms). The results reveal different effects of activity-related ion concentration changes in human cardiac t-tubules (steady-state effects) and intercellular clefts (transient effects) in the modulation of membrane ion transport and Ca2+ turnover.

Uric acid (UA) is a potent scavenger of oxidants in most mammalian and avian species. The aim of this study was to obtain more comprehensive information regarding the relationship between different concentrations of UA and oxidative balance in chicken cardiac cells. First, oxidative damage parameters were measured in chicken cardiac cells treated with different concentrations of UA. UA concentrations within the normal physiological range had no effect, while treatment with a high level of UA, i.e. 1200 μM, increased the malondialdehyde (MDA) and protein carbonyl contents, decreased the superoxide dismutase (SOD) and catalase (CAT) activities, and had no effect on glutathione (GSH) in cardiac muscle cells. In addition, the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was stimulated in cells treated with 1200 μM UA. Next, the role of UA in protecting cells from oxidative damage was investigated in hydrogen peroxide (H2O2)-damaged chicken cardiac cells. Treatment with UA within the normal physiological range reduced the increased MDA and protein carbonyl contents and SOD enzymatic activity induced by H2O2 exposure to some extent and inhibited reactive oxygen species (ROS) formation, presumably as a result of the Nrf2 pathway activation in H2O2-damaged cells. By contrast, the MDA and protein carbonyl contents were increased, SOD enzymatic activity was depressed, and the Nrf2 pathway was further down-regulated in H2O2-damaged cells treated with 1200 μM UA. In conclusion, the results indicated that physiological UA concentration partially alleviated oxidative stress in chicken cardiac muscle cells treated with H2O2. However, supraphysiological UA concentrations promoted oxidative damages directly in primary cultured chicken cardiac muscle cells and aggravated oxidative stress in H2O2-damaged cells. [ABSTRACT FROM AUTHOR]