Heart Cells Research Articles

Empagliflozin treatment pre- and post- acute myocardial infarction reduces no-reflow, inflammatory cell infiltration and infarct size while preserving cardiac function.

Abstract Background and aims Empagliflozin (EMPA) and other members of the family of sodium glucose co-transporter 2 inhibitors have demonstrated clinical benefit in terms of survival and rehospitalizations in heart failure. However, their effect on acute myocardial infarction (AMI) is still under investigation. Microvascular injury (MVI) and no-reflow are major determinants of myocardial infarct size (IS) and prognosis. We investigated EMPA’s cardioprotective potential in AMI in terms of no-reflow, MVI and IS emphasizing on a translational regimen with EMPA treatment after AMI. Methods In a first series of experiments, C57Bl6 male mice (n=10 per group) were randomized into 1) Sham, 2) Control-AMI and 3) EMPA-Pre-AMI (10mg/kg/day orally for 6 weeks) groups. Mice underwent 30 min ischemia (I) and 2h reperfusion (R) or sham operation. Cell sorting and 3’ mRNA sequencing were applied to identify the cell types that are transcriptionally affected by EMPA pretreatment in mice with AMI. In a second series of experiments, the protocol was repeated, and an additional group was added, EMPA-Post-AMI (n=8-11 mice per group) in which oral treatment was performed 1h after R. Assessment of no-reflow via thioflavin S staining and electron microscopy was performed at 48 h. The infiltration of inflammatory cells in the ischemic heart was examined via flow cytometry. IS and myocardial function were determined by cardiac magnetic resonance (CMR). Type-2 diabetes mellitus patients received insulin (n=18) or EMPA (n=24) within 2 months post-AMI. Endothelial glycocalyx and endothelial-related circulating markers were examined at 4 months and 12 months post-AMI. Results EMPA pretreatment reversed AMI-induced alterations in cardiac endothelial cells’ (ECs) transcriptome. As such, it promoted the expression of survival genes, reduced gene expression related to adhesion molecules and ECs matrix degradation. Conversely, EMPA pretreatment exerted minimal effects on cardiomyocyte and fibroblast transcriptome. In support of the effect of EMPA on ECs, EMPA-Pre-AMI and EMPA-Post-AMI groups significantly reduced no-reflow and MVI as indicated by electron microscopy and histology at 48h of R. Moreover, both EMPA treatment pre-AMI and post-AMI reduced the infiltration of inflammatory monocytes and neutrophils in the infarcted myocardium suggesting enhanced vascular integrity. Both EMPA-Pre-AMI and EMPA-Post-AMI reduced IS and preserved cardiac function defined by CMR. Patients receiving EMPA presented with improved endothelial glycocalyx thickness, % global longitudinal strain and preserved pulse wave velocity. Conclusions EMPA treatment either before or after AMI protects against MVI, reduces no-reflow and IS and preserves cardiac function. Our data support the use of EMPA after recanalization in patients with AMI to confer improvement of cardiovascular function.

RACK1 contributes to the upregulation of embryonic genes in a model of cardiac hypertrophy

Receptors for activated C kinases (RACKs) have been shown to coordinate PKC-mediated hypertrophic signalling in mice. However, little information is available on its participation in embryonic gene expression. This study investigated the involvement of RACK1 in the expression of embryonic genes in a zebrafish (ZF) ex vivo heart culture model by using phenylephrine (PE) or a growth factors cocktail (GFs) as a prohypertrophic/regeneration stimulus. Blebbistatin (BL) inhibition has also been studied for its ability to block the signal transduction actions of some PEs. qRT‒PCR and immunoblot analyses confirmed the upregulation of RACK1 in the PE- and GFs-treated groups. BL administration counteracted PE-induced hypertrophy and downregulated RACK1 expression. Immunohistochemical analyses of the heart revealed the colocalization of RACK1 and embryonic genes, namely, Gata4, Wt1, and Nfat2, under stimulation, whereas these genes were expressed at lower levels in the BL treatment group. Culturing ZF heart cells activated via GFs treatment increased the expression of RACK1. The overexpression of RACK1 induced by the transfection of recombinant RACK1 cDNA in ZF heart cells increased the expression of embryonic genes, especially after one week of GFs treatment. In summary, these results support the involvement of RACK1 in the induction of embryonic genes during cardiac hypertrophy/GFs stimulation in a fish heart model, which can be used as an alternative study model for mammals.

Genetic inference and single cell expression analysis of potential targets in heart failure and breast cancer

BackgroundBreast cancer and heart failure are major public health issues globally, characterized by significant genetic heterogeneity and complex molecular mechanisms. This study aims to explore potential genetic targets in heart failure and breast cancer through combining genetic inference and single-cell expression analysis, and to assess the causal relationships of these targets using Mendelian randomization methods.MethodsWe first identified genetic variants associated with heart failure and breast cancer using genome-wide association study (GWAS) data. Subsequently, we analyzed the expression patterns of these genetic variants in different cell types through single-cell RNA sequencing technology. Furthermore, we utilized in vitro experiment to assess the effects of ITM2B on MCF7 using immunofluorescence.ResultsOur study identified multiple genetic variants associated with heart failure and breast cancer, showing specific expression patterns in heart and breast cells. The ITM2B gene is highly expressed in breast cancer. ITM2B shows the highest expression in T cells and the lowest expression in proliferating cells. Silencing the ITM2B gene can promote apoptosis and inhibit proliferation and migration of MCF7 breast cancer cells.ConclusionBy integrating genetic inference and single-cell expression analysis, this study revealed potential genetic targets in heart failure and breast cancer, and validated the causal effects of these targets using Mendelian randomization methods.

Examining the Cardioprotective Effects of Aerobic Exercise Combined with Crocin or Berberine on Methamphetamine-Induced Heart Damage in Female Rats

Background: While the harmful effects of methamphetamine abuse on the heart are well-known, the solutions to deal with these damages are not well-known. Objectives: This study aimed to investigate whether aerobic exercise combined with supplements such as Crocin and Berberine can potentially protect against methamphetamine-induced changes in the heart tissue of female rats. Methods: Forty-two female rats were randomly assigned into seven groups (n = 6). The groups included healthy control, methamphetamine, methamphetamine + exercise, methamphetamine + Crocin, methamphetamine + Berberine, methamphetamine + exercise + Crocin, and methamphetamine + exercise + Berberine group. Methamphetamine (10 mg/kg) was injected intraperitoneally over five days. The animals were administered Crocin via intraperitoneal injection at 40 mg/kg during a four-week withdrawal period. At the same time, Berberine was dissolved in drinking water at 100 mg/kg concentration. The aerobic training consisted of running at 25 m/min for 30 minutes. A light microscope was used to observe the structural changes. Data analysis was performed using non-parametric Kruskal-Wallis and Mann-Whitney U tests by SPSS 26, with a significance level of 5%. Results: The results of the study indicate that methamphetamine use causes hyperemia, inflammation, and histopathological damage in the heart cells and tissue (P = 0.001). The combination of exercise with Crocin significantly eliminated methamphetamine-induced heart tissue damage (P = 0.001) and improved cardio-respiratory endurance compared to control (P = 0.004) and methamphetamine (P = 0.01) groups. The combination of aerobic exercise with Berberine removed methamphetamine-induced heart cell damage (P = 0.001), and improved cardio-respiratory endurance compared to control (P = 0.024) and methamphetamine (P = 0.05) groups. In addition, all intervention groups showed a significant reduction in hyperemia and inflammation compared to the methamphetamine group (P = 0.001). Conclusions: A combination of exercise with either Crocin or Berberine supplements demonstrated potential benefits in mitigating some of the harmful structural effects of methamphetamine and improving cardio-respiratory endurance.

Ferulic acid alleviates cardiac injury by inhibiting avermectin-induced oxidative stress, inflammation and apoptosis

Avermectin (AVM) is a broad-spectrum antibiotic from the macrolide class, extensively employed in fisheries and aquaculture. Nevertheless, its indiscriminate utilisation has resulted in a substantial accumulation of remnants in the aquatic ecosystem, potentially inflicting significant harm to the cardiovascular system of aquatic species. Ferulic acid (FA) is a naturally occurring compound in wheat grain husks. It possesses potent anti-inflammatory and antioxidant properties, which can help reduce cardiovascular damage. Additionally, its affordability makes it an excellent option for aquaculture usage as a feed additive. This article explored the potential of FA as a feed additive to protect against AVM-induced heart damage in carp. We subjected carp to AVM for 30 days and provided them with a diet of 400 mg/kg of FA. FA substantially reduced the pathogenic damage to heart tissue caused by AVM, as shown through hematoxylin-eosin staining. The biochemical analysis revealed that FA markedly enhanced the activity of antioxidant enzymes catalase (CAT), glutathione (GSH), and total antioxidant capacity (T-AOC) while reducing the malondialdehyde (MDA) content. Furthermore, qPCR analysis demonstrated a substantial increase in the mRNA levels of transforming growth factor-β1 (tgf-β1) and interleukin-10 (il-10) simultaneously, significantly reducing the expression levels of interleukin-10 (il-6), interleukin-1β (il-1β), tumor necrosis factor-α (tnf-α) and inductible nitric oxide synthase (inos). Through the mitochondrial apoptotic route, FA reduced AVM-induced cell death in carp heart cells by upregulating bcl-2 while downregulating the mRNA expression levels of bax, fas, caspase8 and caspase9. In summary, FA alleviated cardiac injury by inhibiting AVM-induced oxidative stress, inflammatory response, and apoptosis in carp heart tissue.

Pathogenicity and phylogenetic analysis of ovine contagious ecthyma virus isolated during a sheeppox outbreak in Morocco

Contagious ecthyma (CE), also known as ORF is a highly contagious zoonotic viral skin disease that affects humans, sheep, goats and other domesticated and wild animals. As reported here-in, the objective of this study was to investigate a suspected outbreak of both sheeppox and ORF diseases in a sheep herd during the winter of 2020 in Northwest Morocco. The affected sheep showed nodules and proliferative scabby skin lesions around the mouth and hairless area of the body. Samples of skin crust were collected for virus identification and isolation. A virus was isolated in Vero cells, lamb testis and heart cells and the cytopathic effect was characterized by cells aggregation, ballooning, and detachment. Initially, the suspensions of skin crust were positive for sheeppox virus (SPPV) by PCR. Subsequent testing of the isolated virus from skin crust of affected animals indicated that the virus was SPPV-negative and ORFV-positive by PCR. Furthermore, nucleotide sequences of the B2L aligned with reference ORFV isolates for genetic analysis. Phylogenetic analyses results confirmed that the isolated virus was ORFV and that the virus was closely related to ORFV strains isolated in Sudan and Malaysia.In conclusion, this study is the first reported detection of ORFV in Morocco, and therefore, poses as an imminent threat to the health of humans, domestic and wild animals.

STIM1 functions as a proton sensor to coordinate cytosolic pH with store-operated calcium entry

The meticulous regulation of intracellular pH (pHi) is crucial for maintaining cellular function and homeostasis, impacting physiological processes such as heart rhythm, cell migration, proliferation, and differentiation. Dysregulation of pHi is implicated in various pathologies such as arrhythmias, cancer, and neurodegenerative diseases. Here, we explore the role of STIM1, an ER calcium (Ca2+) sensor mediating Store Operated Ca2+ Entry (SOCE), in sensing pHi changes. Our study reveals that STIM1 functions as a sensor for pHi changes, independent of its Ca2+-binding state. Through comprehensive experimental approaches including confocal microscopy, FRET-based sensors, and mutagenesis, we demonstrate that changes in pHi induce conformational alterations in STIM1, thereby modifying its subcellular localization and activity. We identify two conserved histidine within STIM1 essential for sensing pHi shifts. Moreover, intracellular alkalization induced by agents such as Angiotensin II or NH4Cl enhances STIM1-mediated SOCE, promoting cardiac hypertrophy. These findings reveal a novel facet of STIM1 as a multi-modal stress sensor that coordinates cellular responses to both Ca2+ and pH fluctuations. This dual functionality underscores its potential as a therapeutic target for diseases associated with pH and Ca2+ dysregulation.

The transcription factor PPARA mediates SIRT1 regulation of NCOR1 to protect damaged heart cells

The transcription factor PPARA mediates SIRT1 regulation of NCOR1 to protect damaged heart cells

Expression of mRNA for molecules that regulate angiogenesis, endothelial cell survival, and vascular permeability is altered in endothelial cells isolated from db/db mouse hearts

Metabolic syndrome (MetS) is a condition that includes symptoms, such as obesity, hyperglycemia, and hypertension, which elevate cardiovascular risk. An impaired angiogenic response of endothelial cells (ECs) in heart and peripheral organs has been proposed in MetS, but the mechanisms of this phenomenon have not been thoroughly explored. Results obtained from evaluating the whole myocardium are inconsistent, since different types of cells react differently to MetS environment and a variety of molecular pathways are involved in the angiogenic response. Therefore, the aim of this paper was to study one selected pathway—the VEGF/VEGFR pathway, which regulates the angiogenic response and microvascular permeability in ECs isolated from db/db mouse hearts. The expression of mRNAs for VEGF/VEGFR axis proteins was assessed with RT-PCR in ECs isolated from control and db/db mouse myocardium. The density of CD31-, VEGFR2-, and VE-cadherin-positive cells was examined with confocal microscopy, and the ultrastructure of ECs was analyzed with transmission electron microscopy. The aortic ring assay was used to assess the capacity of ECs to respond to angiogenic stimuli. Our results showed a decreased number of microvessels, diminished expression of VE-cadherin and VEGFR2 and widened gaps between the ECs of microcapillaries. The aortic ring assay showed a diminished number of sprouts in db/db mice. These results may indicate that ECs in MetS enhance the production of mRNA for VEGF/VRGFR axis proteins, yet sprout formation and vascular barrier maintenance are limited. These novel data may provide a foundation for further studies on ECs dysfunction in MetS.

Cardiac Hypertrophy in Pregnant Rats, Descendants of Fructose-Fed Mothers, an Effect That Worsens with Fructose Supplementation.

The role of fructose consumption in the development of obesity, MetS, and CVD epidemic has been widely documented. Notably, among other effects, fructose consumption has been demonstrated to induce cardiac hypertrophy. Moreover, fructose intake during pregnancy can cause hypertrophy of the maternal heart. Our previous research has demonstrated that maternal fructose intake has detrimental effects on fetuses, which persist into adulthood and are exacerbated upon re-exposure to fructose. Additionally, we found that maternal fructose consumption produces changes in female progeny that alter their own pregnancy. Despite these findings, fructose intake during pregnancy is not currently discouraged. Given that cardiac hypertrophy is a prognostic marker for heart disease and heart failure, this study aimed to determine whether metabolic changes occurring during pregnancy in the female progeny of fructose-fed mothers could provoke a hypertrophic heart. To test this hypothesis, pregnant rats from fructose-fed mothers, with (FF) and without (FC) fructose supplementation, were studied and compared to pregnant control rats (CC). Maternal hearts were analyzed. Although both FF and FC mothers exhibited heart hypertrophy compared to CC rats, cardiac DNA content was more diminished in the hearts of FF dams than in those of FC rats, suggesting a lower number of heart cells. Accordingly, changes associated with cardiac hypertrophy, such as HIF1α activation and hyperosmolality, were observed in both the FC and FF dams. However, FF dams also exhibited higher oxidative stress, lower autophagy, and decreased glutamine protection against hypertrophy than CC dams. In conclusion, maternal fructose intake induces changes in female progeny that alter their own pregnancy, leading to cardiac hypertrophy, which is further exacerbated by subsequent fructose intake.

Contributions of mechanical loading and hormonal changes to eccentric hypertrophy during volume overload: a Bayesian analysis using logic-based network models.

Primary mitral regurgitation (MR) is a pathology that alters mechanical loading on the left ventricle and induces a distinctive ventricular remodeling response known as eccentric hypertrophy. Drug therapies may alleviate symptoms, but only mitral valve repair can provide significant recovery of cardiac function and dimensions. However, 20% of patients still develop systolic dysfunction post-operatively despite being treated according to the current guidelines. Thus, better understanding of the hypertrophic process in the setting of ventricular volume overload (VO) is needed to improve and better personalize the management of MR. To address this knowledge gap, we employ a Bayesian approach to combine data from 70 studies on experimental volume overload in dogs and rats and use it to calibrate a logic-based network model of hypertrophic signaling in myocytes. The calibrated model suggests that growth in experimental VO is mostly driven by the neurohormonal response, with an initial increase in myocardial tissue stretch being compensated by subsequent remodeling fairly early in the time course of VO. This observation contrasts with a common perception that volume-overload hypertrophy is driven primarily by increased myocyte strain. The model suggests that Endothelin1 receptor activity plays a central role in driving hypertrophic responses and the activation of the fetal gene program. The model reproduces a number of responses to drug therapy not used in its calibration, and predicts that a combination of endothelin receptor antagonist and angiotensin receptor blockers would have the greatest potential to dampen cardiomyocyte hypertrophy and dysfunction in VO.

Role of Filamin C in Muscle Cells.

Filamin C (FLNC) is a member of a high-molecular weight protein family, which bind actin filaments in the cytoskeleton of various cells. In human genome FLNC is encoded by the FLNC gene located on chromosome7 and is expressed predominantly in striated skeletal and cardiac muscle cells. FilaminC is involved in organization and stabilization of thin actin filaments three-dimensional network in sarcomeres, and is supposed to play a role of mechanosensor transferring mechanical signals to different protein targets. Under mechanical stress FLNC can undergo unfolding that increases the risk of its aggregation. FLNC molecules with an impaired native structure could be eliminated by the BAG3-mediated chaperone-assisted selective autophagy. Mutations in the FLNC gene could be accompanied by the changes in FLNC interaction with its protein partners and could lead to formation of aggregates, which overload the autophagy and proteasome protein degradation systems, thus facilitating development of various pathological processes. Molecular mechanisms of the FLNC-associated congenital disorders, called filaminopathies, remain poorly understood. This review is devoted to analysis of the structure and mechanisms of filamin C function in muscle and heart cells in normal state and in the FLNC-associated pathologies. The presented data summarize the results of research at the molecular, cellular, and tissue levels and allow us to outline promising ways for further investigation of pathogenetic mechanisms in filaminopathies.

Abstract P355: Multiomic Analyses Reveal Sex-specific Mechanisms Governing Cardiac Fibrosis.

Cardiac fibrosis—the deposition of excess extracellular matrix in the heart—occurs during pathological cardiac remodelling and precedes cardiac dysfunction and heart failure. Experimental and clinical data show that both cardiac fibrosis and heart failure exhibit sex-specific differences, particularly in the absence of ischemic injury. However, no study to date has systematically examined this, or the hormonal mechanisms driving these differences, using high-resolution single-cell and spatial omics. To address this gap, we applied single-cell and spatial omics to map the quality and distribution of non-ischemic cardiac fibrosis in human and mouse hearts. Further, to query the impact of sex hormones on cardiac fibrosis development, we analysed hearts of castrated (CAST) and ovariectomized (OVX) mice, which were ectopically infused with angiotensin-II (AngII). Using single cell transcriptomic data of hypertensive mouse hearts, we identified a fibroblast population driving cardiac fibrosis with a unique gene signature. We confirmed the presence of these cells in multiple mouse models and aged donor human hearts. Spatial mapping of fibrosis showed a sex-specific distribution of fibrosis, specifically in the development of perivascular fibrosis in the heart. Hypertensive male mice exhibited extensive perivascular fibrosis, and coronary artery adventitial hypertrophy, which was absent in females. However, OVX resulted in the development of perivascular fibrosis in hypertensive mice suggesting a cardioprotective role of estrogen. Confirming these observations, spatial transcriptomic analyses showed distinct fibrotic signatures driving perivascular and interstitial fibrosis, and transcriptomic differences between females and males. Our findings provide fundamental new insights towards the importance of biological sex in driving cardiac fibrosis, pointing to new mechanisms that may be manipulated to ameliorate development of heart failure.

P227 MACROPHAGE TO MYOFIBROBLAST TRANSITION IN THE DEVELOPMENT OF DIASTOLIC DYSFUNCTION

Diastolic dysfunction (DD) and heart failure (HF) ravage a significant portion of the world's population. These end-stage diseases are most often precluded by hypertension (HTN). Cardiac fibrosis is one of the major factors in the degradation of cardiac function. There are multiple cellular players involved in fibrosis—including, macrophages. Indeed, in the past decade these cells have been shown to differentiate into professional fibrotic cells, myofibroblasts, a process termed macrophage to myofibroblast transition (MMT), in models of kidney injury. Despite this, the role of MMT in fibrotic remodeling in HTN and DD remains unknown. As such, we seek to investigate this phenomenon in the HTN heart and determine the role it plays in the pathological progression of HTN to DD. We utilized cardiac ultrasound and direct left ventricular (LV) pressure catheterization to gauge diastolic function. These gold-standard methods allowed us to assess cardiac function during HTN and investigate the heart at the transition to DD. Furthermore, flow cytometry was utilized to identify MMT cells (α-SMA+, CD68+) in the heart. These methods gave insight into the role that MMT plays in the degradation of heart function during HTN that inevitably leads to DD and HF. Cardiac ultrasound revealed that E/A and deceleration time (DcT) were greatly decreased in DOCA mice 10 days after the start of HTN. Further, LV pressure catheterization revealed decreased cardiac function, as shown by decreased -dp/dt. Finally, HTN and normal hearts were harvested and leukocytes isolated. Indeed α-SMA and CD68 staining showed a significant increase in MMT cells in the HTN heart. This study has shown a rapid onset of DD inside of DOCA + salt HTN mice. In addition, there was a significant increase of MMT cells in these same hearts, elucidating a novel mechanism of cardiac fibrosis. Future studies will aim to parse out the gravity of MMT in HTN to find new pharmaceutical targets against this debilitating disease.

The Interplay between Mechanoregulation and ROS in Heart Physiology, Disease, and Regeneration.

Cardiovascular diseases are currently the most common cause of death in developed countries. Due to lifestyle and environmental factors, this problem is only expected to increase in the future. Reactive oxygen species (ROS) are a key player in the onset of cardiovascular diseases but also have important functions in healthy cardiac tissue. Here, the interplay between ROS generation and cardiac mechanical forces is shown, and the state of the art and a perspective on future directions are discussed. To this end, an overview of what is currently known regarding ROS and mechanosignaling at a subcellular level is first given. There the role of ROS in mechanosignaling as well as the interplay between both factors in specific organelles is emphasized. The consequences at a larger scale across the population of heart cells are then discussed. Subsequently, the roles of ROS in embryogenesis, pathogenesis, and aging are further discussed, exemplifying some aspects of mechanoregulation. Finally, different models that are currently in use are discussed to study the topics above.

Impacts of Plu kaow (Houttuynia cordata Thunb.) Ethanolic Extract on Diabetes and Dyslipidemia in STZ Induced Diabetic Rats: Phytochemical Profiling, Cheminformatics Analyses, and Molecular Docking Studies.

The increasing prevalence of diabetes and dyslipidemia poses significant health challenges, impacting millions of people globally and leading to high rates of illness and death. This study aimed to explore the potential antidiabetic and hypolipidemic effects of Plu kaow (Houttuynia cordata Thunb.) ethanolic extract (PK) in streptozotocin (STZ) induced diabetic rats, focusing on its molecular mechanisms. Diabetes was induced in fasting Long Evans rats using streptozotocin (65 mg/kg b. w.), with glibenclamide (5 mg/kg/day) used as the standard experimental drug. The treated groups received oral supplementation of PK (500 mg/kg/day) for 28 days. The study evaluated blood glucose levels, lipid status, body weight, liver, kidney, and heart function biomarkers, antioxidant activity, and histological examination of various organs. Additionally, untargeted metabolomics, cheminformatics, and molecular docking were employed to elucidate the probable mechanisms of action of PK. Based on metabolomic profiling data, the PK was found to contain various putative antidiabetic agents such as kaempferol 7-neohesperidoside, isochlorogenic acid C, rutin, datiscin, and diosmin and they have been proposed to significantly (p < 0.001) reduce blood glucose levels and modulated hyperlipidemia. PK also improved the tested liver, kidney, and heart function biomarkers and reversed damage to normal pancreatic, liver, kidney, and heart cells in histological analysis. In conclusion, PK shows promise as a potential treatment or management option for diabetes and hyperlipidemia, as well as their associated complications in diabetic rats.

The role of doxorubicin in the formation of cardiotoxicity is a consensus statement. Part II. Cardiotoxicity of doxorubicin unrelated to myocytes and cardioprotection strategy (review)

Introduction. The use of doxorubicin in clinical practice has shown cumulative and dose-dependent toxic effects on cardiomyocytes, leading to an increase of mortality risk among patients with cancer and as a resulting to restrictions in the indications for its use.Text. A dangerous adverse reaction of doxorubicin is cardiomyopathy, leading to congestive heart failure. Cardiotoxicity is based on at least several pathophysiological mechanisms (described in more detail in the first part of the review), leading to damage to cardiomyocytes as a result of oxidative stress with the formation of free radicals, dysfunction of mitochondria, autophagy, release of nitric oxide and inflammatory mediators, as well as changes in gene expression and proteins leading to apoptosis. The current (second) part of the review provides detailed information on the actual understanding of the pathophysiological mechanisms underlying the described cardiotoxicity, the effect of doxorubicin on other heart cells. The use of cardioprotective strategies will reduce the severity and likelihood of developing cardiotoxicity. This article describes strategies based on reducing the maximum cumulative dose, changing the speed of doxorubicin administration, using pegylated liposomal formulations and cardioprotective agents, as well as exercise.Conclusion. Despite the huge number of scientific papers devoted to various aspects of cardiotoxicity of doxorubicin, its prevention and treatment, this issue requires more careful study and development of more advanced methods of early diagnosis, prevention and more effective therapy the complication.

An investigation on the cardioprotective potential of lichen compound protocetraric acid by H2O2-induced toxicity in H9c2 rat heart cells through in vitro and in silico analysis.

Worldwide, cardiovascular diseases (CVDs) are the leading cause of death and require treatment and prevention. Lichens are symbiotic organisms that are known to produce unique secondary metabolites and have been used as folk medicines. The aim of the study is to emphasize the importance of lichens in improving heart health, with the objective of investigating protocetraric acid, a lichen metabolite, for its antioxidant and cardioprotective potential by using in vitro and in silico techniques. Protocetraric acid (PRC) was isolated, characterized, and tested for antioxidant properties using six assays. In cardiovascular investigations, hydroxymethylglutaryl-coenzymeA reductase (HMGCR), angiotensin-converting enzyme inhibitory, and fibrinolytic capacities, along with enzyme inhibitory kinetics studies, were carried out. In silico toxicology and molecular docking analysis were done to determine the binding sites on target proteins. The cytoprotective ability of PRC was evaluated by H2O2-induced toxicity in H9c2 rat heart cells. Out of six lichens, the extract of F. caperata showed comparatively stronger antioxidant activity in terms of 1,1-diphenyl-2-picryl hydrazil (DPPH), scavenging of nitric oxide (SNO), and ferric reducing potential (FRAP) equivalent values. PRC showed significant antioxidant properties, and with respect to cardiovascular studies, PRC exhibited 86% HMGCR and 82% ACE inhibition, while 57% fibrinolysis at 320µM concentration. Inhibitory kinetic tests of PRC showed competitive and uncompetitive HMGCR and ACE inhibition types respectively. PRC showed minimum binding energies of - 7.9, - 8.9, and - 9.0kcal/mol with 1HWK, 1O8A, and 4BZS. The H9c2 cell line pre-treated with PRC was found to reduce H2O2 toxicity as well as increase cell viability. Protocetraric acid is a potent compound that has been experimentally shown to have hypocholesterolemic, hypotensive, and cardioprotective properties for treating cardiovascular diseases.

CureSCi Metadata Catalog-finding and harmonizing studies for secondary analysis of hydroxyurea use for sickle cell disease.

Sickle cell disease (SCD) is a rare group of inherited red blood cell disorders that affect hemoglobin, resulting in serious multi-system complications. The limited number of patients available to participate in research studies can inhibit investigating sophisticated relationships. Secondary analysis is a research method that involves using existing data to answer new research questions. Data harmonization enables secondary analysis by combining data across studies, especially helpful for rare disease research where individual studies may be small. The National Heart, Lung, and Blood Institute Cure Sickle Cell Initiative (CureSCi) Metadata Catalog is a web-based tool to identify SCD study datasets for conducting data harmonization and secondary analysis. We present a proof-of-concept secondary analysis to explore factors associated with discontinuation of hydroxyurea, a safe and effective first line SCD therapy, to illustrate the utility of the CureSCi Metadata Catalog to expedite and enable more robust SCD research. We performed secondary analysis of SCD studies using a multi-step workflow: develop research questions, identify study datasets, identify variables of interest, harmonize variables, and establish an analysis method. A harmonized dataset consisting of eight predictor variables across five studies was created. Secondary analysis involved a generalized linear model was employed to identify factors that significantly impact hydroxyurea discontinuation. The CureSCi Metadata Catalog provided a platform to efficiently find relevant studies and design a harmonization strategy to prepare data for secondary analysis. Multivariate analysis of the harmonized identified that patients who are older, are female, had a history of blood transfusion therapy, had episodes of acute chest syndrome, and had the SC sickle cell genotype are more likely to stop hydroxyurea treatment. This secondary analysis provides a template for how the CureSCi Metadata Catalog expedites dataset discovery of sickle cell studies for identifying relationships between variables or validating existing findings.

Machine Learning in Identifying Marker Genes for Congenital Heart Diseases of Different Cardiac Cell Types.

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.