Advantageous early-life environments cushion the genetic risk for ischemic heart disease.

In one of the first papers on the impact of early-life conditions on individuals' health in older age, Barker and Osmond [Lancet, 327, 1077-1081 (1986)] show a strong positive relationship between infant mortality rates in the 1920s and ischemic heart disease in the 1970s. We merge historical data on infant mortality rates to 370,000 individual records in the UK Biobank using information on local area and year of birth. We replicate the association between the early-life infant mortality rate and later-life ischemic heart disease in our sample. We then go "beyond Barker," by showing considerable genetic heterogeneity in this association that is robust to within-area as well as within-family analyses. We find no association between the polygenic index and heart disease in areas with the lowest infant mortality rates, but a strong positive relationship in areas characterized by high infant mortality. These findings suggest that advantageous environments can cushion one's genetic disease risk.

SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.

BACKGROUND: Dysregulated metabolism of bioactive sphingolipids, including ceramides and sphingosine-1-phosphate, has been implicated in cardiovascular disease, although the specific species, disease contexts, and cellular roles are not completely understood. Sphingolipids are produced by the serine palmitoyltransferase enzyme, canonically composed of 2 subunits, SPTLC1 (serine palmitoyltransferase long chain base subunit 1) and SPTLC2 (serine palmitoyltransferase long chain base subunit 2). Noncanonical sphingolipids are produced by a more recently described subunit, SPTLC3 (serine palmitoyltransferase long chain base subunit 3). METHODS: The noncanonical (d16) and canonical (d18) sphingolipidome profiles in cardiac tissues of patients with end-stage ischemic cardiomyopathy and in mice with ischemic cardiomyopathy were analyzed by targeted lipidomics. Regulation of SPTLC3 by HIF1α under ischemic conditions was determined with chromatin immunoprecipitation. Transcriptomics, lipidomics, metabolomics, echocardiography, mitochondrial electron transport chain, mitochondrial membrane fluidity, and mitochondrial membrane potential were assessed in the cSPTLC3KO transgenic mice we generated. Furthermore, morphological and functional studies were performed on cSPTLC3KO mice subjected to permanent nonreperfused myocardial infarction. RESULTS: Herein, we report that SPTLC3 is induced in both human and mouse models of ischemic cardiomyopathy and leads to production of atypical sphingolipids bearing 16-carbon sphingoid bases, resulting in broad changes in cell sphingolipid composition. This induction is in part attributable to transcriptional regulation by HIF1α under ischemic conditions. Furthermore, cardiomyocyte-specific depletion of SPTLC3 in mice attenuates oxidative stress, fibrosis, and hypertrophy in chronic ischemia, and mice demonstrate improved cardiac function and increased survival along with increased ketone and glucose substrate metabolism utilization. Depletion of SPTLC3 mechanistically alters the membrane environment and subunit composition of mitochondrial complex I of the electron transport chain, decreasing its activity. CONCLUSIONS: Our findings suggest a novel essential role for SPTLC3 in electron transport chain function and a contribution to ischemic injury by regulating complex I activity.

Integrative Proteomic Analysis Reveals the Cytoskeleton Regulation and Mitophagy Difference Between Ischemic Cardiomyopathy and Dilated Cardiomyopathy.

Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) are the two primary etiologies of end-stage heart failure. However, there remains a dearth of comprehensive understanding the global perspective and the dynamics of the proteome and phosphoproteome in ICM and DCM, which hinders the profound comprehension of pivotal biological characteristics as well as differences in signal transduction activation mechanisms between these two major types of heart failure. We conducted high-throughput quantification proteomics and phosphoproteomics analysis of clinical heart tissues with ICM or DCM, which provided us the system-wide molecular insights into pathogenesis of clinical heart failure in both ICM and DCM. Both protein and phosphorylation expression levels exhibit distinct separation between heart failure and normal control heart tissues, highlighting the prominent characteristics of ICM and DCM. By integrating with omics results, Western blots, phosphosite-specific mutation, chemical intervention, and immunofluorescence validation, we found a significant activation of the PRKACA-GSK3ß signaling pathway in ICM. This signaling pathway influenced remolding of the microtubule network and regulated the critical actin filaments in cardiac construction. Additionally, DCM exhibited significantly elevated mitochondria energy supply injury compared to ICM, which induced the ROCK1-vimentin signaling pathway activation and promoted mitophagy. Our study not only delineated the major distinguishing features between ICM and DCM but also revealed the crucial discrepancy in the mechanisms between ICM and DCM. This study facilitates a more profound comprehension of pathophysiologic heterogeneity between ICM and DCM and provides a novel perspective to assist in the discovery of potential therapeutic targets for different types of heart failure.

Genome-wide association and Mendelian randomization analysis provide insights into the shared genetic architecture between high-dimensional electrocardiographic features and ischemic heart disease.

Observational studies have revealed that ischemic heart disease (IHD) has a unique manifestation on electrocardiographic (ECG). However, the genetic relationships between IHD and ECG remain unclear. We took 12-lead ECG as phenotypes to conduct genome-wide association studies (GWAS) for 41,960 samples from UK-Biobank (UKB). By leveraging large-scale GWAS summary of ECG and IHD (downloaded from FinnGen database), we performed LD score regression (LDSC), Mendelian randomization (MR), and polygenic risk score (PRS) regression to explore genetic relationships between IHD and ECG. Finally, we constructed an XGBoost model to predict IHD by integrating PRS and ECG. The GWAS identified 114 independent SNPs significantly (P value < 5 × 10-8/800, where 800 denotes the number of ECG features) associated with ECG. LDSC analysis indicated significant (P value < 0.05) genetic correlations between 39 ECG features and IHD. MR analysis performed by five approaches showed a putative causal effect of IHD on four S wave related ECG features at lead III. Integrating PRS for these ECG features with age and gender, the XGBoost model achieved Area Under Curve (AUC) 0.72 in predicting IHD. Here, we provide genetic evidence supporting S wave related ECG features at lead III to monitor the IHD risk, and open up a unique approach to integrate ECG with genetic factors for pre-warning IHD.

Global IL4Rα blockade exacerbates heart failure after an ischemic event in mice and humans.

Ischemic heart failure continues to be a highly prevalent disease among westernized countries and there is great interest in understanding the mechanisms preventing or exacerbating disease progression. The literature suggests an important role for the activation of interleukin-13 or interleukin-4 signaling in improving ischemic heart failure outcomes after myocardial infarction in mice. Dupilumab, a neutralizing antibody that inhibits the shared IL13/IL4 receptor subunit IL4Rα, is widely used for conditions such as ectopic dermatitis in humans. If global depletion of IL4Rα influences ischemic heart failure, either in mice or in humans taking dupilumab, is unknown. Here, we investigated the pathophysiological effects of global IL4Rα genetic deletion in adult mice after surgically induced myocardial infarction (MI). We also determined heart failure risk in patients with ischemic heart disease and concomitant usage of dupilumab using the collaborative patient data network TriNetX. Global deletion of IL4Rα results in exacerbated cardiac dysfunction associated with reduced capillary size after myocardial infarction in mice. In agreement with our findings in mice, dupilumab treatment significantly increased the risk of heart failure development in patients with preexisting diagnosis of ischemic heart disease. Our results indicate that systemic IL4Rα signaling is protective against heart failure development in adult mice and human patients specifically following an ischemic event. Thus, the compelling evidence presented hereby advocates for the development of a randomized clinical trial specifically investigating heart failure development after myocardial ischemia in patients taking dupilumab for another underlying condition.NEW & NOTEWORTHY A body of literature suggests a protective role for IL4Rα signaling postmyocardial infarction in mice. Here, our observational study demonstrates that humans taking the IL4Rα neutralizing antibody, dupilumab, have increased incidence of heart failure following an ischemic event. Similarly, global IL4Rα deletion in mice exacerbates heart failure postinfarct. To our knowledge, this is the first study reporting an adverse association in humans of dupilumab use with heart failure following a cardiac ischemic event.

Contributions of elevated CRP, hyperglycaemia, and type 2 diabetes to cardiovascular risk in the general population: observational and Mendelian randomization studies.

OBJECTIVE: To investigate the contributions of low-grade inflammation measured by C-reactive protein (CRP), hyperglycaemia, and type 2 diabetes to risk of ischemic heart disease (IHD) and cardiovascular disease (CVD) death in the general population, and whether hyperglycaemia and high CRP are causally related. RESEARCH DESIGN AND METHODS: Observational and bidirectional, one-sample Mendelian randomization (MR) analyses in 112,815 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study, and bidirectional, two-sample MR with summary level data from two publicly available consortia, CHARGE and MAGIC. RESULTS: Observationally, higher plasma CRP was associated with stepwise higher risk of IHD and CVD death, with hazard ratios and 95% confidence intervals (95%CI) of 1.50 (1.38, 1.62) and 2.44 (1.93, 3.10) in individuals with the 20% highest CRP concentrations. The corresponding hazard ratios for elevated plasma glucose were 1.10 (1.02, 1.18) and 1.22 (1.01, 1.49), respectively. Cumulative incidences of IHD and CVD death were 365% and 592% higher, respectively, in individuals with both type 2 diabetes and plasma CRP ≥ 2 mg/L compared to individuals without either. Plasma CRP and glucose were observationally associated (ß-coefficient: 0.02 (0.02, 0.03), p = 3 × 10- 20); however, one- and two-sample MR did not support a causal effect of CRP on glucose (-0.04 (-0.12, 0.32) and - 0.03 (-0.13, 0.06)), nor of glucose on CRP (-0.01 (-0.08, 0.07) and - 0.00 (-0.14, 0.13)). CONCLUSIONS: Elevated concentrations of plasma CRP and glucose are predictors of IHD and CVD death in the general population. We found no genetic association between CRP and glucose, or vice versa, suggesting that lowering glucose pharmacologically does not have a direct effect on low-grade inflammation.

Interaction of ARRDC4 With GLUT1 Mediates Metabolic Stress in the Ischemic Heart.

BACKGROUND: An ancient family of arrestin-fold proteins, termed alpha-arrestins, may have conserved roles in regulating nutrient transporter trafficking and cellular metabolism as adaptor proteins. One alpha-arrestin, TXNIP (thioredoxin-interacting protein), is known to regulate myocardial glucose uptake. However, the in vivo role of the related alpha-arrestin, ARRDC4 (arrestin domain-containing protein 4), is unknown. METHODS: We first tested whether interaction with GLUTs (glucose transporters) is a conserved function of the mammalian alpha-arrestins. To define the in vivo function of ARRDC4, we generated and characterized a novel Arrdc4 knockout (KO) mouse model. We then analyzed the molecular interaction between arrestin domains and the basal GLUT1. RESULTS: ARRDC4 binds to GLUT1, induces its endocytosis, and blocks cellular glucose uptake in cardiomyocytes. Despite the closely shared protein structure, ARRDC4 and its homologue TXNIP operate by distinct molecular pathways. Unlike TXNIP, ARRDC4 does not increase oxidative stress. Instead, ARRDC4 uniquely mediates cardiomyocyte death through its effects on glucose deprivation and endoplasmic reticulum stress. At baseline, Arrdc4-KO mice have mild fasting hypoglycemia. Arrdc4-KO hearts exhibit a robust increase in myocardial glucose uptake and glycogen storage. Accordingly, deletion of Arrdc4 improves energy homeostasis during ischemia and protects cardiomyocytes against myocardial infarction. Furthermore, structure-function analyses of the interaction of ARRDC4 with GLUT1 using both scanning mutagenesis and deep-learning Artificial Intelligence identify specific residues in the C-terminal arrestin-fold domain as the interaction interface that regulates GLUT1 function, revealing a new molecular target for potential therapeutic intervention against myocardial ischemia. CONCLUSIONS: These results uncover a new mechanism of ischemic injury in which ARRDC4 drives glucose deprivation-induced endoplasmic reticulum stress leading to cardiomyocyte death. Our findings establish ARRDC4 as a new scaffold protein for GLUT1 that regulates cardiac metabolism in response to ischemia and provide insight into the therapeutic strategy for ischemic heart disease.

Low HDL cholesterol and the eNOS Glu298Asp polymorphism are associated with inducible myocardial ischemia in patients with suspected stable coronary artery disease.

BACKGROUND: The endothelial nitric oxide synthase (eNOS) gene deficiency is known to cause impaired coronary vasodilating capability in animal models. In the general clinical population, the eNOS gene polymorphisms, able to affect eNOS activity, were associated with cardiometabolic risk features and prevalence of coronary artery disease (CAD). AIM: To investigate the association of eNOS Glu298Asp gene polymorphism, cardiometabolic profile, obstructive CAD and inducible myocardial ischemia in patients with suspected stable CAD. METHODS: A total of 506 patients (314 males; mean age 62 ± 9 years) referred for suspected CAD was enrolled. Among these, 325 patients underwent stress ECG or cardiac imaging to assess the presence of inducible myocardial ischemia and 436 patients underwent non-invasive computerized tomography or invasive coronary angiography to assess the presence of obstructive CAD. Clinical characteristics and blood samples were collected for each patient. RESULTS: In the whole population, 49.6% of patients were homozygous for the Glu298 genotype (Glu/Glu), 40.9% heterozygotes (Glu/Asp) and 9.5% homozygous for the 298Asp genotype (Asp/Asp). Obstructive CAD was documented in 178/436 (40.8%) patients undergoing coronary angiography while myocardial ischemia in 160/325 (49.2%) patients undergoing stress testing. Patients with eNOS Asp genotype (Glu/Asp + Asp/Asp) had no significant differences in clinical risk factors and in circulating markers. Independent predictors of obstructive CAD were age, gender, obesity, and low HDL-C. Independent predictors of myocardial ischemia were gender, obesity, low HDL-C and Asp genotype. In the subpopulation in which both stress tests and coronary angiography were performed, the Asp genotype remained associated with increased myocardial ischemia risk after adjustment for obstructive CAD. CONCLUSION: In this population, low-HDL cholesterol was the only cardiometabolic risk determinant of obstructive CAD. The eNOS Glu298Asp gene polymorphism was significantly associated with inducible myocardial ischemia independently of other risk factors and presence of obstructive CAD.

Screen time in the development of cardiovascular diseases: A two-sample Mendelian randomization study.

BACKGROUND AND AIMS: Coronary artery disease (CAD), heart failure (HF), and ischemic heart disease (IHD) are three common cardiovascular diseases that are closely associated with metabolic activity. The global incidence and prevalence of these conditions are on the rise, primarily due to unhealthy lifestyles, aging populations, and the increasing prevalence of obesity and diabetes. Excessive screen time has emerged as a potential risk factor for various adverse health outcomes, although limited research has explored its relationship with cardiovascular disease outcomes. METHODS AND RESULTS: A Mendelian randomization (MR) study was conducted, employing exposure-associated genetic variants as instrumental variables to explore the causal relationship between screen time use and cardiovascular disease outcomes. Single nucleotide polymorphisms (SNPs) were utilized as pooled data for the genetic variable instrument, investigating the association between screen use duration and three types of cardiovascular diseases: coronary artery disease (CAD), heart failure (HF), and ischemic heart disease (IHD). Through the MR analysis, it was revealed that the use of mobile phones and TV screens exhibited a significant causal association with the occurrence of CAD, heart failure, and IHD. However, no significant association was observed between the use of computers and these three types of cardiovascular diseases. CONCLUSION: Our study suggests that excessive screen time use is associated with the development of cardiovascular disease. However, it should be noted that the consequences of screen time can vary depending on the reasons and purposes for its use. Implementing reasonable control over screen time, particularly for entertainment purposes, holds promise as a potential approach to mitigating cardiovascular disease.

[Anti-myocardial ischemic injury effects and mechanisms of cryptotanshinone in regulating macrophage polarisation through Dectin-1 signalling pathway].

The aim of this study was to investigate the potential mechanism by which cryptotanshinone(CTS) may exert its anti-myo-cardial ischemic effect through the regulation of macrophage polarization via the dendritic cell-associated C-type lectin 1(Dectin-1) signaling pathway. Male C57BL/6 mice, aged six weeks, were utilized to establish myocardial ischemia models and were subsequently divided into five groups: sham, model, CTS low-dose(21 mg·kg~(-1)·d~(-1)), CTS high-dose(84 mg·kg~(-1)·d~(-1)), and dapagliflozin(0.14 mg·kg~(-1)·d~(-1)). The cardiac function, serum enzyme levels, Dectin-1 expression, macrophage polarization, and neutrophil infiltration in the myocardial infarction area were assessed in each group. An in vitro model of M1-type macrophages was constructed using lipopolysaccharide/interfe-ron-γ(LPS/IFN-γ) stimulated RAW264.7 cells to investigate the impact of CTS on macrophage polarization and to examine alterations in key proteins within the Dectin-1 signaling pathway. In the CTS group, compared to the model group mice, there was a significant improvement in the cardiac function and myocardial injury, along with a notable increase in the ratio of M2/M1-type macrophages in the myocardial infarcted area and a decrease in neutrophil infiltration. Additionally, Dectin-1 exhibited low expression. The results of in vitro experiments demonstrated that CTS can decrease the expression of M1-type marker genes and increase the expression of M2-type marker genes. Besides, it can decrease the levels of Dectin-1 and the phosphorylation of its associated proteins, including spleen tyrosine kinase(Syk), protein kinase B(Akt), nuclear factor-kappaB p65(NF-κB p65), and extracellular signal-regulated protein kinases(ERK1/2). Additionally, CTS was found to enhance the phosphorylation of signal transducer and activator of transcription-6(STAT6). The above results suggest that CTS exerts its anti-myocardial ischemic injury effect by regulating macrophage polarization through the Dectin-1 signaling pathway.

An effective disease diagnostic model related to pyroptosis in ischemic cardiomyopathy.

Pyroptosis is involved in ischemic cardiomyopathy (ICM). The study aimed to investigate the pyroptosis-related genes and clarify their diagnostic value in ICM. The bioinformatics method identified the differential pyroptosis genes between the normal control and ICM samples from online datasets. Then, protein-protein interaction (PPI) and function analysis were carried out to explore the function of these genes. Following, subtype analysis was performed using ConsensusClusterPlus, functions, immune score, stromal score, immune cell proportion and human leukocyte antigen (HLA) genes between subtypes were investigated. Moreover, optimal pyroptosis genes were selected using the least absolute shrinkage and selection operator (LASSO) analysis to construct a diagnostic model and evaluate its effectiveness using receiver operator characteristic (ROC) analysis. Twenty-one differential expressed pyroptosis genes were identified, and these genes were related to immune and pyroptosis. Subtype analysis identified two obvious subtypes: sub-1 and sub-2. And LASSO identified 13 optimal genes used to construct the diagnostic model. The diagnostic model in ICM diagnosis with the area under ROC (AUC) was 0.965. Our results suggested that pyroptosis was tightly associated with ICM.

Bioinformatics and experimental analyses of glutamate receptor and its targets genes in myocardial and cerebral ischemia.

BACKGROUND: There is a mutual hemodynamic and pathophysiological basis between the heart and brain. Glutamate (GLU) signaling plays an important role in the process of myocardial ischemia (MI) and ischemic stroke (IS). To further explore the common protective mechanism after cardiac and cerebral ischemic injuries, the relationship between GLU receptor-related genes and MI and IS were analyzed. RESULTS: A total of 25 crosstalk genes were identified, which were mainly enriched in the Toll-like receptor signaling pathway, Th17 cell differentiation, and other signaling pathways. Protein-protein interaction analysis suggested that the top six genes with the most interactions with shared genes were IL6, TLR4, IL1B, SRC, TLR2, and CCL2. Immune infiltration analysis suggested that immune cells such as myeloid-derived suppressor cells and monocytes were highly expressed in the MI and IS data. Memory B cells and Th17 cells were expressed at low levels in the MI and IS data; molecular interaction network construction suggested that genes such as JUN, FOS, and PPARA were shared genes and transcription factors; FCGR2A was a shared gene of MI and IS as well as an immune gene. Least absolute shrinkage and selection operator logistic regression analysis identified nine hub genes: IL1B, FOS, JUN, FCGR2A, IL6, AKT1, DRD4, GLUD2, and SRC. Receiver operating characteristic analysis revealed that the area under the curve of these hub genes was > 65% in MI and IS for all seven genes except IL6 and DRD4. Furthermore, clinical blood samples and cellular models showed that the expression of relevant hub genes was consistent with the bioinformatics analysis. CONCLUSIONS: In this study, we found that the GLU receptor-related genes IL1B, FOS, JUN, FCGR2A, and SRC were expressed in MI and IS with the same trend, which can be used to predict the occurrence of cardiac and cerebral ischemic diseases and provide reliable biomarkers to further explore the co-protective mechanism after cardiac and cerebral ischemic injury.

miR-1322 protects against the myocardial ischemia via LRP8/PI3K/AKT pathway.

INTRODUCTION: Myocardial infarction is a fatal disease that causes millions of deaths worldwide every year. The damage and recovery of cardiomyocytes are closely related to changes in gene expression. miRNA may be a new therapeutic target of myocardial ischemia-reperfusion. METHODS: The differential expression genes were analyzed based on GSE83500, GSE60993 and GSE154733. miRNA expression profile data and clinical data were downloaded from GSE76591. Bioinformatics analysis including limma package, cluster analysis, WGCNA analysis were performed. H9c2 cell hypoxia model and mouse myocardial ischemia model were established. Q-PCR, Western blot and luciferase assay were carried out. RESULTS: miR-1322 was identified as a significantly differentially expressed miRNA in myocardial ischemi. Yin Yang 1(YY1) was significantly highly expressed in cells with hypoxia treatment (P < 0.05), and myocardial ischemia mice (P < 0.01), which was identified as the transcription factor of miR-1322. The protein expression of LRP8 was lower in cells with hypoxia treatment and myocardial ischemia mice (P < 0.05) and LRP8 was the target gene of miR-1322. The overexpression of LRP8 could significantly increase the expression of p-PI3K, p-AKT, and P70 S6K (P < 0.05). LRP8 regulated PI3K/AKT/P70 S6K signaling pathway, eventually resulting in cell apoptosis. CONCLUSION: Our results suggested that miR-1322 can protect against the myocardial ischemia via LRP8/PI3K/AKT pathway.

Relationship between dynamic electrocardiogram and CRP, IL-6, ET-1 expression in myocardial ischemia patients with coronary heart disease.

This study aimed to observe the relationship between dynamic electrocardiogram and CRP, IL-6, and ET-1 expression in individuals with myocardial ischemia and Coronary Heart Disease (CHD). For this purpose, from January 2021 to December 2022, 80 patients with CHD were admitted to the hospital to determine the presence of myocardial ischemia according to coronary angiography. The individuals were separated into a myocardial ischemia group and a no myocardial ischemia group. Dynamic electrocardiogram (DCG), serum CRP, IL-6, and ET-1 were used in the two groups, respectively. The association between dynamic electrocardiogram indexes and serum CRP, IL-6, and ET-1 levels was discovered using a Pearson correlation analysis. Results showed that the SDNN, SDANNI, rMSSD and PNN50 of Patients with Myocardial Ischemia (PWMI) were lower than individuals with CHD without myocardial ischemia (P<0.05). CRP and IL-6 were negatively correlated with SDNN, SDANNI, rMSSD and PNN50 (P<0.001). ET-1 had a bad relationship with rMSSD and PNN50 (P<0.001). Correlation heat map analysis showed that the color difference of IL-6 was the most obvious between PWMI and Patients Without Myocardial Ischemia (POMI), and IL-6 was more strongly correlated with dynamic electrocardiogram-related indexes of myocardial ischemia. In individuals with CHD myocardial ischemia, there is a negative connection between the DCG index and the production of the inflammatory cytokines CRP, IL-6, and ET-1. In conclusion, CRP, IL-6, and ET-1 levels should be monitored in patients with decreased heart rate variability, so as to further determine the level of micro-inflammation and endothelial function.

Bioinformatics Analysis of Differentially Expressed Genes in Ischemic Cardiomyopathy Using GEO Database.

It was to analyze differentially expressed genes and their expression characteristics in ischemic cardiomyopathy (ICM) by bioinformatics and provide targets for drug therapy of ICM. For this purpose, the gene expression data of ICM in the gene expression omnibus (GEO) database were used, the differentially expressed genes between healthy myocardium and ICM myocardium were screened by R language, and then the differentially expressed genes were analyzed by protein-protein interaction (PPI), gene ontology (GO), and KEGG to select the key genes. Results showed that the useful genes of ICM were successfully screened in the GEO database, and KEGG pathway analysis was performed for the differentially expressed genes in ICM tissues, including the main pathways: viral carcinogenesis, energy metabolism, viral response, oxidative phosphorylation, influenza A, extracellular matrix receptor interaction, Epstein-Barr virus infection, chemokine receptor pathway, phagosome, proteasome, and protein digestion and absorption. PPI network analysis showed that C3, F5, FCGR3A, APOB, PENK, LUM, CHRDL1, FCGR3A, CIQB, and FMOD were critical genes. In conclusion, bioinformatics can screen out the key genes in ICM, which is helpful to understand the treatment of drug targets in ICM patients.

Evaluating hs-cTnI serum levels and cTnI gene expression compared with cardiac nuclear scan in patients with angina pectoris.

Exercise stress can cause reversible myocardial ischemia in people with coronary artery disease (CAD). On the other hand, the new troponin biomarker with high sensitivity can detect faster and small amounts of troponin in blood circulation. The present study aimed to investigate the serum troponin level following exercise stress and the result of nuclear heart scans as the gold standard. For this purpose, 93 patients with stable angina and no history of known CAD and organic disease were included in this cross-sectional study. The serum level of the highly sensitive cardiac troponin I (hs-cTnI) was measured 75 minutes after the peak of the exercise test and reached at least 85% of the maximum heart rate. It was compared with the rate of reversible myocardial ischemia based on the nuclear heart scan, the three-month prognosis and the persistence of chest pain were investigated. Also, the expression level of the cTnI gene was evaluated by real-time PCR technique. The results showed that the average age of the patients was 58.9+12.4 years, and 62 (66.66%) patients were female. Reversible myocardial ischemia was observed in 31 patients. The relationship between hs-cTI level and the rate of reversible ischemia cases was significant (p = 0.0041). Also, the cTnI gene expression showed the same results as the serum level. According to the heart nuclear scan report, the hs-cTnI value above 1.6ng/dl had a specificity of 72% and sensitivity of 66%, a positive predictive value of 53%, and a negative predictive value of 78%. There was no significant relationship between hs-cTnI level and prognosis and the continuation of chest pain in patients after three months. Generally, the serum level of high-sensitivity cardiac troponin was higher after exercise in the group with reversible myocardial ischemia.

HOTAIR regulates SIRT3-mediated cardiomyocyte survival after myocardial ischemia/reperfusion by interacting with FUS.

BACKGROUND: Myocardial ischemia/reperfusion (I/R) contributes to serious myocardial injury and even death. Therefore, prevention and mitigation of myocardial I/R is particularly important. LncRNA HOTAIR has been reported to be implicated in myocardial I/R progression. However, the detailed molecular mechanism of HOTAIR in cardiomyocyte was explored in myocardial I/R. METHODS: Firstly, cell model of myocardial I/R was established through hypoxia/reoxygenation (H/R). Apoptosis and cell cycle were evaluated utilizing flow cytometry. The corresponding test kits were conducted to monitor the levels of LDH, Caspase3 and Caspase9. The gene expression and protein levels were detected by qPCR and western blot, respectively. RNA pull-down and RIP were performed to verify the interaction between FUS and lncRNA HOTAIR. RESULTS: In AC16 cardiomyocytes treated with H/R, lncRNA HOTAIR and SIRT3 expression were obviously decreased. Overexpression of HOTAIR or SIRT3 could ameliorate H/R-induced cardiomyocyte injury by promoting cell viability, lowering LDH levels, and suppressing cell apoptosis. Further, lncRNA HOTAIR upregulated the expression of SIRT3 via interacting with FUS, thereby promoting the survival of H/R-injured cardiomyocytes. CONCLUSION: LncRNA HOTAIR can improve myocardial I/R by affecting cardiomyocyte survival through regulation of SIRT3 by binding to the RNA binding protein FUS.

Full-length transcriptomic analysis in murine and human heart reveals diversity of PGC-1α promoters and isoforms regulated distinctly in myocardial ischemia and obesity.

BACKGROUND: Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) acts as a transcriptional coactivator and regulates mitochondrial function. Various isoforms are generated by alternative splicing and differentially regulated promoters. In the heart, total PGC-1α deficiency knockout leads to dilatative cardiomyopathy, but knowledge on the complexity of cardiac isoform expression of PGC-1α remains sparse. Thus, this study aims to generate a reliable dataset on cardiac isoform expression pattern by long-read mRNA sequencing, followed by investigation of differential regulation of PGC-1α isoforms under metabolic and ischemic stress, using high-fat-high-sucrose-diet-induced obesity and a murine model of myocardial infarction. RESULTS: Murine (C57Bl/6J) or human heart tissue (obtained during LVAD-surgery) was used for long-read mRNA sequencing, resulting in full-length transcriptomes including 58,000 mRNA isoforms with 99% sequence accuracy. Automatic bioinformatic analysis as well as manual similarity search against exonic sequences leads to identification of putative coding PGC-1α isoforms, validated by PCR and Sanger sequencing. Thereby, 12 novel transcripts generated by hitherto unknown splicing events were detected. In addition, we postulate a novel promoter with homologous and strongly conserved sequence in human heart. High-fat diet as well as ischemia/reperfusion (I/R) injury transiently reduced cardiac expression of PGC-1α isoforms, with the most pronounced effect in the infarcted area. Recovery of PGC-1α-isoform expression was even more decelerated when I/R was performed in diet-induced obese mice. CONCLUSIONS: We deciphered for the first time a complete full-length transcriptome of the murine and human heart, identifying novel putative PGC-1α coding transcripts including a novel promoter. These transcripts are differentially regulated in I/R and obesity suggesting transcriptional regulation and alternative splicing that may modulate PGC-1α function in the injured and metabolically challenged heart.

Plasma Small Extracellular Vesicle Cardiac miRNA Expression in Patients with Ischemic Heart Failure, Randomized to Percutaneous Intramyocardial Treatment of Adipose Derived Stem Cells or Placebo: Subanalysis of the SCIENCE Study.

Small extracellular vesicles (EVs) and their cargo are an important component of cell-to-cell communication in cardiac disease. Allogeneic adipose derived stem cells (ADSCs) are thought to be a potential approach for cardiac regenerative therapy in ischemic heart disease. The SCIENCE study investigated the effect of ADSCs administered via intramyocardial injection on cardiac function in patients with ischemic heart disease. The aim of this substudy, based on samples from 15 patients, was to explore small EV miRNA dynamics after treatment with ADSCs compared to a placebo. Small EVs were isolated at several timepoints after the percutaneous intramyocardial application of ADSCs. No significant effect of ADSC treatment on small EV concentration was detected. After 12 months, the expression of miR-126 decreased significantly in ADSC patients, but not in the placebo-treated group. However, all cardiac miRNAs correlated with plasma cardiac biomarkers. In line with the overall negative results of the SCIENCE study, with the exception of one miR, we did not detect any significant regulation of small EV miRNAs in this patient collective.

A Network Comprised of miR-15b and miR-29a Is Involved in Vascular Endothelial Growth Factor Pathway Regulation in Thymus Adipose Tissue from Elderly Ischemic Cardiomyopathy Subjects.

As the human thymus ages, it undergoes a transformation into adipose tissue known as TAT. Interestingly, in previous research, we observed elevated levels of vascular endothelial growth factor A (VEGFA) in TAT from patients with ischemic cardiomyopathy (IC), particularly in those over 70 years old. Moreover, in contrast to subcutaneous adipose tissue (SAT), TAT in elderly individuals exhibits enhanced angiogenic properties and the ability to stimulate tube formation. This makes TAT a promising candidate for angiogenic therapies and the regeneration of ischemic tissues following coronary surgery. MicroRNAs (miRNAs) have emerged as attractive therapeutic targets, especially those that regulate angiogenic processes. The study's purpose is to determine the miRNA network associated with both the VEGFA pathway regulation and the enrichment of age-linked angiogenesis in the TAT. RT-PCR was used to analyze angiogenic miRNAs and the expression levels of their predicted target genes in both TAT and SAT from elderly and middle-aged patients treated with coronary artery bypass graft surgery. miRTargetLink Human was used to search for miRNAs and their target genes. PANTHER was used to annotate the biological processes of the predicted targets. The expression of miR-15b-5p and miR-29a-3p was significantly upregulated in the TAT of elderly compared with middle-aged patients. Interestingly, VEGFA and other angiogenic targets were significantly upregulated in the TAT of elderly patients. Specifically: JAG1, PDGFC, VEGFA, FGF2, KDR, NOTCH2, FOS, PDGFRA, PDGFRB, and RHOB were upregulated, while PIK3CG and WNT7A were downregulated. Our results provide strong evidence of a miRNA/mRNA interaction network linked with age-associated TAT angiogenic enrichment in patients with IC.