Cellular nucleic acid binding protein facilitates cardiac repair after myocardial infarction by activating ß-catenin signaling.

The regenerative capacity of the adult mammalian heart is limited, while the neonatal heart is an organ with regenerative and proliferative ability. Activating adult cardiomyocytes (CMs) to re-enter the cell cycle is an effective therapeutic method for ischemic heart disease such as myocardial infarction (MI) and heart failure. Here, we aimed to reveal the role and potential mechanisms of cellular nucleic acid binding protein (CNBP) in cardiac regeneration and repair after heart injury. CNBP is highly expressed within 7 days post-birth while decreases significantly with the loss of regenerative ability. In vitro, overexpression of CNBP promoted CM proliferation and survival, whereas knockdown of CNBP inhibited these processes. In vivo, knockdown of CNBP in CMs robustly hindered myocardial regeneration after apical resection in neonatal mice. In adult MI mice, CM-specific CNBP overexpression in the infarct border zone ameliorated myocardial injury in acute stage and facilitated CM proliferation and functional recovery in the long term. Quantitative proteomic analysis with TMT labeling showed that CNBP overexpression promoted the DNA replication, cell cycle progression, and cell division. Mechanically, CNBP overexpression increased the expression of ß-catenin and its downstream target genes CCND1 and c-myc; Furthermore, Luciferase reporter and Chromatin immunoprecipitation (ChIP) assays showed that CNBP could directly bind to the ß-catenin promoter and promote its transcription. CNBP also upregulated the expression of G1/S-related cell cycle genes CCNE1, CDK2, and CDK4. Collectively, our study reveals the positive role of CNBP in promoting cardiac repair after injury, providing a new therapeutic option for the treatment of MI.

Association of glycation gap with all-cause and cardiovascular mortality in US adults: A nationwide cohort study.

AIM: To investigate the relationship of the glycation gap (GGap) with all-cause and cardiovascular (CV) mortality in US adults. METHODS: This was a retrospective cohort study comprising 12 909 individual participant data from the National Health and Nutrition Examination Survey from 1999 to 2004 and their mortality data through 31 December 2019. Weighted Cox proportional hazards regression models and restricted cubic splines were used to investigate the associations between GGap and mortality. RESULTS: During a median follow-up of 16.8 years, 3528 deaths occurred, including 1140 CV deaths. The associations of GGap with risk of all-cause and CV mortality were U-shaped (both P for non-linearity < .001). Compared with individuals with a GGap of 0.09%-0.38% (61st-80th centiles), the multivariable-adjusted HRs and 95% CIs for individuals with a GGap less than -0.83% (first-fifth centiles) and individuals with a GGap greater than 0.90% (96th-100th centiles) were 1.36 (1.10, 1.69) and 1.21 (1.00, 1.45) for all-cause mortality, and 1.77 (1.16, 2.71) and 1.43 (1.04, 1.95) for CV mortality. The GGap value associated with the lowest risk of all-cause and CV mortality was 0.38% in the general population and 0.78% among individuals with diabetes. CONCLUSIONS: We found a U-shaped association between GGap and all-cause and CV mortality, with significant positive or negative GGap values associated with increased mortality risk, probably because of glycaemic variability and fructosamine-3-kinase activity.

Association of serum osmolality with all-cause and cardiovascular mortality in US adults: A prospective cohort study.

BACKGROUND AND AIMS: The association between serum osmolality, an effective indicator of body hydration status, and long-term mortality in the general population remains undetermined. The present study aimed to investigate the association of serum osmolality with long-term all-cause and cardiovascular mortality among adults in the United States. METHODS AND RESULTS: This cohort study used data from the National Health and Nutrition Examination Survey (NHANES) 2007-2014. Participants were linked to National Death Index mortality data from the survey date through December 31, 2019. Cox proportional hazards regression model was used to calculate hazard ratios (HRs) and 95% CIs, and restricted cubic spline (RCS) regression was conducted. A total of 18312 US adults were included. During a median follow-up of 8.7 years, 1353 total deaths occurred, including 379 cardiovascular deaths. After multivariable adjustments, compared with the 3rd quartile (Q3) of serum osmolality, participants in the 1st (Q1) and 4th (Q4) quartiles were at a significantly higher risk of all-cause mortality (HR 1.41 [95% CI, 1.14-1.75] and 1.29 [95% CI, 1.04-1.61], respectively). RCS revealed a nonlinear relationship of serum osmolality to all-cause and cardiovascular mortality, with an inflection point of 278 mmol/kg. CONCLUSION: In the nationally representative cohort of US adults, serum osmolality was nonlinearly associated with all-cause and cardiovascular mortality. The risk of mortality was lowest around an osmolality of 278 mmol/kg. These findings suggest the importance of serum osmolality management for long-term health outcomes.

SIRT3-dependent mitochondrial redox homeostasis mitigates CHK1 inhibition combined with gemcitabine treatment induced cardiotoxicity in hiPSC-CMs and mice.

Administration of CHK1-targeted anticancer therapies is associated with an increased cumulative risk of cardiac complications, which is further amplified when combined with gemcitabine. However, the underlying mechanisms remain elusive. In this study, we generated hiPSC-CMs and murine models to elucidate the mechanisms underlying CHK1 inhibition combined with gemcitabine-induced cardiotoxicity and identify potential targets for cardioprotection. Mice were intraperitoneally injected with 25 mg/kg CHK1 inhibitor AZD7762 and 20 mg/kg gemcitabine for 3 weeks. hiPSC-CMs and NMCMs were incubated with 0.5 uM AZD7762 and 0.1 uM gemcitabine for 24 h. Both pharmacological inhibition or genetic deletion of CHK1 and administration of gemcitabine induced mtROS overproduction and pyroptosis in cardiomyocytes by disrupting mitochondrial respiration, ultimately causing heart atrophy and cardiac dysfunction in mice. These toxic effects were further exacerbated with combination administration. Using mitochondria-targeting sequence-directed vectors to overexpress CHK1 in cardiomyocyte (CM) mitochondria, we identified the localization of CHK1 in CM mitochondria and its crucial role in maintaining mitochondrial redox homeostasis for the first time. Mitochondrial CHK1 function loss mediated the cardiotoxicity induced by AZD7762 and CHK1-knockout. Mechanistically, mitochondrial CHK1 directly phosphorylates SIRT3 and promotes its expression within mitochondria. On the contrary, both AZD7762 or CHK1-knockout and gemcitabine decreased mitochondrial SIRT3 abundance, thus resulting in respiration dysfunction. Further hiPSC-CMs and mice experiments demonstrated that SIRT3 overexpression maintained mitochondrial function while alleviating CM pyroptosis, and thereby improving mice cardiac function. In summary, our results suggest that targeting SIRT3 could represent a novel therapeutic approach for clinical prevention and treatment of cardiotoxicity induced by CHK1 inhibition and gemcitabine.

Evaluating the Utility of Colchicine in Acute Coronary Syndrome: A Systematic Review and Meta-Analysis.

ABSTRACT: Colchicine has demonstrated promising effects in inhibiting local and systemic inflammation during acute coronary syndrome (ACS). However, the efficacy of colchicine in ACS is controversial. We performed a meta-analysis to assess the utility of colchicine in ACS by systematically searching randomized controlled trials. Recurrent myocardial infarction, coronary revascularization, and stroke were included as efficacy endpoint parameters whereas safety endpoints chosen were all-cause mortality, cardiovascular mortality, infectious events, and gastrointestinal (GI) adverse events. Nine identified studies were included (n = 7207 participants). Colchicine may reduce the risk of coronary revascularization by 54% [relative risk (RR) 0.46, 95% confidence interval (CI) 0.29-0.73; P < 0.01] and stroke by 61% (RR 0.39, 95%CI 0.18-0.81; P = 0.01). We observed no significant difference in all-cause mortality (RR 1.25, 95%CI 0.70-2.24; P = 0.46), cardiovascular mortality (RR 0.99, 95%CI 0.58-1.69; P = 0.98), recurrent myocardial infarction (RR 0.75, 95%CI 0.49-1.14; P = 0.18), and infectious events (RR 0.67, 95%CI 0.08-5.52; P = 0.71). Colchicine increased the risk of GI adverse reactions (RR 1.89, 95%CI 1.25-2.84; P < 0.01). Subgroup analysis of loading doses did not reveal significant differences in all endpoints (all P > 0.05), whereas subgroup analysis of follow-up periods showed a lower risk of GI adverse reactions with longer follow-up ( P < 0.01), which may be related to establishing tolerability. Trial sequential analysis suggested that further data are needed before definitive conclusions can be drawn. Colchicine may decrease the occurrence of stroke and revascularization in ACS, whereas slightly increasing the risk of GI reactions. The loading doses probably did not significantly improve the prognosis of patients.

LncRNA FAF inhibits fibrosis induced by angiotensinogen II via the TGFß1-P-Smad2/3 signalling by targeting FGF9 in cardiac fibroblasts.

The dysregulation of Long noncoding RNAs (lncRNAs) has been implicated in many cardiovascular diseases, including cardiac fibrosis. However, the functions and mechanisms of lncRNAs in cardiac fibroblasts (CFs) have not been fully elucidated. First, we observed a correlation between cardiac remodeling (CR) and lncRNA FAF (FGF9-associated factor, termed FAF) expression in the heart. In vitro, we found that the expression of lncRNA FAF was altered in CFs, whereas it behaved inconsistently in cardiomyocytes (CMs). Next, we investigated the effects of lncRNA FAF on angiotensinogen II (Ang II)-induced cardiac fibrosis in neonatal rat CFs and explored the mechanism underlying these effects. In this study, lncRNA FAF was enriched in CFs and was associated with cardiac fibrosis. Upregulation of lncRNA FAF significantly restrained Ang II-induced increases in cell proliferation, differentiation and collagen accumulation of CFs. Moreover, we found that the function of lncRNA FAF was mainly realized through Transforming growth factor ß1 (TGFß1) secretion and then downregulated phosphorylation of Smad2/3. Additional analysis revealed that Fibroblast growth factor 9 (FGF9) is a direct target of lncRNA FAF, as the overexpression of lncRNA FAF could increase the expression of FGF9 and knockdown of the FGF9 expression could attenuate the down-regulation of lncRNA FAF on TGFß1-P-Smad2/3 pathway. Furthermore, knockdown of the FGF9 expression also abolished the inhibitory effect of FAF on fibrosis. In summary, we demonstrated that the overexpression of lncRNA FAF could inhibit fibrosis induced by Ang II via the TGFß1-P-Smad2/3 signalling by targeting FGF9 in CFs.

Association between circular RNA expression content and severity of coronary atherosclerosis in human coronary artery.

BACKGROUND: Circular RNAs (circRNAs) may act as biomarkers of coronary artery disease (CAD). However, the relationship between expression characteristics of circRNAs and coronary atherosclerosis has not been fully explored. The aim of this study was to determine and characterize the circRNAs from human coronary artery. METHODS: The coronary artery segments were obtained from an 81-year-old male patient with sudden death of myocardial infarction at autopsy. The coronary stenosis and atherosclerosis were evaluated by hematoxylin and eosin (H&E) staining, and the circRNAs expression profile was characterized by RNA sequencing (RNA-seq). The differentially expressed circRNAs were validated by qRT-PCR. RESULTS: The analysis of H&E staining indicated that coronary atherosclerosis grade and extent in the LM was more serious than that in other coronary arteries. Twenty-seven circRNAs were selected for expression validation in coronary artery. CircRNAs corresponding cyclization sites of 3 circRNAs (hsa_circ_0016868, hsa_circ_0001364, hsa_circ_0006731) have been verified by Sanger sequencing. CONCLUSION: The 3 circRNAs are suggested to play a pathological role underlying the coronary arteries atherosclerosis and may serve as a valuable resource as diagnostic or therapeutic targets against CAD.

Potential of Sagittaria trifolia for Phytoremediation of Diesel.

The phytoremediation potential and responses of Sagittaria trifolia to diesel were investigated. In order to elucidate the biochemical and physiological responses of S. trifolia to diesel, the chlorophyll content, root vitality, soluble protein content and antioxidant enzymes activity (peroxidase (POD), catalase (CAT) and antioxidant enzymes superoxide dismutase (SOD)) were determined in the plant tissues after 50 d of diesel treatment. The results showed the presence of S. trifolia significantly improved the removal ratios of diesel, from 21∼36% in the control soils to 54∼85% in the planted soils. The chlorophyll content, root vitality and soluble protein content all increased at low diesel concentration, then decreased at high diesel concentration. The activities of CAT and POD exhibited peak values at 5 g·kg(-1) diesel treatment and declined at higher diesel concentrations. However, the activity of SOD kept stable at lower diesel concentration (1 and 5 g·kg(-1)), and also declined at higher diesel concentration. Collectively, S. trifolia had the ability to tolerate certain amount of diesel, but when the concentration was up to 10 g·kg(-1), the growth of S. trifolia would be restrained. The results also showed that variation of antioxidant enzyme activity was an important response in plants to diesel pollution.

Symptom-to-balloon time and risk of ventricular arrhythmias in patients with STEMI undergoing percutaneous coronary intervention: The VERY-STEMI study.

Background: Ventricular arrhythmias (VAs) mainly occur in the early post-myocardial infarction (MI) period. However, studies examining the association between total myocardial ischemia time interval and the risk of new-onset VAs during a long-term follow-up are scarce. Methods: This study (symptom-to-balloon time and VEntricular aRrhYthmias in patients with STEMI, VERY-STEMI study) was a multicenter, observational cohort and real-world study, which included patients with ST-segment elevation MI (STEMI) undergoing percutaneous coronary intervention (PCI). The primary endpoint was cumulative new-onset VAs during follow-up. The secondary endpoints were the major adverse cardiovascular events (MACE) and changes in left ventricular ejection fraction (ΔLVEF, %). Results: A total of 517 patients with STEMI were included and 236 primary endpoint events occurred. After multivariable adjustments, compared to patients with S2BT of 24 h-7d, those with S2BT ≤ 24 h and S2BT > 7d had a lower risk of primary endpoint. RCS showed an inverted U-shaped relationship between S2BT and the primary endpoint, with an S2BT of 68.4 h at the inflection point. Patients with S2BT ≤ 24 h were associated with a lower risk of MACE and a 4.44 increase in LVEF, while there was no significant difference in MACE and LVEF change between the S2BT > 7d group and S2BT of 24 h-7d group. Conclusions: S2BT of 24 h-7d in STEMI patients was associated with a higher risk of VAs during follow-up. There was an inverted U-shaped relationship between S2BT and VAs, with the highest risk at an S2BT of 68.4 h.

PEX3 promotes regenerative repair after myocardial injury in mice through facilitating plasma membrane localization of ITGB3.

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3ß signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.

Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

BACKGROUND: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. METHODS AND RESULTS: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. CONCLUSIONS: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

P16INK4a Regulates ROS-Related Autophagy and CDK4/6-Mediated Proliferation: A New Target of Myocardial Regeneration Therapy.

Neonatal mice achieve complete cardiac repair through endogenous myocardial regeneration after apical resection (AR), but this capacity is rapidly lost 7 days after birth. As an upstream inhibitor of cyclin-dependent kinase 4/6- (CDK4/6-) mediated cell cycle activity, p16INK4a is widely involved in regulating tumor and senescence. Given that p16INK4a had a significant negative regulation on cell proliferation, targeting cardiomyocytes (CMs) to inhibit p16INK4a seems to be a promising attempt at myocardial regeneration therapy. The p16INK4a expression was upregulated during perimyocardial regeneration time. Knockdown of p16INK4a stimulated CM proliferation, while p16INK4a overexpression had the opposite effect. In addition, p16INK4a knockdown prolonged the proliferation time window of newborn myocardium. And p16INK4a overexpression inhibited cell cycle activity and deteriorated myocardial regeneration after AR. The quantitative proteomic analysis showed that p16INK4a knockdown mediated the cell cycle progression and intervened in energy metabolism homeostasis. Mechanistically, overexpression of p16INK4a causes abnormal accumulation of reactive oxygen species (ROS) to induce autophagy, while scavenging ROS with N-acetylcysteine can alleviate autophagy and regulate p16INK4a, CDK4/6, and CyclinD1 in a covering manner. And the effect of inhibiting the proliferation of p16INK4a-activated CMs was significantly blocked by the CDK4/6 inhibitor Palbociclib. In summary, p16INK4a regulated CM proliferation progression through CDK4/6 and ROS-related autophagy to jointly affect myocardial regeneration repair. Our study revealed that p16INK4a might be a potential therapeutic target for myocardial regeneration after injury.

Association of Urinary Strontium with Cardiovascular Disease Among the US Adults: A Cross-Sectional Analysis of the National Health and Nutrition Examination Survey.

Previous studies have demonstrated the effects of environmental metals on the cardiovascular system. However, the relationship of strontium (Sr) to cardiovascular disease (CVD) in the general population has not been established. This cross-sectional study aimed to investigate the association between urinary Sr (U-Sr) and CVD in the US adults using data of 5255 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2016. Multivariable logistic regression and restricted cubic spline (RCS) regression were performed to assess the association between U-Sr and CVD. After multivariable adjustments, compared to the lowest quartile, the adjusted odds ratios (ORs) of CVD with 95% confidence intervals (CIs) across the quartiles were 0.65 (0.46, 0.92), 0.87 (0.61, 1.25), and 0.78 (0.55, 1.10). RCS plot revealed a nonlinear relationship between U-Sr levels and CVD (P for nonlinearity = 0.004). Threshold effect analysis identified the inflection point of U-Sr for the curve was 90.18 µg/g urinary creatinine (µg/g UCr). Each 1-unit increase in U-Sr was associated with a 1.1% decrease in CVD (OR 0.989; 95% CI 0.980-0.998) on the left side of the inflection point, but no significant association was observed on the right side of the inflection point. This study suggests a nonlinear association of U-Sr with CVD prevalence in the US general adults. These findings may have positive implications for the determination of appropriate Sr levels for public cardiovascular health. Given the cross-sectional study design, further prospective studies are warranted.

Mediation Effect of Body Mass Index on the Association of Urinary Nickel Exposure with Serum Lipid Profiles.

The objective of this study was to determine the relationship of urinary nickel (U-Ni) exposure to serum lipid profiles and the mediation effect of body mass index (BMI) in a US general population. We analyzed the cross-sectional data from 3517 participants in the National Health and Nutrition Examination Survey (NHANES) (2017-March 2020). Multivariable linear regression and restricted cubic spline (RCS) regression were conducted to explore the association of U-Ni with four serum lipids and four lipids-derived indicators. Mediation analysis was performed to examine the effect of BMI on the relationship between U-Ni levels and serum lipid profiles. Compared with the lowest quartile, the ß with 95% confidence intervals (CIs) in the highest quartile were - 12.83 (- 19.42, - 6.25) for total cholesterol (TC) (P for trend < 0.001), - 12.76 (- 19.78, - 5.74) for non-high-density lipoprotein cholesterol (non-HDL-C) (P for trend = 0.001) and - 0.29 (- 0.51, - 0.07) for TC/HDL-C (P for trend = 0.007) in the fully adjusted model. RCS plots showed the linear association of log2-transformed U-Ni levels with TC, non-HDL-C and TC/HDL-C (P for nonlinearity = 0.294, 0.152, and 0.087, respectively). Besides, BMI decreased monotonically in correlation with increasing U-Ni levels (P for trend < 0.001). Mediation analysis revealed that BMI significantly mediated the relationship of U-Ni to TC, non-HDL-C and TC/HDL-C with mediated proportions of 11.17%, 22.20% and 36.44%, respectively. In summary, our findings suggest that BMI mediates the negative association of U-Ni with TC, non-HDL-C, and TC/HDL-C in the US general population.

Association between urinary cadmium level and subclinical myocardial injury in the general population without cardiovascular disease aged ≥ 50 years.

Cadmium (Cd) is a toxic heavy metal linked to an increased risk of cardiovascular disease (CVD). But the relationship between urinary Cd (U-Cd) and electrocardiographic subclinical myocardial injury (SC-MI) in older people is unclear. This study evaluated the connection between U-Cd and SC-MI in people who did not have CVD. The study involved 4269 participants from the National Health and Nutrition Examination Survey III(NHANES III) aged ≥ 50 years and had no history of CVD. The relationship between U-Cd and cardiac infarction/injury score (CIIS) was assessed by multivariable linear regression. Whether U-Cd and SC-MI were correlated was determined by multivariate logistic regression, restricted cubic spline, and subgroup analysis. There was a significant association between U-Cd and CIIS (ß, 1.04, 95% confidence interval (CI): 0.39-1.69; P = 0.003) in the highest quartile and fully adjusted model. After adjusting for relevant confounders, multivariable logistic regression showed that participants in the highest quartile of U-Cd had a greater chance of having SC-MI than those in the first ( OR (95% CI), 1.37(1.13,1.66), P for trend = 0.003), and this relationship was especially strong among hypertensive participants. And a positive linear correlation between U-Cd and the prevalence of SC-MI was shown by restricted cubic spline analysis. U-Cd may be a novel risk element for SC-MI because it is independently and linearly linked to CIIS and SC-MI.

Combination of D-dimer level and neutrophil to lymphocyte ratio predicts long-term clinical outcomes in acute coronary syndrome after percutaneous coronary intervention.

BACKGROUND: High D-dimer (DD) is associated with short-term adverse outcomes in patients with acute coronary syndrome (ACS). In ACS patients who underwent percutaneous coronary intervention (PCI), however, the value of DD (or combined with neutrophil to lymphocyte ratio [NLR]) to predict long-term major adverse cardiovascular events (MACEs) has not been fully evaluated. METHODS: Patients diagnosed with ACS and receiving PCI were included. The primary outcome was MACEs. Cox proportional hazards regression and logistic regression were used to illustrate the relationship between clinical risk factors, biomarkers and MACEs. Survival models were developed based on significant factors and evaluated by the Concordance-index (C-index). RESULTS: The final study cohort was comprised of 650 patients (median age, 64 years; 474 males), including 98 (15%) with MACEs during a median follow-up period of 40 months. According to the cut-off value of DD and NLR, the patients were separated into four groups: high DD or nonhigh DD with high or nonhigh NLR. After adjusting for confounding variables, DD (adjusted hazard ratio [aHR]: 2.39, 95% confidence interval [CI]: 1.52-3.76) and NLR (aHR: 2.71, 95% CI: 1.78-4.11) were independently associated with long-term MACEs. Moreover, patients with both high DD and NLR had a significantly higher risk in MACEs when considering patients with nonhigh DD and NLR as reference (aHR: 6.19, 95% CI: 3.30-11.61). The area under curve increased and reached 0.70 in differentiating long-term MACEs when DD and NLR were combined, and survival models incorporating the two exhibited a stronger predictive power (C-index: 0.75). CONCLUSIONS: D-dimer (or combined with NLR) can be used to predict long-term MACEs in ACS patients undergoing PCI.

Integrated transcriptomic and proteomic analysis reveals potential targets for heart regeneration.

Research on the regenerative capacity of the neonatal heart could open new avenues for the treatment of myocardial infarction (MI). However, the mechanism of cardiac regeneration remains unclear. In the present study, we constructed a mouse model of heart regeneration and then performed transcriptomic and proteomic analyses on them. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and Gene Set Enrichment Analysis (GSEA) of differentially expressed genes (DEGs) were conducted. Western blot (WB) and qPCR analyses were used to validate the hub genes expression. As a result, gene expression at the mRNA level and protein level is not the same. We identified 3186 DEGs and 42 differentially expressed proteins (DEPs). Through functional analysis of DEGs and DEPs, we speculate that biological processes such as ubiquitination, cell cycle, and oxygen metabolism are involved in heart regeneration. Integrated transcriptomic and proteomic analysis identified 19 hub genes and Ankrd1, Gpx3, and Trim72 were screened out as potential regulators of cardiac regeneration through further expression verification. In conclusion, we combined transcriptomic and proteomic analyses to characterize the molecular features during heart regeneration in neonatal mice. Finally, Ankrd1, Gpx3, and Trim72 were identified as potential targets for heart regeneration therapy.

Improved methodology for efficient establishment of the myocardial ischemia-reperfusion model in pigs through the median thoracic incision.

To investigate the feasibility and effectiveness of establishing porcine ischemia-reperfusion models by ligating the left anterior descending (LAD) coronary artery, we first randomly divided 16 male Bama pigs into a sham group and a model group. After anesthesia, we separated the arteries and veins. Subsequently, we rapidly located the LAD coronary artery at the beginning of its first diagonal branch through a mid-chest incision. Then, we loosened and released the ligation line after five minutes of pre-occlusion. Finally, we ligated the LAD coronary artery in situ two minutes later and loosened the ligature 60 min after ischemia. Compared with the sham group, electrocardiogram showed multiple continuous lead ST-segment elevations, and ultrasound cardiogram showed significantly lower ejection fraction and left ventricular fractional shortening at one hour and seven days post-operation in the model group. Twenty-four hours after the operation, cardiac troponin T and creatine kinase-MB isoenzyme levels significantly increased in the model group, compared with the sham group. Hematoxylin and eosin staining showed the presence of many inflammatory cells infiltrating the interstitium of the myocardium in the model group but not in the sham group. Masson staining revealed a significant increase in infarct size in the ischemia/reperfusion group. All eight pigs in the model group recovered with normal sinus heart rates, and the survival rate was 100%. In conclusion, the method can provide an accurate and stable large animal model for preclinical research on ischemia/reperfusion with a high success rate and homogeneity of the myocardial infarction area.

Association between urinary thallium exposure and cardiovascular disease in U.S. adult population.

Exposure to environmental metals, especially heavy metals, can damage human health. However, the association between metals and the prevalence of cardiovascular disease (CVD) remains controversial. The objective of this study was to determine the relationship of urinary metals to CVD in a general population of U.S. adults. We analyzed the cross-sectional data from 6867 adult (age ≥20 years) participants with 12 urinary metals in the National Health and Nutrition Examination Survey (NHANES) (2011-2016). Multivariate logistic regression and restricted cubic spline (RCS) regression were conducted to explore the association between urinary metals and CVD outcomes. Sensitivity analyses were performed to test the robustness of the results. Compared to the lowest quartile, the odds ratios with 95% confidence intervals for CVD across the quartiles were 0.73 (0.38, 1.42), 0.58 (0.42, 0.81), and 0.71 (0.59, 0.84) for urinary thallium (U-Tl) (P for trend <0.001). RCS plot showed the nonlinear association between log2-transformed U-Tl levels and CVD (P for nonlinearity = 0.001). Sensitivity analyses confirmed the robustness. Higher concentrations of urinary cobalt, manganese and tungsten were associated with an increased risk of CVD. In summary, the large sample data suggests U-Tl is nonlinearly and negatively associated with the prevalence of CVD in the U.S. general adults with low exposure levels. Considering the shortcomings of cross-sectional study design, further studies are warranted to verify our results and to clarify the potential mechanisms.

Association of hemoglobin glycation index and glycation gap with cardiovascular disease among US adults.

AIMS: To investigate the association of hemoglobin glycation index (HGI) and glycation gap (GGap), reflecting mismatches between HbA1c and other measures of glycemia, with cardiovascular disease (CVD) in the general population. METHODS: 5966 US adult (age ≥ 20 years) participants were included from the National Health and Nutrition Examination Survey (NHANES) (1999-2004). In this cross-sectional study, predicted HbA1c was calculated based on fasting plasma glucose (FPG) and glycated albumin (GA), respectively. Multivariable binary logistic regression analysis was performed to explore the association of HGI and GGap with CVD prevalence. RESULTS: Compared to the lowest tertile, the ORs with 95% CIs for CVD across the tertiles were 1.41 (1.01, 1.96) and 0.87 (0.58, 1.31) for HGI (P for trend = 0.535) and 1.06 (0.77, 1.47) and 1.60 (1.18, 2.17) for GGap (P for trend = 0.002) in the fully-adjusted model. Besides, the discordantly high GGap/low HbA1c group was associated with higher CVD prevalence compared with the low GGap/high HbA1c group (OR = 1.50, 95% CI, 1.04-2.16, P = 0.030). CONCLUSIONS: GGap derived from GA is associated with CVD independent of traditional risk factors, even HbA1c, in US general adults. Considering the potential limitations of HbA1c, the introduction of GGap is warranted.