Time to Benefit and Harm of Direct Oral Anticoagulants in Device-Detected Atrial Fibrillation: A Pooled Analysis of the NOAH-AFNET 6 and ARTESiA Trials.

BACKGROUND: Direct oral anticoagulants (DOACs) reduce stroke risk in patients with device-detected atrial fibrillation (DD-AFib) but increase major bleeding risk. The time to benefit (TTB) and time to harm (TTH) are not well quantified. OBJECTIVE: To determine TTB and TTH in DOACs-treated DD-AFib patients. METHODS: Studies were identified from PubMed searching until November 2023. The primary efficacy outcome was the time to first stroke event, and the primary safety outcome was the time to the first major bleeding event. Pooled hazard ratio (HR) and its confidence interval (CI) were calculated through reconstructed patient-level data and study-level data. Weibull model and Markov chain Monte Carlo simulation were applied to determine time to specific absolute risk change thresholds. RESULTS: Two trials involving DOACs, NOAH-AFNET 6 and ARTESiA, were identified, which randomized 6,548 adults with mean age over 75 and a median atrial high-rate episode duration ranging from 1.5 to 2.8 hours. DOACs decreased the risk of stroke (HR 0.67, 95% CI: 0.50 to 0.90) but increased the risk of major bleeding (HR 1.57, 95% CI: 1.21 to 2.04). A TTB of 2.67 years was needed to prevent one stroke per 100 DOACs-treated patients, while a TTH of 1.67 years was needed to observe one major bleeding. CONCLUSIONS: In elderly patients with low durations of DD-AFib, DOACs result in a delayed and restricted stroke-preventive benefit while posing an early-onset bleeding risk. Our findings offer new insights into the risk-benefit profile and provide clinicians an additional dimension to facilitate shared decision-making discussions with patients.

PIMT is a novel and potent suppressor of endothelial activation.

Proinflammatory agonists provoke the expression of cell surface adhesion molecules on endothelium in order to facilitate leukocyte infiltration into tissues. Rigorous control over this process is important to prevent unwanted inflammation and organ damage. Protein L-isoaspartyl O-methyltransferase (PIMT) converts isoaspartyl residues to conventional methylated forms in cells undergoing stress-induced protein damage. The purpose of this study was to determine the role of PIMT in vascular homeostasis. PIMT is abundantly expressed in mouse lung endothelium and PIMT deficiency in mice exacerbated pulmonary inflammation and vascular leakage to LPS(lipopolysaccharide). Furthermore, we found that PIMT inhibited LPS-induced toll-like receptor signaling through its interaction with TNF receptor-associated factor 6 (TRAF6) and its ability to methylate asparagine residues in the coiled-coil domain. This interaction was found to inhibit TRAF6 oligomerization and autoubiquitination, which prevented NF-κB transactivation and subsequent expression of endothelial adhesion molecules. Separately, PIMT also suppressed ICAM-1 expression by inhibiting its N-glycosylation, causing effects on protein stability that ultimately translated into reduced EC(endothelial cell)-leukocyte interactions. Our study has identified PIMT as a novel and potent suppressor of endothelial activation. Taken together, these findings suggest that therapeutic targeting of PIMT may be effective in limiting organ injury in inflammatory vascular diseases.

Association Between Platelet Glycoprotein IIb/IIIa Inhibition and In-Hospital Outcomes in ST-Elevation Myocardial Infarction Patients Treated with Coronary Thrombus Aspiration: Findings from the CCC-ACS Project.

PURPOSE: Thrombus aspiration in ST-elevation myocardial infarction (STEMI) with high thrombus burden did not improve clinical outcomes. The clinical efficacy of the bailout use of platelet glycoprotein IIb/IIIa inhibitors (GPIs) in this clinical scenario remains unknown. METHODS: We assessed associations between GPI use and in-hospital major bleeds, ischemic events, and mortality among STEMI patients treated with percutaneous coronary intervention (PCI) and thrombus aspiration in a nationwide acute coronary syndrome registry (the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project). RESULTS: A total of 5896 STEMI patients who received thrombus aspiration were identified, among which 56.3% received GPI therapy. In a 1-to-1 propensity-score-matched cohort, compared with STEMI patients not treated with GPI, GPI use was associated with a 69% increase in major in-hospital bleeds, with an odds ratio (OR) of 1.69, a 95% confidence interval (CI) of 1.08 to 2.65, and a nonsignificant reduction in ischemic events (OR: 0.61, 95% CI: 0.36 to 1.06), as well as a neutral effect on mortality (OR: 0.93, 95% CI: 0.55 to 1.58). However, among patients aged < 60 years, GPI use was associated with a reduction in ischemic events (OR: 0.27, 95% CI: 0.08 to 0.98), and no significant increase in major bleeds was observed. CONCLUSION: In a nationwide registry, routine use of GPI following thrombus aspiration was not associated with reduced in-hospital ischemic events and mortality but at the cost of increased major bleeding. However, for patients aged < 60 years, there may be a potential net benefit.

Endothelial PRMT5 plays a crucial role in angiogenesis after acute ischemic injury.

Arginine methylation mediated by protein arginine methyltransferases (PRMTs) has been shown to be an important posttranslational mechanism involved in various biological processes. Herein, we sought to investigate whether PRMT5, a major type II enzyme, is involved in pathological angiogenesis and, if so, to elucidate the molecular mechanism involved. Our results show that PRMT5 expression is significantly upregulated in ischemic tissues and hypoxic endothelial cells (ECs). Endothelial-specific Prmt5-KO mice were generated to define the role of PRMT5 in hindlimb ischemia-induced angiogenesis. We found that these mice exhibited impaired recovery of blood perfusion and motor function of the lower limbs, an impairment that was accompanied by decreased vascular density and increased necrosis as compared with their WT littermates. Furthermore, both pharmacological and genetic inhibition of PRMT5 significantly attenuated EC proliferation, migration, tube formation, and aortic ring sprouting. Mechanistically, we showed that inhibition of PRMT5 markedly attenuated hypoxia-induced factor 1-α (HIF-1α) protein stability and vascular endothelial growth factor-induced (VEGF-induced) signaling pathways in ECs. Our results provide compelling evidence demonstrating a crucial role of PRMT5 in hypoxia-induced angiogenesis and suggest that inhibition of PRMT5 may provide novel therapeutic strategies for the treatment of abnormal angiogenesis-related diseases, such as cancer and diabetic retinopathy.

The effects of insulin therapy on mortality in diabetic patients undergoing percutaneous coronary intervention.

BACKGROUND: A growing number of studies have reported insulin therapy to be associated with a higher incidence of major adverse cardiac events in diabetic patients with coronary artery disease. However, the relationship between insulin use and the clinical outcomes of patients with diabetes who undergoing percutaneous coronary intervention (PCI) has not been fully clarified. METHODS: A total of 1,069 consecutive patients with diabetes who underwent PCI were enrolled and divided into 2groups: oral hypoglycemic agents (OHA) group (709 patients) and insulin therapy group (360 patients). The primary and secondary endpoints of this study were all-cause death and cardiac death, respectively. RESULTS: At baseline, the maximum creatine kinase-MB (CK-MB), plasma glucose, hemoglobin A1c, high-sensitivity C-reactive protein (CRP), and creatinine levels were higher, while the left ventricular ejection fraction (LVEF) was lower, in the insulin therapy group than in the OHA group. After propensity score matching of baseline characteristics, for patients treated with insulin, the odds ratios of death from any cause in hospital, within 1 year of surgery, and within 2 years of surgery were 12.03 (95% CI: 1.486-97.33, P=0.020), 10.33 (95% CI: 1.21-88.12, P=0.033), and 2.99 (95% CI: 1.22-7.31, P=0.016), respectively, and the odds ratios of cardiac death were 10.33 (95% CI: 1.21-88.12, P=0.033), 6.49 (95% CI: 1.33-31.59, P=0.021), and 5.27 (95% CI: 1.45-19.13, P=0.011), respectively. Generalized estimating equations analysis showed the odds ratios of all-cause death and cardiac death for insulin-treated patients to be 4.77 (95% CI: 1.76-12.95, P=0.002) and 5.38 (95% CI: 1.29-22.96, P=0.023), respectively. CONCLUSIONS: Compared with OHA, insulin therapy significantly increases the risk of in-hospital all-cause and cardiac death in patients with diabetes undergoing PCI, and the risk remains significantly at least 2 years after surgery.

Nur77 Attenuates Inflammasome Activation by Inhibiting Caspase-1 Expression in Pulmonary Vascular Endothelial Cells.

Inflammasomes are intracellular multiprotein complexes that help trigger and maintain the inflammatory response as part of the innate immune system. Recently, it has been increasingly recognized that aberrant inflammasome activation is critically involved in endothelial dysfunction in a variety of human diseases, such as atherosclerosis, acute lung injury (ALI), and type 2 diabetes. The molecular mechanisms underlying endothelial inflammasome activation, however, have not been completely elucidated. In the present study, we identified orphan nuclear receptor Nur77 as a novel regulator in controlling inflammasome activation in vascular endothelial cells (ECs). We demonstrated that LPS-induced inflammasome activation was significantly inhibited by ectopic overexpression of Nur77, predominantly through transcriptional suppression of caspase-1 expression in vascular ECs. Consistent with this observation, we found that LPS-induced inflammasome activation was significantly augmented in lung ECs isolated from Nur77-knockout mice. Mechanistically, we showed that Nur77-induced inhibition of caspase-1 expression was due to an inhibition of IRF1 (IFN regulatory factor 1) expression and its subsequent binding to the caspase-1 promoter. Importantly, in a mouse model of LPS-induced ALI, Nur77 knockout led to a marked activation of caspase-1 in the lung, increased alveolar and circulating IL-1ß levels, and exacerbated ALI, all of which were substantially inhibited by administration of caspase-1 inhibitor. Together, our results support the presence of an important role for Nur77 in controlling inflammasome activation in vascular ECs and suggest that Nur77 could be a novel therapeutic target for the treatment of human diseases associated with aberrant inflammasome activation, such as ALI and atherosclerosis.

Adipose-Derived Mesenchymal Stem Cells-Derived Exosomes Carry MicroRNA-671 to Alleviate Myocardial Infarction Through Inactivating the TGFBR2/Smad2 Axis.

Mesenchymal stem cells (MSCs) and their derived extracellular vesicles have been reported as promising tools for the management of heart disease. The aim of this study was to explore the function of adipose-derived MSCs (adMSCs)-derived exosomes (Exo) in the progression of myocardial infarction (MI) and the molecules involved. Mouse cardiomyocytes were treated with oxygen-glucose deprivation (OGD) to mimic an MI condition in vitro. The adMSCs-derived Exo were identified and administrated into the OGD-treated cardiomyocytes, and then the viability and apoptosis of cells, and the secretion of fibrosis- and inflammation-related cytokines in cells were determined. Differentially expressed microRNAs (miRNAs) in cells after Exo treatment were screened using a microarray analysis. The downstream molecules regulated by miR-671 were explored through bioinformatic analysis. Involvements of miR-671 and transforming growth factor beta receptor 2 (TGFBR2) in the exosome-mediated events were confirmed by rescue experiments. A murine model with MI was induced and treated with Exo for functional experiments in vivo. Compared to phosphate-buffered saline treatment, the Exo treatment significantly enhanced viability while reduced apoptosis of cardiomyocytes, and in reduced myocardial fibrosis and inflammation both in vitro and in vivo. miR-671 was significantly upregulated in cells after Exo treatment. Downregulation of miR-671 blocked the protective functions of Exo. miR-671 targeted TGFBR2 and suppressed phosphorylation of Smad2. Artificial downregulation of TGFBR2 enhanced viability of the OGD-treated cardiomyocytes. This study suggested that adMSC-derived exosomal miR-671 directly targets TGFBR2 and reduces Smad2 phosphorylation to alleviate MI-like symptoms both in vivo and in vitro.

Prevalence of depression in myocardial infarction: A PRISMA-compliant meta-analysis.

BACKGROUND: Depression is common in the aftermath of myocardial infarction (MI) and may not only lead to impaired long-term quality of life, but also cause increased mortality among patients with MI. The reported prevalence of depression among patients with MI varied considerably across studies, for which a pooled prevalence was obtained in the only 1 meta-analysis conducted in March 2004. Subsequently, numerous relevant studies have been published, indicating the need for an update on the pooled prevalence. Therefore, this study was aimed at updating the pooled prevalence of depression among patients with MI. METHODS: A comprehensive literature search in 3 electronic databases, PubMed, Embase, and PsycINFO, was performed in April 2018. The heterogeneity across studies was examined by the Cochran's Q test and quantified by the I statistic. If significant heterogeneity was observed, meta-regression analyses and subgroup analyses were performed to identify the source of heterogeneity. Publication bias was assessed by a funnel plot and verified by the Egger's and Begg's tests. RESULTS: Nineteen eligible studies conducted in 10 countries were included, which consisted of 12,315 patients with MI, among whom 3818 were identified with depression. High heterogeneity was observed across the eligible studies (I = 98.4%), with the reported prevalence of depression ranging from 9.17% to 65.88%. The pooled prevalence of depression among patients with MI was 28.70% (95% CI: 22.39-35.46%) by a random effects model. Subgroup analyses showed that the pooled prevalence differed significantly by region, tool used to identify depression, study quality, sex, race, anterior MI, and diabetes status (P < .05). Meta-regression analyses did not identify any moderators of heterogeneity, and the heterogeneity was high within most subgroups. Nonetheless, for unmarried subjects, the heterogeneity was low (I = 19.5). The Egger's test and the Begg's test indicated no evidence of publication bias (P > .05). CONCLUSIONS: Given the high pooled prevalence of depression found in this study and the association between depression and adverse health outcomes among patients with MI, more psychological resources including early assessment and effective treatment of depression should be allocated to patients with MI.

Lipid Biomarkers in Acute Myocardial Infarction Before and After Percutaneous Coronary Intervention by Lipidomics Analysis.

BACKGROUND Reperfusion injury is one of the leading causes of myocardial cell death and heart failure. This study was performed to identify new candidate lipid biomarkers for the purpose of optimizing the diagnosis of myocardial ischemia reperfusion (I/R) injury, assessing the severity of myocardial I/R injury and trying to find the novel mechanism related to lipids. MATERIAL AND METHODS Forty patients who were diagnosed with ST-segment elevation myocardial infarction (STEMI) were randomly selected for this study. Serum samples from all the patients with STEMI were collected at 3 time periods: after STEMI diagnosis but prior to reperfusion (T0); and then at 2 hours (T2) and 24 hours (T24) after the end of the percutaneous coronary intervention procedure. Plasma lipidomics profiling analysis was performed to identify the lipid metabolic signatures of myocardial I/R injury using lipidomics. RESULTS Sixteen types of potential lipid biomarkers at different time periods (T0, T2, T24) were identified by using lipidomics technology. The T0 time periods exhibited 16 differentially metabolized lipid peaks in the patients after STEMI diagnosis but prior to reperfusion. With the increase of reperfusion times, the contents of these 16 lipid biomarkers decreased gradually, but there was a 1.5- to 2-fold increase of those 16 lipid biomarkers contents at T2 compared with T24. CONCLUSIONS Lipidomics analysis demonstrated differential change before and after reperfusion, suggesting a potential role of some of these lipids as biomarkers for optimizing the diagnosis of myocardial I/R, as well as for therapeutic targets against myocardial I/R injury.

Effect of Hexadecyl Azelaoyl Phosphatidylcholine on Cardiomyocyte Apoptosis in Myocardial Ischemia-Reperfusion Injury: A Hypothesis.

Reperfusion after myocardial ischemia can induce cardiomyocyte death, known as myocardial reperfusion injury. The pathophysiology of the process of reperfusion suggests the confluence multiple pathways. Recent studies have focused on the inflammatory response, which is considered to be the main mechanism during the process of myocardial ischemia-reperfusion injury and can cause cardiomyocyte apoptosis. Peroxisome proliferator-activated receptors gamma activated by endogenous ligands and exogenous ligand can decrease the inflammatory response in cardiomyocytes. Thiazolidinediones are synthetic, high-affinity, selective ligands for peroxisome proliferator-activated receptors gamma, and can inhibit the inflammatory response, decrease myocardial infarct size, and protect cardiac function. However, thiazolidinediones, including rosiglitazone and pioglitazone, can also contribute to adverse cardiovascular events such as congestive heart failure. Therefore, there are some limitations to the use of thiazolidinediones. Most endogenous ligands were of low affinity until hexadecyl azelaoyl phosphatidylcholine was identified as a high-affinity ligand and agonist for peroxisome proliferator-activated receptors gamma. Hexadecyl azelaoyl phosphatidylcholine binds recombinant peroxisome proliferator-activated receptors with an affinity (Kd(app) ≈40 nM) which is equivalent to rosiglitazone. Therefore, hexadecyl azelaoyl phosphatidylcholine is a specific peroxisome proliferator-activated receptors gamma agonist. Given these findings, we hypothesized that the use of hexadecyl azelaoyl phosphatidylcholine can activate the peroxisome proliferator-activated receptors gamma signal pathways and prevent the inflammatory response process of myocardial ischemia-reperfusion injury, with reduced cardiomyocyte apoptosis and death.

Coronary artery ectasia presenting with thrombus embolization and acute myocardial infarction: A case report.

RATIONALE: Coronary artery ectasia (CAE) is characterized by an abnormal dilatation of the coronary arteries. CAE is often associated with the presence of slow coronary flow and may lead to acute myocardial infarction (AMI), even without total occlusion. PATIENT CONCERNS AND DIAGNOSIS: We report a case of a 24-year-old male patient with CAE suffering from AMI. INTERVENTIONS: Percutaneous coronary intervention with aspiration thrombectomy failed to restore adequate blood flow. Heparin and antiplatelet treatment were provided for pharmacological management, but follow-up angiography 15 days later still revealed a poor result. This patient was ultimately treated with antiplatelet therapy in combination with warfarin treatment. OUTCOMES: Follow-up coronary angiography 15 months later showed a restored normal Thrombolysis In Myocardial Infarction grade (TIMI) 3 flow. LESSONS: CAE-related infarct is often associated with high-burden thrombus formation. Long-term warfarin in combination with antiplatelet therapy may be a good alternative intervention to decrease thrombus burden and enhance blood flow.

The limited effect of omega-3 polyunsaturated fatty acids on cardiovascular risk in patients with impaired glucose metabolism: a meta-analysis.

OBJECTIVES: The impacts of marine-derived n-3 polyunsaturated fatty acids (n-3 PUFAs) on cardiovascular risk are not well known. We conducted this meta-analysis to determine the effects of n-3 PUFAs on cardiovascular outcomes and cardiovascular risk markers in patients with impaired glucose metabolism (IGM). DESIGN AND METHODS: We searched PUBMED, EMBASE, The Cochrane Library and reference lists of relevant papers for high quality randomized controlled trials comparing dietary intake of n-3 PUFAs with placebo in IGM patients. Data was extracted and quality assessed independently by two reviewers. Authors were contacted for missing information. Overall estimates were calculated using a random-effects model or a fixed-effects model, and the possibility of publication bias was examined using a funnel plot. Subgroup analyses were conducted to explore the association between the risk markers and study characteristics. RESULTS: Our meta-analysis included 19 studies, 24,788 patients. Compared with placebo, n-3 PUFAs had no statistically significant reduce effect on cardiovascular mortality, major cardiovascular events, all-cause mortality or composite endpoint of all-cause mortality or hospitalization for cardiovascular cause, however it can significantly reduce the level of triglycerides (weighted mean difference [WMD] -0.25mmol/L; 95% CI -0.37 to -0.13: p<0.001; 12 trials, 13,921 patients). CONCLUSION: Marine-derived n-3 polyunsaturated fatty acids have no protective effect on cardiovascular mortality, major cardiovascular events, all-cause mortality and composite endpoint of all-cause mortality or hospitalization for cardiovascular cause in IGM patients, but can reduce triglyceride level.

ß1 adrenergic receptor polymorphisms and heart failure: a meta-analysis on susceptibility, response to ß-blocker therapy and prognosis.

AIMS: The risk stratification of patients for heart failure (HF) remains a challenge, as well as the anticipation of the response to ß-blocker therapy. Since the pivotal role of ß1 adrenergic receptor (ß1-AR) in HF, many publications have studied the associations between the ß1-AR polymorphisms (Ser49Gly and Arg389Gly) and HF, with inconsistent results. Thus, we performed a meta-analysis of studies to evaluate the impact of ß1-AR polymorphisms on susceptibility to HF, the response to ß-blocker therapy and the prognosis of HF. METHODS AND RESULTS: Electronic databases were systematically searched before August 2011. We extracted data sets and performed meta-analysis with standardized methods. A total of 27 studies met our inclusion criteria. It was found that in East Asians, the Gly389 allele and Gly389 homozygotes significantly increased the HF risk, while the Gly389 allele and Gly389 homozygotes trended to decrease the risk of HF in whites. With the similar reduction of heart rate, overall, the Arg389 homozygotes showed a better response to ß-blocker therapy. Furthermore, the Arg389 homozygotes were significantly associated with better LVEF improvement in East Asians and a mixed population. And in white people, the Arg389 homozygotes made a greater LVESd/v improvement and trended to be associated with better LVEDd/v improvement. However, the prognosis of Arg389 homozygotes HF patients was similar to those with Gly389 carriers. The Ser49Gly polymorphism did not impact the risk or prognosis of HF. CONCLUSION: Based on our meta-analysis, the Gly389 allele and Gly389 homozygotes were risk factors in East Asians while trending to protect whites against HF. Furthermore, Arg389 homozygote is significantly associated with a favorable response to ß-blocker treatment in HF patients. However, neither of the two polymorphisms is an independent predictor of the prognosis of HF.

The interaction of four genes in the inflammation pathway significantly predicts prostate cancer risk.

It is widely hypothesized that the interactions of multiple genes influence individual risk to prostate cancer. However, current efforts at identifying prostate cancer risk genes primarily rely on single-gene approaches. In an attempt to fill this gap, we carried out a study to explore the joint effect of multiple genes in the inflammation pathway on prostate cancer risk. We studied 20 genes in the Toll-like receptor signaling pathway as well as several cytokines. For each of these genes, we selected and genotyped haplotype-tagging single nucleotide polymorphisms (SNP) among 1,383 cases and 780 controls from the CAPS (CAncer Prostate in Sweden) study population. A total of 57 SNPs were included in the final analysis. A data mining method, multifactor dimensionality reduction, was used to explore the interaction effects of SNPs on prostate cancer risk. Interaction effects were assessed for all possible n SNP combinations, where n = 2, 3, or 4. For each n SNP combination, the model providing lowest prediction error among 100 cross-validations was chosen. The statistical significance levels of the best models in each n SNP combination were determined using permutation tests. A four-SNP interaction (one SNP each from IL-10, IL-1RN, TIRAP, and TLR5) had the lowest prediction error (43.28%, P = 0.019). Our ability to analyze a large number of SNPs in a large sample size is one of the first efforts in exploring the effect of high-order gene-gene interactions on prostate cancer risk, and this is an important contribution to this new and quickly evolving field.