Protective Effect of Nicorandil on Contrast-Induced Acute Kidney Injury After Emergency Percutaneous Coronary Intervention.

Objective: To investigate the protective effect of nicorandil on contrast-induced acute kidney injury (CIAKI) in patients with acute ST-segment elevation myocardial infarction (STEMI) after emergency percutaneous coronary intervention (PCI). Methods: This is a single-center, retrospective control study. A total of 156 patients with STEMI were divided into the nicorandil group (n = 55) and the control group (n = 101). The incidence of CIAKI, defined as an increase of >25% or absolute values > 44.2 µmol/L in serum creatinine (Scr) from baseline within 72 h of exposure to a contrast agent after exclusion of other causes, was the primary endpoint. The secondary endpoints were: (1) changes of Scr, estimated glomerular filtration rate (eGFR), uric acid, and ß2-microglobulin at 24/48/72 h and 5 to 7 days after PCI; (2) the peak value difference of creatine kinase isoenzymes (CK-MB) after PCI; (3) adverse events within 6 months after PCI. Results: The overall incidence of CIAKI was 21.8%; the incidence of CIAKI in the nicorandil group was significantly lower (12.7% [7/55]) than in the control group (26.7% [27/101]) (P = .043). Compared with the control group, Scr, uric acid, and ß2-microglobulin levels were lower, and the level of eGFR was higher in nicorandil group (P all < .05). The peak value of CK-MB in the nicorandil group was lower than that in the control group (105.30 [56.61, 232.04] vs 178.00 [77.08, 271.91]U/L, P = .042). There was no significant difference in adverse events between the 2 groups within 6 months after PCI. Moreover, multivariate logistic regression analysis showed that hypertension and diabetes were independent risk factors for CIAKI, while nicorandil treatment was a protective factor. Conclusion: Our data suggest that intravenous nicorandil after emergency PCI has a protective effect on the occurrence of CIAKI in STEMI patients.

Efficacy and Safety of Cilostazol for Atherosclerosis: A Meta-analysis of Randomized Controlled Trials.

ABSTRACT: To investigate the efficacy and safety of cilostazol for atherosclerosis. PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to May 29, 2021, were searched for randomized clinical trials (RCTs). Ten trials with 1577 patients were included. Treatment with cilostazol significantly reduced carotid intima-media thickness [mean difference (MD), -0.12 mm; 95% confidence interval (CI), -0.17 to -0.06]. According to the difference in intervening measures, the cilostazol group was superior to the control group in inhibiting the progression of carotid intima-media thickness: cilostazol versus placebo (MD, -0.04 mm; 95% CI, -0.06 to -0.02; P < 0.00001), cilostazol versus no antiplatelet drug (MD, -0.14 mm; 95% CI, -0.26 to -0.03; P = 0.02), cilostazol versus aspirin (MD, -0.17 mm; 95% CI, -0.32 to -0.02; P = 0.02), cilostazol + aspirin versus aspirin (MD, -0.08 mm; 95% CI, -0.14 to -0.02; P = 0.007), cilostazol + aspirin versus clopidogrel + aspirin (MD, -0.07 mm; 95% CI, -0.14 to -0.00; P = 0.04), and cilostazol + clopidogrel + aspirin versus clopidogrel + aspirin (MD, -0.16 mm; 95% CI, -0.30 to -0.02; P = 0.03). Cilostazol treatment considerably decreased triglyceride (MD, -20.18 mg/dL; 95% CI, -39.03 to -1.34) and improved high-density lipoprotein cholesterol (MD, 4.35 mg/dL; 95% CI, 2.61-6.10). Cilostazol therapy significantly increased the risk of adverse events of headache (odds ratio, 12.91; 95% CI 5.33-31.29). Our research has revealed that cilostazol has potent antiatherosclerotic effects and can reverse atherosclerosis progress even in high-risk patients, such as those with type 2 diabetes mellitus, and does not increase the risk of bleeding.

Quantitative proteomics reveal three potential biomarkers for risk assessment of acute myocardial infarction.

Acute myocardial infarction (AMI) is the one of the main cause of death worldwide. Exosomes carry important information about intercellular communication and could be diagnostic marker for many diseases. Here, we aimed to find potential key proteins for the early diagnosis of AMI. A label free proteomics strategy was used to identify the differentially expressed proteins (DEPs) of AMI patients' plasma exosome. By bioinformatics analysis and enzyme-linked immunosorbent assay to validate the candidate proteins. Compared to healthy control plasma exosome, we totally identified 72 differentially expressed proteins (DEPs) in AMI patients. Also, we found that complement and coagulation cascades was activated by KEGG analysis and GSEA. PLG, C8B and F2 were selected as candidate molecules for further study, and then validated another 40 plasma samples using enzyme-linked immunosorbent assay. Finally, we found that the expression levels of these three proteins (PLG, C8B and F2) were significantly higher than those of healthy controls (P < 0.05). ROC analysis revealed that PLG, C8B and F2 had potential value for AMI early diagnosis. In conclusion, our study identified three potential biomarkers for AMI diagnosis. But there remains a need to further study the mechanism of the biomarkers.

Sex differences in assessing stenosis severity between physician visual assessment and quantitative coronary angiography.

BACKGROUND: Physician visual assessment (PVA) in invasive coronary angiography (ICA) is the current clinical method to determine stenosis severity and guide percutaneous coronary intervention. This study sought to evaluate the effect of sex differences in assessing coronary stenosis severity between PVA and quantitative coronary angiography (QCA). METHODS: 209 patients with coronary artery disease (288 coronary lesions) underwent ICA and fractional flow reserve (FFR). ICA image processing including PVA and QCA was used to quantify diameter stenosis (DS). The difference of DS (ΔDS) between PVA and QCA was defined as DSPVA-DSQCA. DS ≥50% was considered anatomically obstructive. FFR ≤0.8 was defined as myocardial ischemia. RESULTS: Mean ± SD age was 63 ± 9 years. There were no significant differences in DSPVA (61.1 ± 16.3% vs 60.1 ± 18.9%) and DSQCA (53.1 ± 12.1% vs 55.4 ± 14.3%) between females and males. However, ΔDS between PVA and QCA was higher in females (8.0 ± 10.9%) than in males (4.7 ± 10.9%) (P = 0.03). Thirty-four of 72 vessels (47.2%) in female patients and 75 of 216 vessels (34.7%) in male patients were classified differently by at least one grade using PVA compared to QCA assessment. DSPVA and DSQCA were negatively correlated with FFR in females (rPVA = -0.397, rQCA = -0.448) with an even stronger negative correlation in males (rPVA = -0.607, rQCA = -0.607). ROC analysis demonstrated that DSQCA had better discrimination capability for myocardial ischemia (FFR ≤ 0.80) than DSPVA in both sexes (P < 0.05). CONCLUSIONS: A systematic bias was found in PVA (QCA reference) for overestimating severity of coronary artery disease in females compared to males.

Knockdown of ZFAS1 improved the cardiac function of myocardial infarction rats via regulating Wnt/ß-catenin signaling pathway.

Myocardial infarction (MI) is a big health threat in the world, and it is characterized by high morbidity and mortality. However, current treatments are not effective enough, and novel therapeutic strategies need to be explored. ZFAS1 has been proved to be involved in the regulation of MI, but the specific mechanism remains unclear. MI rats were constructed through left anterior descending artery ligation, and hypoxia cell model was also established. The proliferation, invasion, and migration of cells were detected via CCK8, traswell, and wound healing methods. Immunohistochemistry staining, western blotting, and qRT-PCR were used to detect the levels of molecules. Knockdown of ZFAS1 significantly increased the proliferation, migration, and invasion of cardiac fibroblasts. Knockdown of ZFAS1 remarkably improved cardiac function via decreasing infarction ratio and increasing vWF expression, left ventricular ejection fraction, and left ventricular fractional shortening compared with group MI. Knockdown of ZFAS1 also suppressed Wnt/ß-catenin pathway in vivo. The inhibition of Wnt/ß-catenin remarkably reversed the influence of shZFAS1 on cardiac function and cardiac fibroblasts viability. Therefore, Knockdown of ZFAS1 could improve the cardiac function of myocardial infarction rats via regulating Wnt/ß-catenin signaling pathway. The present study might provide new thoughts for the prevention and treatment of MI damage.

Effects of Ivabradine on Cardiac Remodeling in Patients With Stable Symptomatic Heart Failure: A Systematic Review and Meta-analysis.

PURPOSE: Ivabradine reduces heart rate (HR) in patients with heart failure (HF). However, its effect on cardiac remodeling is not obvious. The goal of this study was to explore the extra effect of ivabradine on cardiac remodeling in patients with HF. METHODS: We searched PubMed from database inception to January 31, 2020, Cochrane and Embase from database inception to February 2, 2020, and Web of Science and ClinicalTrials.gov from database inception to February 3, 2020, for randomized controlled trials on ivabradine treatments in patients with stable symptomatic HF, left ventricular ejection fraction (LVEF) < 45%, and resting HR ≥ 60 beats/min in sinus rhythm. We pooled the mean differences (MDs) or standardized mean differences and their 95% CIs. An inverse variance was used to combine data. Fixed- or random-effects models were used to outline the outcomes based on heterogeneity levels. We assessed the heterogeneity among studies according to the I2 statistic. A sensitivity analysis for select results was performed to assess the robustness of the outcomes. FINDINGS: Of 2277 trials, 9 trials fulfilled the inclusion criteria. A total of 1523 patients were enrolled in 9 studies. There were 796 participants in the ivabradine group and 727 participants in the control group. The duration of follow-up ranged from 6 weeks to 19.6 months. The mean (SD) age of the participants was 59.7 (11.2) years, and 1187 participants (77.9%) were men. Therapy with ivabradine was related to reversing cardiac remodeling with a significant increase in LVEF (MD = 3.04%; 95% CI, 2.07%-4.00%; p < 0.001), decrease in the left ventricular end-systolic volume index (LVESVI) (MD = -7.30 mL/m2; 95% CI, -12.94 to -1.66 mL/m2; p = 0.01), and reduction in the left ventricular end-diastolic volume index (LVEDVI) (MD = -7.27 mL/m2; 95% CI, -14.04 to -0.50 mL/m2; p = 0.04). In the subgroup of enrolled patients with a resting HR of ≥70 beats/min, greater progress in LVEF was detected in the ivabradine group (MD = 3.60%; 95% CI, 2.40%-4.81%; p < 0.001), and a higher improvement in LVESVI was identified in the ivabradine group (MD = -11.06 mL/m2; 95% CI, -21.15 to -0.98 mL/m2; p = 0.03). IMPLICATIONS: In patients with stable symptomatic HF, LVEF <45%, and resting HR ≥ 60 beats/min in sinus rhythm, ivabradine use was associated with reversing cardiac remodeling with a significant increase in LVEF, a decrease in LVESVI, and a reduction in LVEDVI.

Efficacy and safety of sacubitril-valsartan in heart failure: a meta-analysis of randomized controlled trials.

AIMS: Sacubitril-valsartan has been shown to have superior effects over angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with heart failure (HF) and hypertension. The efficacy and safety of sacubitril-valsartan in patients with HF are controversial. We performed a meta-analysis of randomized controlled trials to assess and compare the effect and adverse events of sacubitril-valsartan, valsartan, and enalapril in patients with HF. METHODS AND RESULTS: We conducted a systematic search using PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov. Randomized controlled trials involving the use of sacubitril-valsartan in patients with HF were included. We assessed the pooled odds ratio (OR) of all-cause mortality, cardiovascular mortality, and hospitalization for HF in fixed-effects models and the pooled risk ratio (RR) of symptomatic hypotension, worsening renal function, and hyperkalaemia in fixed-effects models. Of the 315 identified records, six studies involving 14 959 patients were eligible for inclusion. Sacubitril-valsartan reduced the endpoints of all-cause mortality and cardiovascular mortality in patients with HF with reduced ejection fraction (HFrEF) in three trials with pooled ORs of 0.83 (P = 0.0006) and 0.78 (P < 0.0001), respectively. Regarding the composite outcome of hospitalization for HF in five trials, the pooled OR was 0.79 (P < 0.00001). Compared with enalapril or valsartan, sacubitril-valsartan was associated with a high risk of symptomatic hypotension (RR 1.47, P < 0.00001), low risk of worsening renal function (RR 0.81, P = 0.005), and low rate of serious hyperkalaemia (≥6.0 mmol/L) (RR 0.76, P = 0.0007) in all six trials. CONCLUSIONS: Compared with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, sacubitril-valsartan significantly decreased the risk of death from all causes or cardiovascular causes in HFrEF and hospitalization for HF in both patients with HFrEF and HF with preserved ejection fraction. Sacubitril-valsartan reduced the risk of renal dysfunction and serious hyperkalaemia but was associated with more symptomatic hypotension.

Interrupted or Uninterrupted Oral Anticoagulants in Patients Undergoing Atrial Fibrillation Ablation.

BACKGROUND AND PURPOSE: The safety and efficacy of uninterrupted, minimally interrupted (one dose skipped) or completely interrupted (24 h skipped) oral anticoagulant therapy in patients with atrial fibrillation (AF) ablation are poorly defined. We conducted a network meta-analysis to explore the effect of interrupted or uninterrupted oral anticoagulants in patients with AF undergoing ablation. METHODS: The Cochrane Library, PubMed and Embase databases were systematically searched for studies comparing uninterrupted, minimally interrupted or completely interrupted non-vitamin K antagonist oral anticoagulants (NOACs) with continuous or interrupted warfarin in patients undergoing AF ablation. RESULTS: Twelve randomized clinical trials (RCTs) with a total of 5597 patients with AF undergoing catheter ablation were included. For thromboembolism, minimally interrupted NOACs (OR 0.03, 95% CI 0.01-0.35), uninterrupted NOACs (OR 0.04, 95% CI 0.01-0.23) and continuous VKAs (OR 0.05, 95% CI 0.01-0.21) were better than interrupted warfarin. The risk of total bleeding appeared higher in the completely interrupted NOAC group compared with the minimally interrupted NOACs (OR 2.74, 95% CI 1.18-6.37), uninterrupted NOACs (OR 2.15, 95% CI 1.05-4.38) and uninterrupted warfarin (OR 2.04, 95% CI 1.02-4.08). To reduce the risk of total bleeding, minimally interrupted NOACs (OR 0.15, 95% CI 0.08-0.27), uninterrupted NOACs (OR 0.19, 95% CI 0.14-0.42) and uninterrupted warfarin (OR 0.24, 95% CI 0.15-0.39) were better than interrupted warfarin. In the event of major bleeding, there was no significant difference in the interrupted NOAC, uninterrupted NOAC, interrupted VKA and uninterrupted VKA groups. CONCLUSIONS: These three NOAC strategies may have similar safety and efficacy in terms of thromboembolism and major bleeding complications. The total bleeding risk of completely interrupted oral anticoagulants is higher than that of uninterrupted and minimally interrupted NOACs. For thromboembolism, minimally interrupted NOACs, uninterrupted NOACs and continuous VKAs were better than interrupted warfarin.

CSN5 attenuates Ang II-induced cardiac hypertrophy through stabilizing LKB1.

CSN5 is a critical subunit of the COP9 signalosome (CSN) and has been involved in various cellular processes, but little is known about the role of CSN5 in cardiac disease. In the present study, we found that the expression of CSN5 was increased in Angiotensin II (Ang II)-induced cardiac hypertrophic mice hearts and Ang II-treated cardiomyocytes. We also observed that overexpression of CSN5 significantly inhibited Ang II-induced cardiac hypertrophy, whereas CSN5 silence exhibited the opposite phenotypes. Further investigation demonstrated that CSN5 maintained the activity of AMP-activated protein kinase (AMPK) in cardiomyocyte by enhancement of LKB1. Mechanistically, we found that CSN5 directly interacted and deubiquitinated LKB1 for its stabilization in cardiomyocytes. Finally, our results demonstrated that the anti-hypertrophic effect of CSN5 was partially dependent on stabilization of LKB1. Collectively, these findings suggested that strategies based on activation of CSN5/LKB1 axis might be promising in the treatment of hypertrophic cardiomyopathy.

XPO1-mediated nuclear export of RNF146 protects from angiotensin II-induced endothelial cellular injury.

Endothelial cells death induced by angiotensin II (Ang II) plays a role in vascular injury. RNF146 is identified as a E3 ubiquitin ligase, which promotes cell survival under many types of stresses. However, the role of RNF146 in endothelial cellular injury is unknown. In human umbilical vein endothelial cells (HUVECs), Ang II treatment led to cell death by oxidative stress and promoted RNF146 to accumulate in nucleus in time dependent manner. Nuclear export signal was found in the RNF146's sequence. The interaction between RNF146 and XPO1 was further confirmed by co-immunoprecipitation. Inhibition of XPO1 with KPT-185 increased the level of RNF146 in nucleus. The expression of XPO1 was suppressed responding to Ang II treatment. Overexpression of XPO1 facilitated the nuclear shuttling of RNF146, which protected from Ang II-induced cell death. Moreover, overexpression of RNF146 in HUVECs reduced the cell death induced by Ang II, whereas inhibition of XPO1 abolished the protective effect of RNF146. Therefore, our data demonstrated that RNF146 was a protective factor against cell death induced by AngII in human endothelial cells, which was dependent on XPO1-mediated nuclear export.