Azvudine for the Treatment of COVID-19 in Pre-Existing Cardiovascular Diseases: A Single-Center, Real-World Experience.

COVID-19 can lead to adverse outcomes in patients with pre-existing diseases. Azvudine has been approved for treating COVID-19 in China, but the real-world data is limited. It is aimed to investigate the efficacy of Azvudine in patients with COVID-19 and pre-existing cardiovascular diseases. Patients with confirmed COVID-19 and pre-existing cardiovascular diseases are retrospectively enrolled. The primary outcome is all-cause death during hospitalization. Overall, 351 patients are included, with a median age of 74 years, and 44% are female. 212 (60.6%) patients are severe cases. Azvudine is used in 106 (30.2%) patients and not in 245 (69.8%). 72 patients died during hospitalization. After multivariate adjustment, patients who received Azvudine a lower risk of all-cause death (hazard ratio: 0.431; 95% confidence interval: 0.252-0.738; p = 0.002) than controls. Azvudine therapy is also associated with lower risks of shock and acute kidney injury. For sensitivity analysis in the propensity score-matched cohort (n = 90 for each group), there is also a significant difference in all-cause death between the two groups (hazard ratio: 0.189; 95% confidence interval: 0.071-0.498; p < 0.001). This study indicated that Azvudine therapy is associated with better outcomes in COVID-19 patients with pre-existing cardiovascular diseases.

Edoxaban for stroke prevention in atrial fibrillation and factors associated with dosing: patient characteristics from the prospective observational ETNA-AF-China registry.

Real-world data on effectiveness and safety of a single non-vitamin K antagonist oral anticoagulant in the Chinese population with atrial fibrillation (AF) are limited. This study reports characteristics of patients treated with edoxaban and factors associated with dosing patterns from routine care in China. ETNA-AF-China (NCT04747496) is a multicentre, prospective, observational study enrolling edoxaban-treated patients from four economic regions with a targeted 2-year follow-up. Of the 4930 patients with AF (mean age: 70.2 ± 9.5 years; male, 57.1%), the mean creatinine clearance (CrCl), CHA2DS2-VASc, and HAS-BLED scores were 71.2 mL/min, 2.9, and 1.6. Overall, 6.4% of patients were perceived as frail by investigators. Available label dose reduction criteria (N = 4232) revealed that 3278 (77.5%) patients received recommended doses and 954 (22.5%) non-recommended doses. Northeast (53.0%) and West (43.1%) regions had the highest prescriptions of 60 mg and 30 mg recommended doses, respectively. Non-recommended 30 mg doses were more frequently prescribed in patients with antiplatelet use and history of heart failure than recommended 60 mg. Multivariate analysis identified advanced age as the strongest associated factor with non-recommended doses. Frailty had the strongest association with 30 mg except for age, and history of TIA was the most relevant factor associated with 60 mg. In conclusion, patients in the ETNA-AF-China study were predominantly aged 65 years and older, had mild-to-moderate renal impairment and good label adherence. Advanced age was associated with non-recommended doses, with frailty most common for non-recommended 30 mg and a history of TIA for the non-recommended 60 mg dose.

Lysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis by promoting the degradation of CDC42 in mice.

Non-alcoholic steatohepatitis (NASH) has received great attention due to its high incidence. Here, we show that lysosomal-associated protein transmembrane 5 (LAPTM5) is associated with NASH progression through extensive bioinformatical analysis. The protein level of LAPTM5 bears a negative correlation with NAS score. Moreover, LAPTM5 degradation is mediated through its ubiquitination modification by the E3 ubquitin ligase NEDD4L. Discovered by experiments conducted on male mice, hepatocyte-specific depletion of Laptm5 exacerbates mouse NASH symptoms. In contrast, Laptm5 overexpression in hepatocytes exerts diametrically opposite effects. Mechanistically, LAPTM5 interacts with CDC42 and promotes its degradation through a lysosome-dependent manner under the stimulation of palmitic acid, thus inhibiting activation of the mitogen-activated protein kinase signaling pathway. Finally, adenovirus-mediated hepatic Laptm5 overexpression ameliorates aforementioned symptoms in NASH models.

Loss of MD1 Promotes Inflammatory and Apoptotic Atrial Remodelling in Diabetic Cardiomyopathy by Activating the TLR4/NF-κB Signalling Pathway.

INTRODUCTION: Myeloid differentiation protein 1 (MD1), a negative regulator of toll-like receptor 4 (TLR4), is widely expressed in the heart. Recent studies have shown that MD1 plays an important role in cardiac remodelling. However, the effects and potential mechanisms underlying MD1-mediated atrial remodelling in diabetic cardiomyopathy (DCM) remain unclear. Therefore, this study was designed to explore the role of MD1 in DCM-related atrial remodelling. METHODS: MD1 knockout (MD1-KO) mice and wild-type (WT) littermates were injected with streptozotocin (STZ) to establish a diabetic mouse model. These mice were then used to evaluate MD1 expression and its effects on atrial remodelling in vivo. RESULTS: MD1 expression was significantly decreased in STZ-induced diabetic mice. The loss of MD1 aggravated atrial fibrosis, inflammation, and apoptosis in DCM mice and promoted atrial remodelling. MD1-KO diabetic mice also showed higher susceptibility to atrial fibrillation (AF) and worse cardiac function. Mechanistically, the deletion of MD1 promoted the activation of the TLR4/NF-κB signalling pathway, resulting in atrial remodelling in DCM mice via increased p65 phosphorylation. CONCLUSIONS: The deletion of MD1 plays an important role in inflammatory and apoptotic atrial remodelling and increases susceptibility to AF in DCM mice, providing a new target for the preventive treatment of DCM-related atrial remodelling.

Indobufen or Aspirin on Top of Clopidogrel After Coronary Drug-Eluting Stent Implantation (OPTION): A Randomized, Open-Label, End Point-Blinded, Noninferiority Trial.

BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin as a background therapy has become the standard care after percutaneous coronary intervention. However, some adverse noncardiac effects limited the use of aspirin in clinical practice. Thus, evaluation of pharmacological alternatives to aspirin is attractive. Previous data indicated that indobufen could lessen the unwanted side effects of aspirin while retaining the antithrombotic efficacy, but its combination with a P2Y12 inhibitor still lacks randomized clinical trial evidence. METHODS: In this randomized, open-label, noninferiority trial, patients with negative cardiac troponin undergoing coronary drug-eluting stent implantation were randomly assigned in a 1:1 ratio to receive either indobufen-based DAPT (indobufen 100 mg twice a day plus clopidogrel 75 mg/d for 12 months) or conventional DAPT (aspirin 100 mg/d plus clopidogrel 75 mg/d for 12 months). The primary end point was a 1-year composite of cardiovascular death, nonfatal myocardial infarction, ischemic stroke, definite or probable stent thrombosis, or Bleeding Academic Research Consortium criteria type 2, 3, or 5 bleeding. The end points were adjudicated by an independent Clinical Event Committee. RESULTS: Between January 11, 2018, and October 12, 2020, 4551 patients were randomized in 103 cardiovascular centers: 2258 patients to the indobufen-based DAPT group and 2293 to the conventional DAPT group. The primary end point occurred in 101 patients (4.47%) in the indobufen-based DAPT group and 140 patients (6.11%) in the conventional DAPT group (absolute difference, -1.63%; Pnoninferiority<0.001; hazard ratio, 0.73 [95% CI, 0.56-0.94]; P=0.015). Cardiovascular death, nonfatal myocardial infarction, ischemic stroke, and stent thrombosis were observed in 0.13%, 0.40%, 0.80%, and 0.22% of patients in the indobufen-based DAPT group and 0.17%, 0.44%, 0.83%, and 0.17% of patients in the conventional DAPT group (all P>0.05). The occurrence of Bleeding Academic Research Consortium criteria type 2, 3, or 5 bleeding events was lower in the indobufen-based DAPT group compared with the conventional DAPT group (2.97% versus 4.71%; hazard ratio, 0.63 [95% CI, 0.46-0.85]; P=0.002), with the main decrease in type 2 bleeding (1.68% versus 3.49%; hazard ratio, 0.48 [95% CI, 0.33-0.70]; P<0.001). CONCLUSIONS: In Chinese patients with negative cardiac troponin undergoing drug-eluting stent implantation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of 1-year net clinical outcomes, which was driven mainly by a reduction in bleeding events without an increase in ischemic events. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR-IIR-17013505.

Corrigendum: Resveratrol Ameliorates Cardiac Remodeling in a Murine Model of Heart Failure With Preserved Ejection Fraction.

[This corrects the article DOI: 10.3389/fphar.2021.646240.].

Development and validation of a risk prediction model for postoperative pneumonia in adult patients undergoing Stanford type A acute aortic dissection surgery: a case control study.

BACKGROUND: Pneumonia is a common complication after Stanford type A acute aortic dissection surgery (AADS) and contributes significantly to morbidity, mortality, and length of stay. The purpose of this study was to identify independent risk factors associated with pneumonia after AADS and to develop and validate a risk prediction model. METHODS: Adults undergoing AADS between 2016 and 2019 were identified in a single-institution database. Patients were randomly divided into training and validation sets at a ratio of 2:1. Preoperative and intraoperative variables were included for analysis. A multivariate logistic regression model was constructed using significant variables from univariate analysis in the training set. A nomogram was constructed for clinical utility and the model was validated in an independent dataset. RESULTS: Postoperative pneumonia developed in 170 of 492 patients (34.6%). In the training set, multivariate analysis identified seven independent predictors for pneumonia after AADS including age, smoking history, chronic obstructive pulmonary disease, renal insufficiency, leucocytosis, low platelet count, and intraoperative transfusion of red blood cells. The model demonstrated good calibration (Hosmer-Lemeshow χ2 = 3.31, P = 0.91) and discrimination (C-index = 0.77) in the training set. The model was also well calibrated (Hosmer-Lemeshow χ2 = 5.73, P = 0.68) and showed reliable discriminatory ability (C-index = 0.78) in the validation set. By visual inspection, the calibrations were good in both the training and validation sets. CONCLUSION: We developed and validated a risk prediction model for pneumonia after AADS. The model may have clinical utility in individualized risk evaluation and perioperative management.

Long non-coding RNA NORAD aggravates acute myocardial infarction by promoting fibrosis and apoptosis via miR-577/COBLL1 axis.

Acute myocardial infarction (AMI) is one of the most common and serious cardiovascular diseases. With high morbidity and mortality, AMI has attracted the most attention. Emerging studies indicated that long noncoding RNAs (lncRNAs) play an important role in the progression of AMI. However, the role of NORAD in AMI remained unclear. The current study aimed to investigate the function and mechanism of NORAD in AMI. Bioinformatics tools and a wide range of assays including RT-qPCR, flow cytometry, TTC staining, western blot, luciferase reporter and caspase-3 activity assays were conducted to investigate the function and mechanism of NORAD in AMI. We found out that NORAD was significantly upregulated in AMI rats. Knockdown of NORAD alleviated H9c2 cell injury by reducing apoptosis and decreasing expression levels of fibrogenic factors. In addition, NORAD inhibition ameliorated AMI in a rat model by decreasing infarct size and fibrosis. We confirmed that NORAD bound to miR-577, which was downregulated in ischemia-reperfusion (I/R) rats and hypoxia-exposed H9c2 cells. Additionally, miR-577 combined with the 3'UTR of COBLL1, which was upregulated in I/R rats and hypoxia-exposed H9c2 cells. At last, rescue assay validated that the suppressive effects of NORAD knockdown on apoptosis and expression levels of fibrogenic factors were counteracted by COBLL1 overexpression. Overall, NORAD aggravates acute myocardial infarction by promoting fibrosis and apoptosis via the miR-577/COBLL1 axis. This novel discovery suggested that NORAD may serve as a potential therapeutic target for AMI patients.

Dual-specificity Phosphatase 9 protects against Cardiac Hypertrophy by targeting ASK1.

The functions of dual-specificity phosphatase 9 (DUSP9) in hepatic steatosis and metabolic disturbance during nonalcoholic fatty liver disease were discussed in our prior study. However, its roles in the pathophysiology of pressure overload-induced cardiac hypertrophy remain to be illustrated. This study attempted to uncover the potential contributions and underpinning mechanisms of DUSP9 in cardiac hypertrophy. Utilizing the gain-and-loss-of-functional approaches of DUSP9 the cardiac phenotypes arising from the pathological, echocardiographic, and molecular analysis were quantified. The results showed increased levels of DUSP9 in hypertrophic mice heart and angiotensin II treated cardiomyocytes. In accordance with the results of cellular hypertrophy in response to angiotensin II, cardiac hypertrophy exaggeration, fibrosis, and malfunction triggered by pressure overload was evident in the case of cardiac-specific conditional knockout of DUSP9. In contrast, transgenic mice hearts with DUSP9 overexpression portrayed restoration of the hypertrophic phenotypes. Further explorations of molecular mechanisms indicated the direct interaction of DUSP9 with ASK1, which further repressed p38 and JNK signaling pathways. Moreover, blocking ASK1 with ASK1-specific inhibitor compensated the pro-hypertrophic effects induced by DUSP9 deficiency in cardiomyocytes. The main findings of this study suggest the potential of DUSP9 in alleviating cardiac hypertrophy at least partially by repressing ASK1, thereby looks promising as a prospective target against cardiac hypertrophy.

MicroRNA miR-215-5p Regulates Doxorubicin-induced Cardiomyocyte Injury by Targeting ZEB2.

ABSTRACT: Doxorubicin (DOX) is a chemotherapeutic drug for treating various cancers. However, the DOX-induced cardiotoxicity greatly limits its clinical application. MicroRNAs are emerged as critical mediators of cardiomyocyte injury. This work explored the function of miR-215-5p in the regulation of DOX-induced mouse HL-1 cardiomyocyte injury. An in vitro model of DOX-treated cardiotoxicity was established in cardiac mouse cell line HL-1. Gene expression was measured by reverse transcription quantitative polymerase chain reaction. Cell viability was detected using CCK-8. Cell death and apoptosis were tested using transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL), flow cytometry, and caspase-3/7 activity assays. Luciferase reporter assay was used to examine the target of miR-215-5p. We found that DOX induced cardiomyocyte injury and upregulated miR-215-5p in HL-1 cells. Inhibition of miR-215-5p attenuated DOX-induced cardiomyocyte death and apoptosis in vitro. Mechanistical experiments indicated that zinc finger E-box-binding homeobox (ZEB2) was targeted by miR-215-5p. In addition, ZEB2 expression was reduced in DOX-treated HL-1 cells. Rescue assays indicated that ZEB2 knockdown reversed the effects of miR-215-5p inhibition. In conclusion, miR-215-5p inhibition protects HL-1 cells against DOX-induced injury by upregulating ZEB2 expression.

Resveratrol Ameliorates Cardiac Remodeling in a Murine Model of Heart Failure With Preserved Ejection Fraction.

Objective: Accumulating evidence suggested that resveratrol (RES) could protect against adverse cardiac remodeling induced by several cardiovascular diseases. However, the role of RES in the setting of heart failure with preserved ejection fraction (HFpEF) and the underlying mechanisms of its action remain understood. This study was to determine whether RES could ameliorate HFpEF-induced cardiac remodeling and its mechanisms. Methods: In vivo, C57BL/6 mice served as either the sham or the HFpEF model. The HFpEF mice model was induced by uninephrectomy surgery and d-aldosterone infusion. RES (10 mg/kg/day, ig) or saline was administered to the mice for four weeks. In vitro, transforming growth factor ß1 (TGF-ß1) was used to stimulate neonatal rat cardiac fibroblasts (CFs) and Ex-527 was used to inhibit sirtuin 1 (Sirt1) in CFs. Echocardiography, hemodynamics, western blotting, quantitative real-time PCR, histological analysis, immunofluorescence, and ELISA kits were used to evaluate cardiac remodeling induced by HFpEF. Sirt1 and Smad3 expressions were measured to explore the underlying mechanisms of RES. Results: HFpEF mice developed left ventricular hypertrophy, preserved ejection fraction, diastolic dysfunction, and pulmonary congestion. Moreover, HFpEF mice showed increased infiltration of neutrophils and macrophages into the heart, including increased interleukin (IL)-1ß, IL-6, and TNF-α. We also observed elevated M1 macrophages and decreased M2 macrophages, which were exhibited by increased mRNA expression of M1 markers (iNOS, CD86, and CD80) and decreased mRNA expression of M2 markers (Arg1, CD163, and CD206) in HFpEF hearts. Moreover, HFpEF hearts showed increased levels of intracellular reactive oxygen species (ROS). Importantly, HFpEF mice depicted increased collagen-I and -III and TGF-ß mRNA expressions and decreased protein expression of phosphorylated endothelial nitric-oxide synthase (p-eNOS). Results of western blot revealed that the activated TGF-ß/Smad3 signaling pathway mediated HFpEF-induced cardiac remodeling. As expected, this HFpEF-induced cardiac remodeling was reversed when treated with RES. RES significantly decreased Smad3 acetylation and inhibited Smad3 transcriptional activity induced by HFpEF via activating Sirt1. Inhibited Sirt1 with Ex-527 increased Smad3 acetylation, enhanced Smad3 transcriptional activity, and offset the protective effect of RES on TGF-ß-induced cardiac fibroblast-myofibroblast transformation in CFs. Conclusion: Our results suggested that RES exerts a protective action against HFpEF-induced adverse cardiac remodeling by decreasing Smad3 acetylation and transcriptional activity via activating Sirt1. RES is expected to be a novel therapy option for HFpEF patients.

LITAF acts as a novel regulator for pathological cardiac hypertrophy.

Pathological hypertrophy generally progresses to heart failure. Exploring effective and promising therapeutic targets might lead to progress in preventing its detrimental outcomes. Our current knowledge about lipopolysaccharide-induced tumor necrosis factor-α factor (LITAF) is mainly limited to regulate inflammation. However, the role of LITAF in other settings that are not that relevant to inflammation, such as cardiac remodeling and heart failure, remains largely unknown. In the present study, we found that the expression of LITAF decreased in hypertrophic hearts and cardiomyocytes. Meanwhile, LITAF protected cultured neonatal rat cardiomyocytes against phenylephrine-induced hypertrophy. Moreover, using LITAF knockout mice, we demonstrated that LITAF deficiency exacerbated cardiac hypertrophy and fibrosis compared with wild-type mice. Mechanistically, LITAF directly binds to the N-terminal of ASK1, thus disrupting the dimerization of ASK1 and blocking ASK1 activation, ultimately inhibiting ASK1-JNK/p38 signaling over-activation and protecting against cardiac hypertrophy. Furthermore, AAV9-mediated LITAF overexpression attenuated cardiac hypertrophy in vivo. Conclusions: Our findings uncover the novel role of LITAF as a negative regulator of cardiac remodeling. Targeting the interaction between LITAF and ASK1 could be a promising therapeutic strategy for pathological cardiac remodeling.

Dual-Specificity Phosphatase 26 Protects Against Cardiac Hypertrophy Through TAK1.

Background Heart pathological hypertrophy has been recognized as a predisposing risk factor for heart failure and arrhythmia. DUSP (dual-specificity phosphatase) 26 is a member of the DUSP family of proteins, which has a significant effect on nonalcoholic fatty liver disease, neuroblastoma, glioma, and so on. However, the involvement of DUSP26 in cardiac hypertrophy remains unclear. Methods and Results Our study showed that DUSP26 expression was significantly increased in mouse hearts in response to pressure overload as well as in angiotensin II-treated cardiomyocytes. Cardiac-specific overexpression of DUSP26 mice showed attenuated cardiac hypertrophy and fibrosis, while deficiency of DUSP26 in mouse hearts resulted in increased cardiac hypertrophy and deteriorated cardiac function. Similar effects were also observed in cellular hypertrophy induced by angiotensin II. Importantly, we showed that DUSP26 bound to transforming growth factor-ß activated kinase 1 and inhibited transforming growth factor-ß activated kinase 1 phosphorylation, which led to suppression of the mitogen-activated protein kinase signaling pathway. In addition, transforming growth factor-ß activated kinase 1-specific inhibitor inhibited cardiomyocyte hypertrophy induced by angiotensin II and attenuated the exaggerated hypertrophic response in DUSP26 conditional knockout mice. Conclusions Taken together, DUSP26 was induced in cardiac hypertrophy and protected against pressure overload induced cardiac hypertrophy by modulating transforming growth factor-ß activated kinase 1-p38/ c-Jun N-terminal kinase-signaling axis. Therefore, DUSP26 may provide a therapeutic target for treatment of cardiac hypertrophy and heart failure.

Piperine protects against pyroptosis in myocardial ischaemia/reperfusion injury by regulating the miR-383/RP105/AKT signalling pathway.

miRNA-mediated pyroptosis play crucial effects in the development of myocardial ischaemia/reperfusion (I/R) injury (MIRI). Piperine (PIP) possesses multiple pharmacological effects especially in I/R condition. This study focuses on whether PIP protects MIRI from pyroptosis via miR-383-dependent pathway. Rat MIRI model was established by 30 minutes of LAD ligation and 4 hours of reperfusion. Myocardial enzymes, histomorphology, structure and function were detected to evaluate MIRI. Recombinant adenoviral vectors for miR-383 overexpression or miR-383 silencing or RP105 knockdown were constructed, respectively. Luciferase reporter analysis was used to confirm RP105 as a target of miR-383. Pyroptosis-related markers were measured by Western blotting assay. The results showed that I/R provoked myocardial injury, as shown by the increases of LDH/CK releases, infarcted areas and apoptosis as well as worsened function and structure. Pyroptosis-related mediators including NLRP3, cleaved caspase-1, cleaved IL-1ß and IL-18 were also reinforced after MIRI. However, PIP treatment greatly ameliorated MIRI in parallel with pyroptotic repression. In mechanistic studies, MIRI-caused elevation of miR-383 and decrease of RP105/PI3K/AKT pathway were reverted by PIP treatment. Luciferase reporter assay confirmed RP105 as a miR-383 target. miR-383 knockdown ameliorated but miR-383 overexpression facilitated pyroptosis and MIRI. Moreover, the anti-pyroptotic effect from miR-383 silencing was verified to be relied on the RP105/PI3K/AKT signalling pathway. Additionally, our present study further indicated the miR-383/RP105/AKT-dependent approach resulting from PIP administration against pyroptosis in MIRI. Therefore, PIP treatment attenuates MIRI and pyroptosis by regulating miR-383/RP105/AKT pathway, and it may provide a therapeutic manner for the treatment of MIRI.

microRNA-491-5p protects against atherosclerosis by targeting matrix metallopeptidase-9.

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are critical processes that are involved in atherosclerosis. The aim of this study was to explore the role of microRNA-491-5p (miR-491-5p) in the progression of atherosclerosis by regulating the growth and migration of VSMCs. In this study, we showed that the expression of miR-491-5p was downregulated in the atherosclerotic plaque tissues and plasma samples of the patients with atherosclerosis. The bioinformatic analysis and dual-luciferase reporter assay identified that matrix metallopeptidase-9 (MMP-9) was a target gene of miR-491-5p. The results showed a significant upregulation of MMP-9 in the atherosclerotic plaque tissues and plasma samples. Subsequently, the results also showed that downregulation of miR-491-5p significantly promoted the proliferation and migration of VSMCs and inhibited the apoptosis in VSMCs. Furthermore, we detected the effects of miR-491-5p mimic on the growth and migration of VSMCs, and the results illustrated that miR-491-5p mimic could inhibit the proliferation and migration of VSMCs and promote the apoptosis of VSMCs. Notably, MMP-9 plasmid could reverse all the effects of miR-491-5p mimic on VSMCs. Collectively, our study provides the first evidence that miR-491-5p inhibited the growth and migration of VSMCs by targeting MMP-9, which might provide new biomarkers and potential therapeutic targets for atherosclerosis treatment.

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19.

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P<0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P<0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P<0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P<0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P<0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials.

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19.

RATIONALE: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. OBJECTIVE: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. METHODS AND RESULTS: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. CONCLUSIONS: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

Varying coefficient transformation cure models for failure time data.

This article discusses regression analysis of right-censored failure time data where there may exist a cured subgroup, and also covariate effects may be varying with time, a phenomena that often occurs in many medical studies. To address the problem, we discuss a class of varying coefficient transformation models along with a logistic model for the cured subgroup. For inference, a sieve maximum likelihood approach is developed with the use of spline functions, and the asymptotic properties of the proposed estimators are established. The proposed method can be easily implemented, and the conducted simulation study suggests that the proposed method works well in practical situations. An illustrative example is provided.

Potential of circulating pro-angiogenic microRNA expressions as biomarkers for rapid angiographic stenotic progression and restenosis risks in coronary artery disease patients underwent percutaneous coronary intervention.

BACKGROUND: This study aimed to investigate the correlation of pro-angiogenic microRNA (miRNA) expressions with rapid angiographic stenotic progression (RASP) and restenosis risks in coronary artery disease (CAD) patients underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES). METHODS: A total of 286 CAD patients underwent PCI with DES were consecutively recruited in this study. Plasma samples were collected before PCI operation, and 14 pro-angiogenic miRNAs were measured by real-time quantitative reverse transcription-polymerase chain reaction. Rapid angiographic stenotic progression at nontarget lesions and restenosis at stented lesions were evaluated by quantitative coronary angiography at 12 months after PCI operation. RESULTS: The occurrence rates of RASP and restenosis were 39.5% and 22.4%, respectively. Let-7f, miR-19a, miR-19b-1, miR-92a, miR-126, miR-210, and miR-296 were decreased in RASP patients than non-RASP patients, among which let-7f, miR-19a, miR-126, miR-210, and miR-296 independently correlated with lower RASP occurrence by multivariate analysis, followed by receiver-operating characteristic (ROC) curve exhibited that these five miRNAs showed great value in predicting RASP risk with area under curve (AUC) 0.879 (95% CI: 0.841-0.917). Besides, let-7f, miR-19a, miR-92a, miR-126, miR-130a, and miR-210 were reduced in restenosis patients than non-restenosis patients, among them miR-19a, miR-126, miR-210, and miR-378 independently correlated with lower restenosis occurrence by multivariate analysis, followed by ROC curve disclosed that these four miRNAs had good value in predicting restenosis risk with AUC 0.776 (95% CI: 0.722-0.831). CONCLUSIONS: Circulating let-7f, miR-19a, miR-126, miR-210, and miR-296 independently correlate with reduced RASP risk, while miR-19a, miR-126, miR-210, and miR-378 independently correlate with decreased restenosis risk in CAD patients underwent PCI with DES.

Antibody to oxidized low-density lipoprotein inhibits THP1 cells from apoptosis by suppressing NF-κB pathway activation.

BACKGROUND: This study aimed to investigate whether the oxidized low-density lipoprotein (Ox-LDL) antibody is able to inhibit THP1 cell apoptosis by suppressing NF-κB pathway. METHODS: THP1 cells were induced to macrophages with phorbol 12-myristate 13-acetate (PMA). Macrophages were divided into control group, Ox-LDL group and antibody group, cells in which were treated with phosphate buffered saline (PBS), Ox-LDL (50 mg/mL), Ox-LDL (50 µg/mL) plus Ox-LDL antibody (100 mg/L), respectively, for 24 h. The apoptosis rate was determined by inverted microscopy and flow cytometry. The protein and mRNA expression of NF-κB (P65), caspase-3 and BCL2 was detected by Western blotting and reverse transcription polymerase chain reaction (RT-PCR), respectively. RESULTS: The apoptosis rate reduced significantly in antibody group as compared to Ox-LDL and control groups (P<0.05). The protein and mRNA expression of NF-κB pathway was markedly lowered in antibody group than in Ox-LDL and control groups (P<0.05), which reduced the Ox-LDL induced inflammation. CONCLUSIONS: Ox-LDL antibody may be used to attenuate Ox-LDL induced inflammation and apoptosis, preventing atherosclerosis patients from acute coronary syndrome (ACS).