Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Vaccination for Negative Conversion Time of Nucleic Acid in Nonsevere COVID-19 Patients Infected by SARS-CoV-2 Omicron Variant.

SARS-CoV-2 Omicron variant is significantly different from all the previous variants and has rapidly replaced other variants as the dominant variant across the globe. An easily obtained, inexpensive, and rapid marker is needed to predict the negative conversion time (NCT) of nucleic acid in nonsevere COVID-19 patients infected by the Omicron variant. This retrospective study enrolled 226 patients infected by the Omicron variant between April 23, 2022, and May 16, 2022. The median age of the patients was 61 (interquartile range (IQR), 48-70) years, and 56.2% were male. 84 patients (37.2%) had at least one comorbidity, and 49 patients (21.7%) were classified into the moderate illness group. 145 patients (64.2%) received at least one dose of vaccine, in which 67 patients (29.6%) received a booster dose of vaccine. The median duration of NCT was 8 (IQR, 7-11) days. Univariate Cox analyses found that high NLR (>2.22), aged ≥65 years, vaccination, and moderate illness were significantly related to the NCT of nucleic acid. Multivariate Cox regression analysis showed that high NLR (NLR > 2.22, hazard ratio (HR):0.718, 95% CI: 0.534-0.964, p = 0.028) and vaccination (vaccinated ≥1 dose, HR: 1.536, 95% CI: 1.147-2.058, p = 0.004) were independently associated with NCT of nucleic acid. NLR is a rapid, simple, and useful prognostic factor for predicting NCT of nucleic acid in nonsevere COVID-19 patients with the Omicron variant. In addition, vaccination may also play a valuable role in predicting the NCT of nucleic acid.

Insulin secretion impairment induced by rosuvastatin partly though autophagy in INS-1E cells.

Statins are used extensively for the clinical treatment of cardiovascular diseases. Recent studies suggest that statins increase the risk of new-onset diabetes mellitus (NODM). However, the mechanisms of statin-induced NODM remain unclear. The present study investigated the effects of autophagy on insulin secretion impairment induced by rosuvastatin (RS) in rat insulinoma cells (INS-1E) cells. INS-1E cells were cultured and treated with RS at different concentrations (0.2-20 µM) for 24 h. Insulin secretion in INS-1E cells was detected by enzyme-linked immunosorbent assay, and the co-localization of microtubule-associated protein light chain 3 (LC3) and lysosome-associated membrane protein 2 (LAMP-2) was observed by immunofluorescence staining. Western blotting was used to assess the conversion of LC3 and p62. The results showed that the insulin secretion and cell viability decrease induced by RS treatment for 24 h occurred in a dose-dependent manner in INS-1E cells. RS significantly inhibited the expression of LC3-II but increased the protein expression of p62. Simultaneously, RS diminished the co-localization of LC3-II and LAMP-2 fluorescence signals. These results suggested that RS-inhibited autophagy in INS-1E cells. Rapamycin, an autophagy agonist, reversed the insulin secretion and cell viability suppression induced by RS in INS-1E cells. RS also decreased the phosphorylation of the mammalian target of rapamycin (mTOR). The results indicated that RS impairs insulin secretion in INS-1E cells, which may be partly due to the inhibition of autophagy via an mTOR-dependent pathway.

Effects of Remote Ischaemic Conditioning on Heart Rate Variability and Cardiac Function in Patients With Mild Ischaemic Heart Failure.

BACKGROUND: Cardioprotective effects of remote ischaemic conditioning (RIC) in the setting of ischaemic heart disease have been shown recently. But the effects of RIC on heart rate variability (HRV) and cardiac function in patients with stable ischaemic heart failure (IHF) are still unknown. METHODS: Fifty patients with stable IHF were enrolled and randomly divided into RIC group and control group. Remote ischaemic conditioning treatment was performed twice a day for 6 weeks. A remote is chaemic conditioning protocol consisted of 4×5min inflation/deflation of the blood pressure cuff applied in the upper arm to create intermittent arm ischaemia. B-type natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), 24-hour ambulatory electrocardiogram, and 6-minute walk distance (6MWD) were all assessed in two groups. RESULTS: Forty-seven patients completed the study. Remote ischaemic conditioning was well-tolerated by patients in the RIC group after 6 weeks treatment and LVEF showed a significant increase, from 39.2% to 43.4% (p<0.001), as well as decreased BNP, increased 6MWD and HRV, but this was not observed in the control group. In addition, the patients treated with RIC also showed improved NYHA class, LVEF, 6MWD, BNP level and HRV compared to control group. CONCLUSIONS: This study suggests that a 6-week course of RIC treatment could improve cardiac function and HRV in patients with mild and stable IHF, supporting widespread use of RIC in the daily lives of these patients.

The findings of electrocardiography in patients with cardiac amyloidosis.

OBJECTIVE: The electrocardiography (ECG) was the simplest and common adjunctive diagnostic tool for cardiac amyloidosis (CA). We sought to clarify the findings of ECG in patients with CA in order to early identification of CA according to the findings of ECG. METHODS: A total of 276 patients with diagnosis of systemic amyloidosis admitted to Peking Union Medical College Hospital from January 2000 to December 2011, were enrolled. Two groups were classified according to the cardiac involvement or not, namely CA (n = 189) and control (n = 87) groups. The low voltage on limb leads defined by the amplitude of the QRS complex in each limb leads ≤0.5 mV. The pseudo-infarct pattern defined by the presence of pathologic Q waves on at least two contiguous leads on ECG without obstructive coronary artery disease. RESULTS: The mean age was 55 ± 12 (15-88) years, 168 patients (61%) were male. Atrial arrhythmia (15.9% vs 3.4%, P = 0.003), low voltage on limb leads (54.5% vs 20.7%, P < 0.001), atrioventricular block (14.8% vs 1.1%, P = 0.001) and pseudo-infarct pattern (40.2% vs 4.6%, P < 0.001) were more prevalent in CA than control groups. The combination of low voltage on limb leads and pseudo-infarct pattern was more common (28.0% vs 2.3%, P < 0.001) in CA than control groups. The sensitivity, specificity, positive and negative predictive values of the presence of low voltage on limb leads and pseudo-infarct pattern for the diagnosis of CA were 28%, 98%, 96%, and 39%, respectively. CONCLUSION: In CA patients, low voltage on limb leads and pseudo-infarct pattern were the most common ECG findings. Atrial arrhythmia and atrioventricular block were the most common arrhythmias in CA patients. The combination of low voltage on limb leads and pseudo-infarct pattern had high specificity and positive predictive value for the diagnosis of CA.

Danon disease as a cause of concentric left ventricular hypertrophy in patients who underwent endomyocardial biopsy.

BACKGROUND: Danon disease is an X-linked dominant disorder; concentric left ventricular hypertrophy (LVH) is one of its manifestations. In this study, we investigated the prevalence of Danon disease in patients with concentric LVH who underwent endomyocardial biopsy (EMB). METHODS AND RESULTS: A total of 50 patients with concentric LVH underwent EMB from January 2008 to December 2010. Cardiac amyloidosis was diagnosed in 14 patients; genetic analysis of lysosome-associated membrane protein 2 (LAMP2) was done in the remaining 36 patients. Three novel LAMP2 frameshift mutations were found. They were c.808_809 insG in exon 6, c.320_321 insCATC in exon 3, and c.257_258delCC in exon 3, leading to a premature stop codon on cDNA analysis. The prevalence of Danon disease was seen in 6% (3 of 50) of unselected concentric LVH patients who underwent EMB, or 8% (3 of 36) after excluding cardiac amyloidosis through EMB. All the three patients were male teenagers with a mean age of 15 ± 1 years, and had mild mental retardation, two of the three with Wolff-Parkinson-White (WPW) syndrome and markedly increased left ventricular voltage. All the three patients had increased serum hepatic enzymes and creatine kinase (CK) concentrations. There was no death or cardiovascular hospitalization during 20 ± 15 months of follow-up. CONCLUSIONS: Danon disease may account for a number of patients with concentric LVH who underwent EMB. Danon disease should be suspected in the male teenager with concentric LVH, especially with elevated serum hepatic enzymes and CK concentrations, and/or WPW syndrome with markedly increased voltage of the left ventricle. Genetic analysis of LAMP2 can help make the diagnosis.

[Causes of insufficient anticoagulation in Chinese patients with non-valvlar atrial fibrillation].

OBJECTIVE: To evaluate the factors responsible for the insufficient application of oral anticoagulation (OAC) in Chinese patients with non-valvular atrial fibrillation. METHODS: The research is a single center registration study in a tertiary referral hospital in Beijing. The general characteristics, history of atrial fibrillation, comorbidities and anticoagulation treatment were obtained from all patients.Factors affecting the oral Walfarin use were evaluated by univariable and multivariable regression analysis. RESULTS: OAC therapy with Walfarin was applied on Only 214(39.4%) out of 576 consecutive patients with non-valvular atrial fibrillation. The OAC rate was 30.3% among non-ablation patients. Patients with persistent atrial fibrillation, diabetes, chronic heart failure, history of ischemic stroke/TIA and higher CHA2DS2-VASc score were more likely prescribed with Walfarin. Multivariable regression analysis showed that persistent fibrillation, history of chronic heart failure, ischemic stroke/TIA and non-coronary heart disease predicted the treatment with Walfarin. CONCLUSIONS: OAC use is extremely low in Chinese patients with non-valvular atrial fibrillation. More efforts are warranted to improve OAC use in these patients.

Risk Factors and Disease Profile Associated with the Nucleic Acid Conversion Time of COVID-19 Patients Infected with the SARS-CoV-2 Omicron Variant in Fangcang Shelter Hospitals.

Purpose: This study aimed to determine the clinical profile connected to the nucleic acid conversion time of COVID-19 patients harboring the SARS-CoV-2 Omicron variant at the hospitals at the Fangcang shelter. Methods: We reported 39,584 COVID-19 patients who were hospitalized in Shanghai, China, between April 5 and May 5, 2022, and who had contracted the Omicron strain of SARS-CoV-2. Demographic data, medical and vaccination history, clinical symptoms, and NCT were reported for the patient. Results: The median age of the patients with COVID-19 included in this study was 45 (interquartile range [IQR]: 33-54), and 64.2% of them were male. The two most prevalent comorbidities among the patients were hypertension and diabetes. Additionally, we discovered that the percentage of unimmunized patients was negligible (13.2%). We found that male sex, age under 60, and other comorbidities including hypertension and diabetes are significant risk factors for extending NCT when we analyzed the risk variables for NCT. We discovered that vaccination with two or more doses can significantly reduce NCT. The analysis of the young (18-59 years) and older (60 years) populations produced the same outcomes. Conclusion: Our findings confirm that a full COVID-19 vaccine series or booster doses are highly recommended to significantly reduce NCT. In order to reduce NCT, it is also advised that elderly people who have no clear contraindications take vaccination shots.

Value of Laboratory Indicators in Predicting Pneumonia in Symptomatic COVID-19 Patients Infected with the SARS-CoV-2 Omicron Variant.

Background: The pathogenicity of Omicron is different from that of the previous strains. The value of hematological indicators in patients at high risk of Omicron infection remains unclear. We need rapid, inexpensive and widely available biomarkers to guide the early detection of people at risk of pneumonia and to provide early intervention. We aimed to assess the value of hematological indicators as risk factors for pneumonia in symptomatic COVID-19 patients infected with the SARS-CoV-2 Omicron variant. Patients and Methods: The study enrolled 144 symptomatic COVID-19 patients with Omicron infection. We collected available clinical details, including laboratory tests and CT examinations. Univariate and multivariate logistic analyses and receiver operating characteristic (ROC) curve analyses were used to assess the value of laboratory markers in predicting the development of pneumonia. Results: Among the 144 patients, 50 (34.7%) had pneumonia. The ROC analysis revealed that the areas under the ROC curve (AUC) for leukocytes, lymphocytes, neutrophils, and fibrinogen were 0.603 (95% confidence interval (CI): 0.501-0.704, P=0.043), 0.615 (95% CI: 0.517-0.712, P=0.024), 0.632 (95% CI: 0.534-0.730, P=0.009) and 0.635 (95% CI: 0.539-0.730, P=0.008), respectively. The AUC for neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), fibrinogen to lymphocyte ratio (FLR), and fibrinogen to D-dimer ratio (FDR) were 0.670 (95% CI: 0.580-0.760, P=0.001), 0.632 (95% CI: 0.535-0.728, P=0.009), 0.669 (95% CI: 0.575-0.763, P=0.001) and 0.615 (95% CI: 0.510-0.721, P=0.023), respectively. Univariate analysis showed that elevated levels of NLR (odds ratio (OR): 1.219, 95% CI: 1.046-1.421, P=0.011), FLR (OR: 1.170, 95% CI: 1.014-1.349, P=0.031) and FDR (OR: 1.131, 95% CI: 1.039-1.231, P=0.005) were significantly correlated with the presence of pneumonia. Multivariate analysis indicated elevated NLR (OR: 1.248, 95% CI: 1.068-1.459, P=0.005) and FDR (OR: 1.160, 95% CI: 1.054-1.276, P=0.002) levels were associated with the existence of pneumonia. The AUC for the combination of NLR and FDR was 0.701 (95% CI: 0.606-0.796, P<0.001, sensitivity 56.0%, specificity 83.0%). Conclusion: NLR and FDR can predict the presence of pneumonia in symptomatic COVID-19 patients infected with the SARS-CoV-2 Omicron variant.

Factors associated with COVID-19 vaccination coverage in hypertensive patients with Omicron infection in Shanghai, China.

The potential future burden of COVID-19 is determined by the level of susceptibility of the population to infection. The protective effect provided by those previously infected diminishes over several months, while individuals with mixed immunity have the highest degree and persistence of protection. This study aimed to clarify the vaccination status of COVID-19 patients with hypertension and to analyze the characteristics and risk factors of non-vaccinated patients to protect this vulnerable population in the future. The study ultimately enrolled 4576 hypertensive patients with Omicron infection from April 6, 2022, to May 15, 2022. Among them, 3556 patients (77.7%) had received at least one dose of vaccine, and 2058 patients (45.0%) received a booster dose. In the multivariate logistic analysis, male (OR 1.328, 95% CI 1.138-1.550, p < .001), age (60-69 years vs.18-49 years) (OR 0.348, 95% CI 0.270-0.448, p < .001), age (≥70 years vs.18-49 years) (OR 0.130, 95% CI 0.100-0.169, p < .001), diabetes mellitus (OR 0.553, 95% CI 0.463-0.661, p < .001), chronic pulmonary diseases (OR 0.474, 95% CI 0.260-0.863, p = .015), chronic kidney disease (OR 0.177, 95% CI 0.076-0.410, p < .001), and cancer (OR 0.225, 95% CI 0.094-0.535, p = .001) were associated with vaccinated status. The vaccine coverage rate, especially the booster vaccine, was low for hypertensive patients with Omicron infection. Females, increasing age, and coexisting chronic diseases were associated with more inadequate vaccine coverage in hypertensive COVID-19 patients. Targeted interventions are required to address the under-vaccination of diverse hypertensive populations.

Impact of Different Traditional Chinese Medicine Constitutions on the Clinical Outcomes of COVID-19 Patients Infected with SARS-CoV-2 Omicron Variant: A Retrospective Observational Study.

Purpose: Traditional Chinese Medicine (TCM) constitution and disease occurrence, development, and prognosis are interrelated. This study aimed to investigate the association between TCM constitution and the time to negative nucleic acid test results in patients with coronavirus disease 2019 (COVID-19) infected with the SARS-CoV-2 Omicron variant. Patients and Methods: We identified COVID-19 patients (≥18 years) infected with the SARS-CoV-2 Omicron variant and collected clinical data, including clinical symptoms, time to negative nucleic acid test results, and TCM constitution. Linear and logistic regression analyses explored the relationship between TCM constitution and the time to negative nucleic acid test results in patients with the COVID-19 Omicron variant. Results: We included 486 patients with COVID-19, with a mean age of 40.2 years; 321 (66.0%) men and 165 (34.0%) women. Balanced constitution accounted for 43.8%, and unbalanced constitution accounted for 56.2%. Chi-square test showed that different TCM constitutions had significant differences in the influence of clinical symptoms of COVID-19 patients (P < 0.01). After controlling for various factors, multiple linear regression analysis revealed that an unbalanced constitution was significantly positively correlated with time to negative nucleic acid test results (P < 0.05). After controlling for various factors, logistic regression analysis revealed that an unbalanced constitution was closely related to the 7-day nucleic acid test conversion rate (odds ratio (OR): 0.53, 95% confidence interval (CI): 0.36-0.80, P < 0.05). After dividing the unbalanced constitution into deficiency constitution and non-deficiency constitution, the non-deficiency constitution was closely associated with the 7-day nucleic acid test conversion rate (OR = 0.45, 95% CI: 0.28-0.74, P < 0.05). Further analysis revealed that damp-heat constitution in the non-deficiency constitution was associated with the 7-day nucleic acid test conversion rate (OR = 0.33, 95% CI: 0.18-0.60, P < 0.05). Conclusion: In patients with COVID-19, an unbalanced constitution is associated with a longer time to negative nucleic acid test results and lower 7-day nucleic acid test conversion rates.

Machine Learning Revealed Ferroptosis Features and a Novel Ferroptosis-Based Classification for Diagnosis in Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is a leading cause of death and disability worldwide. Early diagnosis of AMI and interventional treatment can significantly reduce myocardial damage. However, owing to limitations in sensitivity and specificity, existing myocardial markers are not efficient for early identification of AMI. Transcriptome-wide association studies (TWASs) have shown excellent performance in identifying significant gene-trait associations and several cardiovascular diseases (CVDs). Furthermore, ferroptosis is a major driver of ischaemic injury in the heart. However, its specific regulatory mechanisms remain unclear. In this study, we screened three Gene Expression Omnibus (GEO) datasets of peripheral blood samples to assess the efficiency of ferroptosis-related genes (FRGs) for early diagnosis of AMI. To the best of our knowledge, for the first time, TWAS and mRNA expression data were integrated in this study to identify 11 FRGs specifically expressed in the peripheral blood of patients with AMI. Subsequently, using multiple machine learning algorithms, an optimal prediction model for AMI was constructed, which demonstrated satisfactory diagnostic efficiency in the training cohort (area under the curve (AUC) = 0.794) and two external validation cohorts (AUC = 0.745 and 0.711). Our study suggests that FRGs are involved in the progression of AMI, thus providing a new direction for early diagnosis, and offers potential molecular targets for optimal treatment of AMI.

[Value of cardiac magnetic resonance imaging for the diagnosis of cardiac amyloidosis].

OBJECTIVE: To observe the clinical features and cardiac magnetic resonance imaging (CMR) characteristics of patients with endomyocardial biopsy (EMB)-proven cardiac amyloidosis (CA). METHODS: EMB proven CA patients underwent CMR examination from September 2006 to December 2010 were included. The findings of clinical manifestation, electrocardiogram, echocardiography and CMR were analyzed. RESULTS: Among the 18 patients with EMB verified CA, 5 patients underwent CMR. All 5 patients had heart failure symptoms and electrocardiogram was abnormal. Echocardiogram showed concentric left ventricular hypertrophy, granular appearance of the myocardium, left atrial enlargement and moderate to severe left ventricular diastolic dysfunction. CMR revealed increased thickness of the left ventricular wall (especially at the inter-ventricular septum), enlarged bilateral auricle, restricted left ventricular filling with normal or mild to moderate reduced systolic function. Pleural and pericardial effusions were observed in 2 patients. Abnormal late gadolinium enhancement (LGE) was detected in all 5 patients. CMR revealed different patterns of LGE. Left ventricular global subendocardial delayed gadolinium enhancement or transmural delayed gadolinium enhancement were found, and patients also showed line-, granular- or patchy-like enhancement. The degree and range of LGE paralleled the disease course and were consistent with electrocardiogram changes. CONCLUSIONS: As a noninvasive diagnostic tool, CMR is valuable in the diagnosis of CA. For patients with clinical suspicion of CA, CMR could be a helpful diagnostic tool, especially in the hospitals where EMB is not available.

A network meta-analysis of non-vitamin K antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and diabetes mellitus.

PURPOSE: With the aim of recommending proper anticoagulation for patients with atrial fibrillation (AF) and diabetes mellitus, we performed the network meta-analysis comparing the non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in terms of efficacy (stroke or systemic embolism) and safety (major bleeding) outcome. METHODS: A systematic search of PubMed, EMBASE, Web of Science and Cochrane Library was performed with the items "dabigatran, edoxaban, apixaban, rivaroxaban, warfarin, AF and diabetes mellitus". On the basis of R (version 3.5.1, R Foundation for Statistical Computing) and JAGS (version 4.3.0) to perform the network meta-analysis, our work was also conducted with the help of NetMetaXL (version1.6.1) and winBUGS (version1.4.3) to obtain the cumulative ranking curve (SUCRA) of treatments. RESULTS: With respect to the most effective drug for preventing systemic embolism or stroke, there was a high probability that dabigatran150 (SUCRA 0.88) would ranked first, followed by apixaban (SUCRA 0.63), dabigatran110 (SUCRA 0.59) and rivaroxaban (SUCRA 0.51). In comparison, probability of ranking the safest drug for preventing major bleeding was edoxaban (SUCRA 0.94), followed by dabigatran110 (SUCRA 0.59) and rivaroxaban (SUCRA 0.52). CONCLUSION: In patients suffering from AF and diabetes, dabigatran 110 mg (bid) was more likely to become the choice for its performance on preventing systemic embolism or stroke and major bleeding, followed by rivaroxaban 20 mg (QD).

Efficacy and safety of non-vitamin K anticoagulants and warfarin in patients with atrial fibrillation and heart failure: A network meta-analysis.

BACKGROUND: To recommend the proper anticoagulant drug and its dose for patients with atrial fibrillation (AF) and heart failure (HF), we conducted a network meta-analysis (NMA) to make the comparisons among non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin with regard to efficacy (stroke or systemic embolism) and safety (major bleeding). METHODS: We searched PubMed, EMBASE, Web of Science and Cochrane Library with the items: "dabigatran, edoxaban, apixaban, rivaroxaban, warfarin, atrial fibrillation and heart failure" through April 14, 2020, focusing on the RCTs comparing the effect of NOACs to warfarin in patients with AF and HF. The NMA was performed based on R (version3.5.1) recalling JAGS (version4.3.0) with gemtc package. Moreover, NetMetaXL (version1.6.1) and winBUGS (version1.4.3) were employed to obtain the cumulative ranking curve area (SUCRA) of the anticoagulants. RESULT: There was a high probability that dabigatran150 (SUCRA 0.82) ranked the first for the most effective drug, followed by apixaban (SUCRA 0.81), edoxaban60 (SUCRA 0.57) and rivaroxaban (SUCRA 0.52). However, with respect to safety for preventing major bleeding, edoxaban30 (SUCRA 0.99) ranked as the safest drug, followed by apixaban (SUCRA 0.71), edoxaban 60 (SUCRA 0.59) and dabigatran150 (SUCRA 0.55). CONCLUSION: Apixaban, edoxaban60 and dabigatran150 were more likely to become the choice for preventing stroke or systemic embolism and major bleeding in patients with AF and HF. Nevertheless, more trials need to be performed to focus on the effect of NOACs on the efficacy outcome due to the sparse data. In addition, caution should be excised over selecting the NOAC and its dose on account of the lacking head-to-head comparisons.

Efficacy and Safety of Non-Vitamin K Anticoagulants for Atrial Fibrillation in Relation to Different Renal Function Levels: A Network Meta-Analysis.

BACKGROUND: We performed a network meta-analysis (NMA) comparing the efficacy (stroke or systemic embolism) and safety (major bleeding) among different non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and renal impairment, with the aim of recommending the proper drug and the dose based on renal function. METHODS: We searched PubMed, EMBASE, Web of Science, and Cochrane Library with the items "dabigatran, edoxaban, apixaban, rivaroxaban, warfarin, and atrial fibrillation" through August 2019. NMA was analyzed with R (version 3.5.1, R Foundation for Statistical Computing) with the packages gemtc recalling JAGS (version 4.3.0) for the efficacy and safety of each drug with regard to different levels of renal function. NetMetaXL (version 1.6.1) and winBUGS (version 1.4.3) were used to obtain the cumulative ranking curve (SUCRA) of each drug. RESULT: In patients with normal renal function, dabigatran150 was ranked as the most effective drug (SUCRA 0.90), followed by dabigatran110 (SUCRA 0.68), apixaban (SUCRA 0.66), and rivaroxaban (SUCRA 0.59). With regard to the safety for preventing major bleeding, there was high probability that edoxaban30 (SUCRA 0.99) ranked first, compared to dabigatran110 (SUCRA 0.78) and edoxaban60 (SUCRA 0.66). For patients with mild renal impairment, with respect to the most effective drug for preventing stroke or systemic embolism, edoxaban60 ranked first (SUCRA 0.98), in comparison with dabigatran150 (SUCRA 0.74) and apixaban (SUCRA 0.64). Possibility of ranking first for the safest drug was edoxaban30 (SUCRA 0.99), followed by dabigatran110 (SUCRA 0.70) and apixaban (SUCRA 0.69). In patients with moderate renal function, dabigatran150 (SUCRA 0.95) ranked as the most effective drug in comparison with apixaban (SUCRA 0.66). Dabigatran110 (SUCRA 0.53), rivaroxaban (SUCRA 0.51), and edoxaban60 (SUCRA 0.50) had the similar probability of ranking third. When referred to the safest drug, probability of ranking first for preventing major bleeding was edoxaban30 (SUCRA 0.98), followed by apixaban (SUCRA 0.85) and edoxaban60 (SUCRA 0.64). CONCLUSION: In patients with AF and renal impairment and for patients with normal renal function, dabigatran 110 mg (bid) might have a better effect on the clinical results. And it does not coincide with patients taking dabigatran 110 mg with dose reduction for other factors including aged ≥75 years, renal impairment (CrCL 30-50 mL/min), gastritis, esophagitis, or gastroesophageal reflux, receiving concomitant verapamil, and so on. For patients with mild renal impairment, apixaban 5 mg (bid) would be a better choice for preventing stroke or systemic embolism and major bleeding, while apixaban 5 mg (bid) and edoxaban 60 mg (qd) were recommended for patients with moderate renal impairment. However, considering the fact of no RCTs for the head-to-head comparison, caution should be exercised over selecting each of NOACs for patients.

Pioglitazone Ameliorates Atorvastatin-Induced Islet Cell Dysfunction through Activation of FFA1 in INS-1 Cells.

Increasing evidence shows that statins increase the risk of new-onset diabetes mellitus, but the exact mechanism is not clearly known. Free fatty acid receptor 1 (FFA1) has been recognized to mediate insulin secretion, and pioglitazone has direct effects on glucose-stimulated insulin secretion in addition to the reversion of insulin resistance. In this study, we found that atorvastatin decreased potassium-stimulated insulin secretion and inhibited the expression of FFA1, PDX-1, and BETA2/NeuroD in INS-1 cells. Further study demonstrated that pioglitazone prevented the impairment of insulin secretion induced by atorvastatin and enhanced the expression of FFA1, PDX-1, and BETA2/NeuroD reduced by atorvastatin in INS-1 cells. In addition, the preventive effect of pioglitazone on atorvastatin-induced impairment of insulin secretion and the enhancement of the expression of PDX-1 and BETA2/NeuroD was abolished by knockdown of FFA1 using siRNA or the PLC inhibitor, U-73122, respectively. Ultimately, FFA1 may mediate the atorvastatin-induced pancreatic ß-cell dysfunction and pioglitazone may ameliorate this deleterious effect through the upregulation of FFA1 expression.

Prevention of neointimal formation after angioplasty using tetramethylpyrazine-coated balloon catheters in a rabbit iliac artery model.

BACKGROUND: Restenosis remains a clinical problem; drug-coated balloons (DCBs) have demonstrated high efficiency in this situation. DCBs prevent neointimal hyperplasia by inhibiting cell proliferation and migration. Tetramethylpyrazine (TMP) is a traditional Chinese medicine originally isolated from the rhizome of Ligusticum Walliichii, which can inhibit platelet aggregation and smooth muscle cell proliferation. We hypothesized that TMP-coated balloons (TCB) could reduce neointimal hyperplasia through the NF-κB signalling pathway. METHODS: Twenty-one New-Zealand White rabbits (2.5-3.0 kg, male) were fed high-fat diets; 36 bilateral iliac artery stenosis models were successfully established by balloon straining. Rabbits were randomly treated with TCB (n=20) or plain balloons (PBA, n=16) (3 died during model construction). Angiographies were recorded at baseline, the immediate period, and 4 weeks later. Animals were euthanized and arteries collected for histological analysis and immunohistochemical staining. Protein expression of proliferating cell nuclear antigen (PCNA) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 of the vessel samples were analyzed using Western blotting. RESULTS: No difference existed in the baseline lesion characteristics or procedural results. Angiographic follow-up was successfully performed on 18 rabbits (TCB: n=20, PBA: n=16), except for 3 deaths related to the operation. Treatment with TCB was superior to that with PBA, with lower late lumen loss (0.45±0.23 vs. 0.84±0.17 mm, P<0.01). Pathological analysis confirmed the efficiency of TCB through decreasing the area stenosis rate compared with PBA (46.48%±8.22% vs. 75.24%±6.10%, P<0.01). As determined by Western blotting, significant reductions occurred in PCNA and NF-κB p65 protein intensity in the TCB group versus the PBA group (all P<0.01). TCB efficiently mitigated restenosis in the rabbit iliac artery model. CONCLUSIONS: This study elucidated that TCB could restrain intimal hyperplasia of vessels by inhibiting the activation of the NF-κB pathway to reduce inflammatory response and decrease the rate of cell proliferation through suppressing PCNA expression.

Blockade of RBP-J-Mediated Notch Signaling Pathway Exacerbates Cardiac Remodeling after Infarction by Increasing Apoptosis in Mice.

BACKGROUND: Ischemic heart disease (IHD) is the major cause of death in patients with cardiovascular disease. Cardiac remodeling is a common pathological change following myocardial infarction (MI), and cardiomyocyte apoptosis plays a key role in this change. Transcription factor recombination signal-binding protein-J (RBP-J)-mediated Notch signaling pathway has been implicated in several inherited cardiovascular diseases, including aortic valve diseases, but whether the RBP-J-mediated Notch signaling pathway plays a role in cardiomyocyte apoptosis after MI is unclear. METHOD: We crossed RBP-Jfl/fl mice and Myh6-Cre/Esr1 transgenic mice to delete RBP-J in vivo and to partly inhibit the canonical Notch signaling pathway. MI was induced in mice by permanent ligation of the left anterior descending coronary artery followed by the knockout of RBP-J. Cardiac function and morphology were assessed by echocardiography and histological analysis 4 weeks after infarction. In addition, the expression and regulation of apoptosis-related molecules were examined by real time PCR and western blot. RESULTS: RBP-J knockout decreased the survival rate and deteriorated post-MI remodeling and function in mice, and this effect was associated with increased cardiomyocyte apoptosis. The potential mechanisms might be related to the downregulated expression of bcl-2, upregulated expression of bax, and cleaved-caspase 3 to exacerbate cardiomyocyte apoptosis. CONCLUSION: These findings show that the RBP-J-mediated Notch signaling pathway in cardiomyocytes limits ventricular remodeling and improves cardiac function after MI. The RBP-J-mediated Notch signaling pathway has a protective role in cardiomyocyte apoptosis following cardiac injury.

Tollip Negatively Regulates Vascular Smooth Muscle Cell-Mediated Neointima Formation by Suppressing Akt-Dependent Signaling.

BACKGROUND: Tollip, a well-established endogenous modulator of Toll-like receptor signaling, is involved in cardiovascular diseases. The aim of this study was to investigate the role of Tollip in neointima formation and its associated mechanisms. METHODS AND RESULTS: In this study, transient increases in Tollip expression were observed in platelet-derived growth factor-BB-treated vascular smooth muscle cells and following vascular injury in mice. We then applied loss-of-function and gain-of-function approaches to elucidate the effects of Tollip on neointima formation. While exaggerated neointima formation was observed in Tollip-deficient murine neointima formation models, Tollip overexpression alleviated vascular injury-induced neointima formation by preventing vascular smooth muscle cell proliferation, dedifferentiation, and migration. Mechanistically, we demonstrated that Tollip overexpression may exert a protective role in the vasculature by suppressing Akt-dependent signaling, which was further confirmed in rescue experiments using the Akt-specific inhibitor (AKTI). CONCLUSIONS: Our findings indicate that Tollip protects against neointima formation by negatively regulating vascular smooth muscle cell proliferation, dedifferentiation, and migration in an Akt-dependent manner. Upregulation of Tollip may be a promising strategy for treating vascular remodeling-related diseases.