Cytochrome b561 regulates iron metabolism by activating the Akt/mTOR pathway to promote Breast Cancer Cells proliferation.

Breast cancer (BC) is the leading cause of cancer-related mortality in women, necessitating the development of novel therapeutic targets. While cytochrome b561 (CYB561) expression is associated with poor prognosis in BC, the precise role of CYB561 in BC and its potential mechanisms remain unclear. In the present study, we found that CYB561 plays an essential role in BC growth. CYB561 expression was up-regulated in surgically resected cancerous tissues and in six BC cell lines. Lentivirus-mediated CYB561 knockdown in BC cells significantly reduced their proliferation, migration, and invasiveness. CYB561 participates in the regulation of iron metabolism in BC. CYB561 knockdown reduced total iron content, increased ferrous iron content, and down-regulated the expression of proteins associated with iron metabolism (transferrin receptor 1, divalent metal transporter 1, and ferritin heavy chain 1). Conversely, up-regulation of CYB561 through co-incubation with exogenous iron (ferric ammonium citrate) produced contrary outcomes. Additionally, CYB561 activated the protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling pathway in BC cells. Down-regulation of CYB561 expression inhibited the Akt/mTOR signaling pathway activity. The application of an mTOR agonist (MHY1485) rescued this negative effect, as well as the inhibitory effect of CYB561 knockdown on cell proliferation. Importantly, the dual mTOR inhibitor MLN0128 (50 nM, 48 h) down-regulated CYB561 expression and the iron metabolism-related proteins transferrin receptor, divalent metal transporter 1, and ferritin heavy chain 1, whereas the mTOR agonist MHY1485 rescued the down-regulation of CYB561 knockdown on iron metabolism-related proteins. We conclude that CYB561 promotes the proliferation of BC cells by regulating iron metabolism through the activation of the Akt/mTOR signaling pathway.

Prevalence, associated factors, and gene polymorphisms of obesity in Tibetan adults in Qinghai, China.

OBJECTIVES: To explore the prevalence and associated factors of obesity in Tibetan adults in Qinghai, China, and to determine the association between the FTO (rs1121980 and rs17817449) and MC4R gene (rs17782313 and rs12970134) polymorphisms with obesity. METHODS: A cross-sectional survey was conducted in 2015 in Qinghai to selected Tibetan adults aged 20 to 80 years. Prevalence of obesity (BMI ≥ 28 kg/m2) and overweight (BMI 24 ~ 27.9 kg/m2) were evaluated. Multivariable logistic models were used to determine the associated factors. Pair-matched subjects of obesity cases and normal-weight controls were selected for the gene polymorphism analyses. Conditional logistic models were used to assess the association between gene polymorphisms with obesity. Additive and multiplicative gene-environment interactions were tested. RESULTS: A total of 1741 Tibetan adults were enrolled. The age- and sex- standardized prevalence of obesity and overweight was 18.09% and 31.71%, respectively. Male sex, older age, heavy level of leisure-time exercise, current smoke, and heavy level of occupational physical activity were associated with both obesity and overweight. MC4R gene polymorphisms were associated with obesity in Tibetan adults. No significant gene-environment interaction was detected. CONCLUSION: The prevalence of obesity and overweight in Tibetan adults was high. Both environmental and genetic factors contributed to the obesity prevalent.

Icosapent ethyl therapy for very high triglyceride levels: a 12-week, multi-center, placebo-controlled, randomized, double-blinded, phase III clinical trial in China.

OBJECTIVES: Eicosapentaenoic acid in its ethyl ester form is the single active component of icosapent ethyl (IPE). This study was a phase III, multi-center trial assessing the safety and efficiency of IPE for treating very high triglyceride (TG) in a Chinese cohort. METHODS: Patients having TG levels (5.6-22.6 mmol/L) were enrolled and randomly assigned to receive a treatment of oral intake of 4 g or 2 g/day of IPE, or placebo. Before and after 12 weeks of treatment, TG levels were assessed and the median was calculated to determine the change between the baseline and week 12. In addition to examining TG levels, the impact of such treatments on other lipid changes was also investigated. The official Drug Clinical Trial Information Management Platform has registered this study (CTR20170362). RESULTS: Random assignments were performed on 373 patients (mean age 48.9 years; 75.1% male). IPE (4 g/day) lowered TG levels by an average of 28.4% from baseline and by an average of 19.9% after correction for placebo (95% CI: 29.8%-10.0%, P < 0.001). In addition, plasma concentration of non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein (VLDL) cholesterol, and VLDL-TG remarkedly reduced after IPE (4 g/day) treatment by a median of 14.6%, 27.9%, and 25.2%, respectively compared with participants in placebo group. Compared to the placebo, neither 4 nor 2 g of IPE daily elevated LDL-C levels with statistical significance. IPE was well tolerated by all the treatment groups. CONCLUSIONS: IPE at 4 g/day dramatically lowered other atherogenic lipids without a noticeable increase in LDL-C, thereby decreasing TG levels in an exceptionally high-TG Chinese population.

Rosuvastatin Slows Progression of Carotid Intima-Media Thickness: The METEOR-China Randomized Controlled Study.

BACKGROUND: Atherosclerosis is the leading cause of cardiovascular disease worldwide, including in China. Primary prevention, through lipid-lowering, could avert development of atherosclerosis. Carotid intima-media thickness (CIMT) is a well-validated measure of atherosclerosis used in intervention studies as the primary outcome and alternative end point for cardiovascular disease events. METHODS: This randomized, double-blind, placebo-controlled, multicenter, parallel-group study assessed the effects of rosuvastatin 20 mg/d compared with placebo on progression of CIMT over 104 weeks in Chinese people with subclinical atherosclerosis. The primary end point was the annualized rate of change in mean of the maximum CIMT measurements taken 7× over the study period from each of 12 carotid artery sites (near and far walls of the right and left common carotid artery, carotid bulb, and internal carotid artery). Secondary end points included CIMT changes at different artery sites and lipid-parameter changes. Safety was also assessed. RESULTS: Participants were randomized (1:1) to receive rosuvastatin (n=272) or placebo (n=271). Baseline characteristics were well balanced between groups. The change in mean of the maximum CIMT of the 12 carotid sites was 0.0038 mm/y (95% CI, -0.0023-0.0100) for the rosuvastatin group versus 0.0142 mm/y (95% CI, 0.0080-0.0204) for the placebo group, with a difference of -0.0103 mm/y (95% CI, -0.0191 to -0.0016; P=0.020). For the CIMT secondary end points, the results were generally consistent with the primary end point. There were clinically relevant improvements in lipid parameters with rosuvastatin. We observed an adverse-event profile consistent with the known safety profile of rosuvastatin. CONCLUSIONS: Rosuvastatin 20 mg/d significantly reduced the progression of CIMT over 2 years in Chinese adults with subclinical atherosclerosis and was well tolerated. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02546323.

Nine-month angiographic and 2-year clinical outcomes of the RECOVERY trial: A randomized study of the biodegradable polymer sirolimus-eluting COMBO dual-therapy stent versus a polymer-free sirolimus-eluting stent in Chinese patients.

OBJECTIVES: We evaluated the safety and efficacy of the novel dual-therapy sirolimus-eluting and endothelial progenitor cell (EPC) capture COMBO stent. BACKGROUND: (Very) late stent thrombosis (ST) and neo-atherosclerosis limit the performance of drug-eluting stents. The capture of EPCs accelerates stent re-endothelialization, thereby potentially decreasing the risk of restenosis and ST. METHODS: In total, 440 patients with de novo lesions in native coronary arteries were randomized (1:1) to either receive the COMBO stent (n = 220) or Nano polymer-free sirolimus-eluting stent (n = 220). The primary endpoint was the 9-month angiographic in-segment late lumen loss (LLL). Secondary endpoints included target lesion failure (TLF), a patient-oriented composite endpoint (PoCE), and ST. RESULTS: At 9 months, the COMBO in-segment LLL (0.29 ± 0.46 mm) was non-inferior to that of the Nano comparator stent (0.31 ± 0.44 mm; pnon-inferiority < .0001). Clinical outcomes were also similar between the COMBO and Nano stents, with TLF rates of 9.3% and 7.9% (p = .61) at 12 months, and 9.4% and 8.0% (p = .62) at 24 months, respectively. The PoCE rate was 14.8% and 10.6% (p = .19) at 12 months, and 16.0% and 11.3% (p = .16) at 24 months, respectively. Ischemia-driven target lesion revascularization rates were 6.0% and 3.7% (p = .26) at 12 months, and 6.2% and 3.8% (p = .26) at 24 months, respectively. No case of ST occurred in either group. CONCLUSIONS: The RECOVERY trial has shown the COMBO stent was effective, meeting the primary non-inferiority angiographic endpoint, and safe, with an overall low rate of clinical events in both stent groups, including no ST for up to 2 years.

Prevalence and risk factors of refractive error in Qinghai, China: a cross-sectional study in Han and Tibetan adults in Xining and surrounding areas.

BACKGROUND: Our study aimed to explore the prevalence and risk factors of refractive error (RE) in Han and Tibetan population aged 50-79 years in Xining and surrounding areas in Qinghai Province on Qinghai-Tibet Plateau. METHODS: As part of the China National Health Survey, our cross-sectional study compared the age-adjusted prevalence of RE in Han and Tibetan older adults aged 50-79 years in Xining and surrounding areas. A multivariate logistic regression model was used to identify risk factors for myopia and hyperopia. RESULTS: Among 769 Han participants and 476 Tibetan participants, the age-adjusted prevalence of myopia (spherical equivalent (SE) < - 0.5D), hyperopia (SE > + 0.5D), high myopia (SE < -6.0D) and astigmatism (cylindrical equivalent > = 0.5D) is 28.56, 22.82, 2.80, and 69.38%. Han participants have higher age-adjusted prevalence of myopia (32.93% vs 21.64%, p < 0.001), high myopia (3.93% vs 1.02%, p = 0.001) and astigmatism (72.14% vs 64.94%, p = 0.021) compared to Tibetan participants. Being Tibetan is the protective factor of myopia compared to being Han (OR 0.58, 95%CI 0.42-0.79, p < 0.001). Older age (p = 0.032), longer time length in rural area (p = 0.048), undergraduate/graduate education level (p = 0.031), lighter active level (p = 0.007) and lower BMI (p = 0.015) are risk factors for myopia. Older age (all p < 0.001) and pterygium status of the same eye (p = 0.013) also increase the hyperopia risk. CONCLUSIONS: Our study found an overall prevalence of myopia of 28.56% in Xining and surrounding areas in adults older than 50 years. Han population has higher myopia risk than Tibetan population. More medical and social resources should be allocated to improve the vision and life quality of older adults.

EPAS1 regulates proliferation of erythroblasts in chronic mountain sickness.

Excessive erythrocytosis (EE) is a characteristic of chronic mountain sickness (CMS). Currently, the pathogenesis of CMS remains unclear. This study was intended to investigate the role of EPAS1 in the proliferation of erythroblasts in CMS. Changes of HIF-1α and EPAS1/HIF-2α in the bone marrow erythroblasts of 21 patients with CMS and 14 control subjects residing at the same altitudes were determined by RT-qPCR and western blotting. We also developed a lentiviral vector, Lv-EPAS1/sh-EPAS1, to over-express/silence EPAS1 in K562 cells. Cells cycle and proliferation were detected by flow cytometry. Transcriptome analyses were carried out on Illumina. CMS patients showed a higher expression of EPAS1/HIF-2α in the bone marrow erythroblasts than those of controls. Variations in EPAS1 expression in CMS patients were positively correlated with RBC levels, and negatively correlated with SaO2. Over-expressing of EPAS1 in K562 cells accelerated the erythroid cells cycle progression and promoted the erythroid cells proliferation-and vice versa. Transcriptome data indicated that proliferation-related DEGs were significantly enriched in EPAS1 overexpression/silencing K562 cells. Our results suggest that EPAS1 might participate in the pathogenesis of EE by regulating the proliferation of erythroblasts.

Two-year safety evaluation of a biodegradable polymer sirolimus-eluting stent with increased drug elution and polymer absorption kinetics in complex patient and lesion cohort.

OBJECTIVES: The aim of the present report was to compare 2-year safety outcomes of two biodegradable polymer (BP) sirolimus-eluting stents (SESs) with different drug eluting and polymer absorption kinetics in a subgroup of complex patients and lesions. BACKGROUND: The previously published PANDA III study showed the BuMA BP SES, with faster drug elution and polymer absorption, was non-inferior to the Excel SES in target lesion failure (TLF). METHODS: In PANDA III trial, patients who fulfilled one or more of the following criteria were included: Small vessel disease (reference vessel diameter ≤ 2.5 mm); long lesion (lesion length ≥ 20 mm); chronic total occlusion lesion; and diabetic patients. RESULTS: Among 2,348 patients randomly assigned to treatment with BuMA (n = 1,174) or Excel SES (n = 1,174) in the PANDA III study, 858 in the BuMA group and 855 in the Excel group satisfied the inclusion criteria. At 2-year follow-up, the incidence of definite/probable stent thrombosis (ST) was significantly lower with BuMA SES as compared with Excel SES (0.7% vs. 1.9%, p = 0.03). This difference was mainly caused by decreased subacute stent thrombosis rate (0% vs. 0.6%, p = 0.03). In patients who did not fulfill the complex patient and lesion criteria, there were no between-group difference in ST (0.7% vs. 0%, p = 0.50). Myocardial infarction and TLF rates were similar (5.7% vs. 6.0%, p = 0.79 and 8.8% vs. 7.5%, p = 0.34, respectively), whereas patient-oriented composite endpoint was higher with BuMA SES mainly due to high risk of revascularization (15.6% vs. 11.4%, p = 0.01; 8.4% vs. 4.6%, p < 0.01). CONCLUSIONS: Two-year subgroup analysis of the all-comer PANDA III trial revealed the increased safety benefit of the BuMA SES is more prominently seen in complex patient and lesion population. CLINICAL TRIAL: ClinicalTrial.gov, Identifier-NCT02017275.

Downregulation of intrinsic apoptosis pathway in erythroblasts contributes to excessive erythrocytosis of chronic mountain sickness.

Chronic mountain sickness (CMS) has a higher incidence in the plateau region and is characterized by excessive erythrocytosis and hypoxemia. Bcl-2 family plays an important role in the process of erythropoiesis and the regulation of apoptosis. This study aimed to examine the change in apoptosis of erythroblasts in CMS patients and explore the involvement of Bcl-2 family. Bone marrow mononuclear cells (BMMNCs) were isolated by density gradient centrifugation from 18 CMS patients and 17 control participants. The apoptotic rate, mitochondrial membrane potential (MMP), the protein expression of caspase-3, TNFR, Fas, Bcl-2, Bax and Cyt-C were examined by flow cytometry, and mRNA expression was determined by real-time PCR. The results showed that apoptotic rate of erythroblasts was lower and MMP was higher in CMS group than in control group. The mRNA and protein expression levels of Bcl-2 were higher while Bax level was lower in CMS group than in control group. In CMS group, the apoptosis rate of CD71+ erythroblasts was negatively correlated with the ratio of CD71+ cells in BMMNCs and positively correlated with hemoglobin level. In conclusion, erythroblasts apoptosis is decreased due to the regulation of the expression of Bcl-2 family members in the erythroblasts of CMS patients.

A risk score to predict postdischarge bleeding among acute coronary syndrome patients undergoing percutaneous coronary intervention: BRIC-ACS study.

BACKGROUND: Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) prevents ischemic events while increasing bleeding risk. Real-world-based metrics to accurately predict postdischarge bleeding (PDB) occurrence and its potential impact on postdischarge major cardiovascular event (MACE) remain undefined. This study sought to evaluate the impact of PDB on MACE occurrence, and to develop a score to predict PDB risk among Chinese acute coronary syndrome (ACS) patients after PCI. METHODS AND RESULTS: From May 2014 to January 2016, 2496 ACS patients who underwent PCI were recruited consecutively from 29 nationally representative Chinese tertiary hospitals. Among 2,381 patients (95.4%, 2,381/2,496) who completed 1-year follow-up, the cumulative incidence of PDB (bleeding academic research consortium type [BARC] ≥2) and postdischarge MACE (a composite of all-cause death, nonfatal myocardial infarction, ischemic stroke, or urgent revascularization) was 4.9% (n = 117) and 3.3% (n = 79), respectively. The association between PDB and MACE during 1-year follow-up, as well as the impact of DAPT with ticagrelor or clopidogrel on PDB were evaluated. PDB was associated with higher risk of postdischarge MACE (7.7 vs. 3.1%; adjusted hazard ratio: 2.59 [95% confidence interval: 1.17-5.74]; p = .02). For ticagrelor versus clopidogrel, PDB risk was higher (8.0 vs. 4.4%; 2.05 [1.17-3.60]; p = .01), while MACE risk was similar (2.0 vs. 3.4%; 0.70 [0.25-1.93]; p = .49). Based on identified PDB predictors, the constructed bleeding risk in real world Chinese acute coronary syndrome patients (BRIC-ACS) score for PDB was established. C-statistic for the score for PDB was 0.67 (95% CI: 0.62-0.73) in the overall cohort, and >0.70 in subgroups with non-ST- and ST-segment elevation myocardial infarction, diabetes and receiving more than two drug eluting stents. CONCLUSIONS: In Chinese ACS patients, PDB with BARC ≥2 was associated with higher risk for MACE after PCI. The constructed BRIC-ACS risk score provides a useful tool for PDB discrimination, particularly among high ischemic and bleeding risk patients.

Comparison of two biodegradable-polymer-based sirolimus-eluting stents with varying elution and absorption kinetics in patients with acute myocardial infarction: A subgroup analysis of the PANDA III trial.

BACKGROUND: Implantation of early-generation metallic drug-eluting stents (DES) in patients with acute myocardial infarction (AMI) is associated with poor vessel wall healing. Use of biodegradable polymer (BP) DES might improve safety outcomes; however, the impact of varying drug elution and polymer absorption kinetics of BP-DES on clinical outcomes in the AMI population is unknown. METHODS: This subgroup analysis of the randomized PANDA III trial included 732 patients (366 in each group) presenting with recent (<1 month) AMI. Primary endpoint was 1-year target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (MI), or ischemia-driven target lesion revascularization. Secondary endpoints included a patient-oriented composite endpoint (PoCE) of all-cause death, all MI, or any revascularization; individual TLF and PoCE components; and definite/probable stent thrombosis (ST). RESULTS: There were no significant differences between-groups in baseline clinical, angiographic, or procedural characteristics other than the proportion of post-dilatation, which was performed more frequently with the BuMA stent (53.9% vs. 44.5%; P = 0.004). After 1 year, compared to Excel SES implantation in patients with AMI, BuMA was associated with similar incidences of TLF and PoCE (5.5% vs. 8.3%, P = 0.14; 8.8% vs. 9.9%, P = 0.61, respectively) but lower incidences of MI (2.5% vs. 6.1%, P = 0.02), target vessel MI (2.2% vs. 5.8%, P = 0.01), and definite/probable ST (0.3% vs. 2.2%, P = 0.04). CONCLUSIONS: BuMA SES, with faster drug elution rate and polymer absorption kinetics, might improve safety outcomes compared to Excel SES in the high-risk AMI population. © 2017 Wiley Periodicals, Inc.

Effect of Metoprolol Succinate in Patients with Stable Angina and Elevated Heart Rate Receiving Low-Dose ß-Blocker Therapy.

Aims: ß-blockers are underused in Chinese patients with coronary heart disease. The prescribed dose is often low. The aim of this study was to investigate the effect of metoprolol succinate doses of 95 mg and 190 mg on heart rate (HR) control, as well as drug tolerance, in Chinese patients with stable angina, low-dose ß-blocker use and unsatisfactory HR control. Methods: This was a multicenter, randomized, open-label, parallel-group trial in 15 clinical sites. Patients with stable angina, taking low-dose ß-blockers (equivalent to metoprolol succinate 23.75-47.5 mg/day), and having a resting HR of ≥ 65 bpm were enrolled and randomized to either the metoprolol 95-mg group or the 190-mg group. The change in 24-h average HR from baseline recorded by Holter monitoring and the percentages of patients with resting HR controlled to ≤ 60 bpm were compared between the two groups. Results: Two hundred thirty-one patients entered the intent-to-treat population for the main analysis. The change in 24-h average HR from baseline was -0.62 ± 0.66 bpm in the 95 mg group and -2.99 ± 0.62 bpm in the 190 mg group (p = 0.0077) after 8 weeks of treatment. The percentages of patients with resting HR controlled to ≤ 60 bpm were 24.1% (95% CI: 16.35%, 31.93%) and 40.0% (95% CI: 31.05%, 48.95%), respectively (p = 0.0019). Only 4 and 2 of the patients, respectively, discontinued the study drugs because of hypotension or bradycardia. Conclusions: The metoprolol succinate dose of 190 mg is superior to the 95 mg dose in terms of HR control, in Chinese patients with stable angina, low-dose ß-blocker use and unsatisfactory HR control. Both doses were well tolerated.

PI3K-Akt Signal Transduction Molecules Maybe Involved in Downregulation of Erythroblasts Apoptosis and Perifosine Increased Its Apoptosis in Chronic Mountain Sickness.

BACKGROUND Chronic mountain sickness (CMS) has a higher incidence in the plateau region. The one of its principal characters is excessive erythrocytosis. The PI3K-Akt pathway plays an important role in the process of erythropoiesis, and could downregulate apoptosis by regulating apoptosis-related molecules. In this paper, we explored the change in apoptosis of erythroblasts and the effect of the PI3K-Akt signal pathway on erythroblasts apoptosis in CMS. MATERIAL AND METHODS A total of 22 CMS and 20 non-CMS participants were involved in this study. Bone marrow mononuclear cells were cultured and treated with celecoxib and perifosine in vitro for 72 hours. The apoptotic rate, the mRNA expressions of Akt, Bcl-xl, and caspase-9, and the protein expressions of Akt, p-Akt, Bcl-xl, and caspase-9 were determined by flow cytometry, quantitative RT-PCR, and western-blot technique. RESULTS The apoptotic rate of cultured erythroblasts was lower in the CMS group than in the non-CMS group. It was increased after perifosine intervention. The mRNA and protein expressions of Akt and Bcl-xl were higher and caspase-9 was lower in the CMS group than the non-CMS group. Perifosine induced decreased Bcl-xl mRNA and proteins and p-Akt proteins, and increased caspase-9 mRNA and proteins in vitro. In the CMS group, the hemoglobin concentration was correlated with apoptotic rate negatively and with Bcl-xl mRNA positively in erythroblasts; the erythroblasts apoptotic rate was negatively associated with the Akt mRNA and Bcl-xl mRNA. CONCLUSIONS The erythroblasts apoptosis was downregulated and the PI3K-Akt signal pathway appeared to be involved in the mechanism of decreased erythroblasts apoptosis in CMS.

Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice.

Fenofibrate (FF), as a peroxisome-proliferator-activated receptor α (PPARα) agonist, has been used clinically for decades to lower lipid levels. In the present study, we examined whether FF can be repurposed to prevent the pathogenesi of the heart in Type 1 diabetes and to describe the underlying mechanism of its action. Streptozotocin (STZ)-induced diabetic mice and their age-matched control mice were treated with vehicle or FF by gavage every other day for 3 or 6 months. FF prevented diabetes-induced cardiac dysfunction (e.g. decreased ejection fraction and hypertrophy), inflammation and remodelling. FF also increased cardiac expression of fibroblast growth factor 21 (FGF21) and sirtuin 1 (Sirt1) in non-diabetic and diabetic conditions. Deletion of FGF21 gene (FGF21-KO) worsened diabetes-induced pathogenic effects in the heart. FF treatment prevented heart deterioration in the wild-type diabetic mice, but could not do so in the FGF21-KO diabetic mice although the systemic lipid profile was lowered in both wild-type and FGF21-KO diabetic mice. Mechanistically, FF treatment prevented diabetes-impaired autophagy, reflected by increased microtubule-associated protein 1A/1B-light chain 3, in the wild-type diabetic mice but not in the FGF21-KO diabetic mice. Studies with H9C2 cells in vitro demonstrated that exposure to high glucose (HG) significantly increased inflammatory response, oxidative stress and pro-fibrotic response and also significantly inhibited autophagy. These effects of HG were prevented by FF treatment. Inhibition of either autophagy by 3-methyladenine (3MA) or Sirt1 by sirtinol (SI) abolished FF's prevention of HG-induced effects. These results suggested that FF could prevent Type 1 diabetes-induced pathological and functional abnormalities of the heart by increasing FGF21 that may up-regulate Sirt1-mediated autophagy.

BNIP3 in hypoxia-induced mitophagy: Novel insights and promising target for non-alcoholic fatty liver disease.

BNIP3 localizes to the outer mitochondrial membrane, has been demonstrated to be extensively involved in abnormalities to mitochondrial metabolic function and dynamicsand in non-alcoholic fatty liver disease (NAFLD). However, its role in NAFLD under hypoxia remains unclear. This study aimed to investigate the expression and the role of BNIP3 in NAFLD under hypoxia, and explore its involvement in regulating NAFLD mitophagy, fatty acid ß-oxidation both in vivo and in vitro. BNIP3-mediated mitophagy level was analyzed using real-time quantitative polymerase chain reaction, Western blotting, immunofluorescence and electron microscopy. The role of BNIP3 in fatty acid ß-oxidation was evaluated using lipid droplet staining, triglyceride content determination, and cellular energy metabolism. The results showed that compared with the HFD-2200 m, the body weight, inflammatory liver injury, and lipid deposition were significantly reduced in the HFD-4500 m group (P < 0.05), but autophagy and mitophagy were increased, and the expression of the mitophagy receptor BNIP3 was increased (P < 0.05). Compared to the control group, BNIP3 knockdown in the hypoxia group resulted in decreased levels of CPT1, ATGL, and p-HSL in lipid-accumulating hepatocytes, lipid droplet accumulation and triglyceride content increased (P < 0.05). Moreover, the ability of lipid-accumulating hepatocytes to oxidize fatty acids was reduced by BNIP3 knockdown in the hypoxia group (P < 0.05). Therefore, it can be concluded that, in NAFLD mice under hypoxia, BNIP3-mediated mitophagy promotes fatty acid ß-oxidation. This study elucidated the role of BNIP3 in promoting fatty acid ß-oxidation in NAFLD under hypoxia, and suggests BNIP3 may serve as a novel potential therapeutic target for NAFLD.

Comparison of Drug-Coated Balloon and Drug-Eluting Stent for the Treatment of Small Vessel Disease (from the Dissolve SVD Randomized Trial).

The Dissolve drug-coated balloons (DCBs) is a new-generation DCB coated with paclitaxel of balloon surface, with midchain triglyceride excipient. Although the use of DCBs is a promising technique, little is known about the the clinical efficacy of the novel Dissolve DCB in coronary small vessel disease. This study was a prospective, randomized, multicenter, noninferiority trial comparing the Dissolve DCB with the Resolute drug-eluting stent (DES) in patients with a reference vessel diameter ≥2.25 and ≤2.75 mm. Patients with a reference vessel diameter ≥2.00 and <2.25 mm were enrolled in the very small vessel registry. The angiographic and clinical follow-up were planned at 9 months and 1 year in all patients, respectively. The primary end point was 9-month in-segment percentage diameter stenosis. A total of 247 patients with small vessel disease from 10 Chinese sites were included (Dissolve DCB, n = 118; Resolute DES, n = 129); 30 patients were treated with the DCB in the very small vessel cohort. The 9-month in-segment percentage diameter stenosis was 31.2 ± 2.0% with Dissolve DCB versus 26.1 ± 2.1% with Resolute DES; the 1-sided 97.5% upper confidence limit of the difference was 10.3% (p for noninferiority = 0.0002). At 12 months, the DCB and DES groups were associated with similar rates of target lesion failure (8.5% vs 6.1%, p = 0.28) and major adverse cardiac and cerebrovascular events (20.9% vs 13.6%, p = 0.12). In conclusion, the Dissolve DCB was noninferior to the Resolute DES for the primary end point of 9-month in-segment percentage diameter stenosis in this multicenter, head-to-head, randomized trial (a safety and efficacy study of Dissolve In Treatment Of Coronary Small Vessel Disease; NCT03376646).

Diagnostic accuracy of CT-FFR with a new coarse-to-fine subpixel algorithm in detecting lesion-specific ischemia: a prospective multicenter study.

INTRODUCTION AND OBJECTIVES: A new computed tomography-derived fractional flow reserve (CT-FFR) technique with a "coarse-to-fine subpixel" algorithm has been developed to generate precise lumen contours. The aim of this study was to assess the diagnostic performance of this new CT-FFR algorithm for discriminating lesion-specific ischemia using wire-based FFR ≤ 0.80 as the reference standard in patients with coronary artery disease. METHODS: This prospective, multicenter study screened 330 patients undergoing coronary CT angiography (CCTA) and invasive FFR (median interval 2 days) from 6 tertiary hospitals. CT-FFR was evaluated in a blinded fashion with a "coarse-to-fine subpixel" algorithm for lumen contour. RESULTS: Between March 2019 and May 2020, we included 316 patients with 324 vessels. There was a good correlation between CT-FFR and invasive FFR (r=0.76, P<.001). The diagnostic sensitivity, specificity, and accuracy on a per-vessel level were 95.3%, 89.8%, and 92.0% for CT-FFR, and 96.4%, 26.4%, and 53.1% for CCTA>50% stenosis, respectively. CT-FFR showed improved discrimination of ischemia compared with CCTA alone overall (AUC, 0.95 vs 0.74, P<.001) and in intermediate (AUC, 0.96 vs 0.62, P<.001) and "gray zone" lesions (AUC, 0.88 vs 0.61, P<.001). The diagnostic specificity, accuracy, and AUC for CT-FFR (71.9%, 82.8%, and 0.84) outperformed CCTA (9.4%, 48.3%, and 0.66) in patients or in vessels with severe calcification (all P<.05). CONCLUSIONS: CT-FFR with a new "coarse-to-fine subpixel" algorithm showed high performance in identifying hemodynamically significant stenosis. The diagnostic performance of CT-FFR was superior to that of CCTA in intermediate lesions, "gray zone" lesions, and severely calcified lesions. Clinical Trial Register: NCT04731285.

A Randomized Comparison of 2 Different Drug-Coated Balloons for In-Stent Restenosis.

BACKGROUND: Although use of drug-coated balloons (DCB) is a promising technique, little is known about the clinical efficacy of the Dissolve DCB in drug-eluting stent (DES) in-stent restenosis (ISR). OBJECTIVES: This study sought to evaluate the efficacy and safety of the Dissolve DCB in patients with DES ISR. METHODS: This was a prospective, multicenter, randomized, noninferiority trial comparing Dissolve DCB with SeQuent Please DCB in patients with DES ISR. Angiographic and clinical follow-up was planned at 9 months in all patients. The primary endpoint was 9-month in-segment late loss. RESULTS: A total of 260 patients with ISR from 10 Chinese sites were included (Dissolve DCB, n = 128; SeQuent Please DCB, n = 132). Nine-month in-segment late loss was 0.50 ± 0.06 mm with Dissolve DCB vs 0.47 ± 0.07 mm with SeQuent Please DCB; the 1-sided 97.5% upper confidence limit of the difference was 0.18 mm (P for noninferiority = 0.03). Rates of target lesion failure and binary restenosis were numerical higher in the Dissolve DCB cohort compared with the SeQuent Please DCB cohort at 9 months (17.5% vs 10.7%; P = 0.12; 23.4% vs 16.4%; P = 0.19, respectively). At 9 months, major adverse cardiac and cerebrovascular events occurred in 36 patients (28.3%) vs 30 patients (22.9%) in the Dissolve DCB and SeQuent Please DCB groups, respectively. CONCLUSIONS: In this head-to-head randomized trial, the Dissolve DCB was noninferior to the SeQuent Please DCB for 9-month in-segment late loss. However, Dissolve DCB with its numerical increase in target lesion failure and binary restenosis warrants assessment in larger clinical trials (A Safety and Efficacy Study of Dissolve™ in Treatment of Coronary In-Stent Restenosis; NCT03373695).

Comparison between a dedicated stent positioning system and conventional stenting of aorto-ostial lesions: a prospective, multi-center, randomized controlled study.

Background: The accurate placement of stents for treatment of coronary aorto-ostial lesions (AOLs) is technically challenging. The purpose of this study was to evaluate the efficacy and safety of a stent positioning system with a dedicated nitinol device and compare them with those of the conventional approach for stenting of coronary AOLs. Methods: In this prospective, multi-center, open-label, randomized study, conducted from November 2015 to April 2019, patients with coronary AOLs that underwent percutaneous coronary intervention (PCI) were randomly allocated (allocation ratio 1:1) using block randomization method to either a stent positioning system group or a conventional technique group. The primary endpoint was the range of stent slippage when positioning. The following secondary endpoints were applied: (I) the extent of swing of the guiding catheters during stent positioning; (II) the rate of accurate stent placement; (III) the procedure time; and (IV) the incidence of major adverse cardiovascular events (MACEs) including cardiac death, myocardial infarction, target lesion revascularization, and stent thrombosis. Results: During the study period, 139 patients with aorto-ostial coronary artery stenosis were included at 5 centers. A total of 69 patients were allocated to the stent positioning system group and 70 patients to the conventional technique group. Angiographic and clinical success were achieved in 100% of the patients included in both groups. The range of stent slippage was significantly shorter in the stent positioning system group than it was in the conventional technique group [0.64 (0.22; 1.35) vs. 1.11 (0.48; 1.72) mm, P=0.01]. The rate of accurate placement of stents was higher in the stent positioning system group than it was in the conventional technique group (74.6% vs. 57.1%, P=0.03). The extent of guiding catheter swing during the stent positioning [0.24 (0.19; 0.53) vs. 0.23 (0.19; 0.53) mm; P=0.95] and the MACEs rates (1.4% vs. 2.9%, P>0.99) were similar between the 2 groups. The procedural time of the stent positioning system was longer than that of the conventional approach [1.00 (0.50; 1.50) vs. 0.80 (0.50; 1.50) min, P=0.09]. Conclusions: The dedicated stent positioning system was is safer and provides more accurate placement of stents for coronary AOLs than the conventional approach, and the associated prolongation of procedure time is insignificant. Trial Registration: Chinese Clinical Trial Registry (ChiCTR), Unique identifier: ChiCTR2100053869. URL: https://www.chictr.org.cn/showproj.html?proj=133280.

Effect of Mavacamten on Chinese Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy: The EXPLORER-CN Randomized Clinical Trial.

Importance: Mavacamten has shown clinical benefits in global studies for patients with obstructive hypertrophic cardiomyopathy (oHCM), but evidence in the Asian population is lacking. Objective: To evaluate the safety and efficacy of mavacamten compared with placebo for Chinese patients with symptomatic oHCM. Design, Setting, and Participants: This phase 3, randomized, double-blind, placebo-controlled clinical trial was conducted at 12 hospitals in China. Between January 4 and August 5, 2022, patients with oHCM and a left ventricular outflow tract (LVOT) gradient of 50 mm Hg or more and New York Heart Association (NYHA) class II or III symptoms were enrolled and received treatment for 30 weeks. Interventions: Patients were randomized 2:1 to receive mavacamten (starting at 2.5 mg once daily) or placebo for 30 weeks. Main Outcomes and Measures: The primary end point was change in Valsalva LVOT peak gradient from baseline to week 30. Left ventricular outflow tract gradients and left ventricular ejection fraction (LVEF) were assessed by echocardiography, while left ventricular mass index (LVMI) was determined by cardiac magnetic resonance imaging. Analysis was performed on an intention-to-treat basis. Results: A total of 81 patients (mean [SD] age, 51.9 [11.9] years; 58 men [71.6%]) were randomized. Mavacamten demonstrated a significant improvement in the primary end point compared with placebo (least-squares mean [LSM] difference, -70.3 mm Hg; 95% CI, -89.6 to -50.9 mm Hg; 1-sided P < .001). Similar trends were demonstrated for resting LVOT peak gradient (LSM difference, -55.0 mm Hg; 95% CI, -69.1 to -40.9 mm Hg). At week 30, more patients receiving mavacamten than placebo achieved a Valsalva LVOT peak gradient less than 30 mm Hg (48.1% [26 of 54] vs 3.7% [1 of 27]), less than 50 mm Hg (59.3% [32 of 54] vs 7.4% [2 of 27]), and NYHA class improvement (59.3% [32 of 54] vs 14.8% [4 of 27]). Greater improvements were also observed with mavacamten regarding the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (LSM difference, 10.2; 95% CI, 4.4-16.1), N-terminal pro-B-type natriuretic peptide level (proportion of geometric mean ratio, 0.18; 95% CI, 0.13-0.24), high-sensitivity cardiac troponin I level (proportion of geometric mean ratio, 0.34; 95% CI, 0.27-0.42), and LVMI (mean difference, -30.8 g/m2; 95% CI, -41.6 to -20.1 g/m2). Safety and tolerability were similar between mavacamten and placebo. No patients experienced LVEF less than 50%. Conclusions: Mavacamten significantly improved Valsalva LVOT gradient vs placebo for Chinese patients. All secondary efficacy end points were also improved. Mavacamten was well tolerated with no new safety signals. This study supports the efficacy and safety of mavacamten in diverse populations, including Chinese patients. Trial Registration: ClinicalTrials.gov Identifier: NCT05174416.