Clean air policy reduces the atherogenic lipid profile levels: Results from China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) Study.

Evidence of the associations between long-term exposure to PM2.5 and O3 and human blood lipid concentrations is abundant yet inconclusive. Whether clean air policies could improve lipid profiles remains unclear. In total, 2979312 participants from a Chinese nationwide prospective study were included. For cross-sectional analyses, linear mixed-effects models were utilized to assess the associations of pollutants with lipid profiles (TC, LDL-C, TG, HDL-C). For longitudinal analyses, a quasi-experimental design and difference-in-differences models were employed to investigate the impact of China's Clean Air Act. In the cross-sectional analyses, each IQR increase in PM2.5 was associated with 2.49 % (95 % CI: 2.36 %, 2.62 %), 2.51 % (95 % CI: 2.26 %, 2.75 %), 3.94 % (95 % CI: 3.65 %, 4.23 %), and 1.54 % (95 % CI: 1.38 %, 1.70 %) increases in TC, LDL-C, TG, and HDL-C, respectively. For each IQR increase in O3, TC, LDL-C, TG, and HDL-C changed by 1.06 % (95 % CI: 0.95 %, 1.17 %), 1.21 % (95 % CI: 1.01 %, 1.42 %), 1.78 % (95 % CI: 1.54 %, 2.02 %), and -0.63 % (95 % CI: -0.76 %, -0.49 %), respectively. Longitudinal analyses showed that the intervention group experienced greater TC, LDL-C, and HDL-C reductions (1.77 %, 4.26 %, and 7.70 %, respectively). Our findings suggest that clean air policies could improve lipid metabolism and should be implemented in countries with heavy air pollution burdens.

Low-Density Lipoprotein Cholesterol, Cardiovascular Disease Risk, and Mortality in China.

Importance: Limited evidence supports the association between low-density lipoprotein cholesterol (LDL-C) and mortality across different atherosclerotic cardiovascular disease (ASCVD) risk stratifications. Objective: To explore the associations between LDL-C levels and mortality and to identify the optimal ranges of LDL-C with the lowest risk of mortality in populations with diverse ASCVD risk profiles. Design, Setting, and Participants: The ChinaHEART project is a prospective cohort study that recruited residents aged 35 to 75 years from 31 provinces in mainland China between November 2014 and December 2022. Participants were categorized into low-risk, primary prevention, and secondary prevention cohorts on the basis of their medical history and ASCVD risk. Data analysis was performed from December 2022 to October 2023. Main Outcomes and Measures: The primary end point was all-cause mortality, and secondary end points included cause-specific mortality. Mortality data were collected from the National Mortality Surveillance System and Vital Registration. The association between LDL-C levels and mortality was assessed by using Cox proportional hazard regression models with various adjusted variables. Results: A total of 4 379 252 individuals were recruited, and 3 789 025 (2 271 699 women [60.0%]; mean [SD] age, 56.1 [10.0] years) were included in the current study. The median (IQR) LDL-C concentration was 93.1 (70.9-117.3) mg/dL overall at baseline. During a median (IQR) follow-up of 4.6 (3.1-5.8) years, 92 888 deaths were recorded, including 38 627 cardiovascular deaths. The association between LDL-C concentration and all-cause or cardiovascular disease (CVD) mortality was U-shaped in both the low-risk cohort (2 838 354 participants) and the primary prevention cohort (829 567 participants), whereas it was J-shaped in the secondary prevention cohort (121 104 participants). The LDL-C levels corresponding to the lowest CVD mortality were 117.8 mg/dL in the low-risk group, 106.0 mg/dL in the primary prevention cohort, and 55.8 mg/dL in the secondary prevention cohort. The LDL-C concentration associated with the lowest all-cause mortality (90.9 mg/dL vs 117.0 mg/dL) and CVD mortality (87 mg/dL vs 114.6 mg/dL) were both lower in individuals with diabetes than in individuals without diabetes in the overall cohort. Conclusions and Relevance: This study found that the association between LDL-C and mortality varied among different ASCVD risk cohorts, suggesting that stricter lipid control targets may be needed for individuals with higher ASCVD risk and those with diabetes.

Association and its population heterogeneities between low-density lipoprotein cholesterol and all-cause and cardiovascular mortality: A population-based cohort study.

BACKGROUND: The association and population heterogeneities between low-density lipoprotein cholesterol (LDL-C) and all-cause and cardiovascular mortality remain unknown. We aimed to examine the dose-dependent associations of LDL-C levels with specific types of cardiovascular disease (CVD) mortality and heterogeneities in the associations among different population subgroups. METHODS: A total of 2,968,462 participants aged 35-75 years from China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) (2014-2019) were included. Cox proportional hazard models and Fine-Gray subdistribution hazard models were used to estimate associations between LDL-C categories (<70.0, 70.0-99.9, 100.0-129.9 [reference group], 130.0-159.9, 160.0-189.9, and ≥190.0 mg/dL) and all-cause and cause-specific mortality. RESULTS: During a median follow-up of 3.7 years, 57,391 and 23,241 deaths from all-cause and overall CVD were documented. We observed J-shaped associations between LDL-C and death from all-cause, overall CVD, coronary heart disease (CHD), and ischemic stroke, and an L-shaped association between LDL-C and hemorrhagic stroke (HS) mortality (P for non-linearity <0.001). Compared with the reference group (100.0-129.9 mg/dL), very low LDL-C levels (<70.0 mg/dL) were significantly associated with increased risk of overall CVD (hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 1.06-1.14) and HS mortality (HR: 1.37, 95% CI: 1.29-1.45). Very high LDL-C levels (≥190.0 mg/dL) were associated with increased risk of overall CVD (HR: 1.51, 95% CI: 1.40-1.62) and CHD mortality (HR: 2.08, 95% CI: 1.92-2.24). The stronger associations of very low LDL-C with risk of CVD mortality were observed in individuals with older age, low or normal body mass index, low or moderate 10-year atherosclerotic CVD risk, and those without diagnosed CVD or taking statins. Stronger associations between very high LDL-C levels and all-cause and CVD mortality were observed in younger people. CONCLUSIONS: People with very low LDL-C had a higher risk of all-cause, CVD, and HS mortality; those with very high LDL-C had a higher risk of all-cause, CVD, and CHD mortality. On the basis of our findings, comprehensive health assessment is needed to evaluate cardiovascular risk and implement appropriate lipid-lowering therapy for people with very low LDL-C.

Association of the triglyceride-glucose index with all-cause and cause-specific mortality: a population-based cohort study of 3.5 million adults in China.

Background: The triglyceride-glucose (TyG) index has been recognized as a crucial risk factor for cardiovascular diseases. However, the association between the TyG index and mortality in the general population remains elusive. Methods: Participants were enrolled from the China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART), a nationwide prospective cohort study. The outcomes of interest were all-cause, cardiovascular, and cancer mortality. Restricted cubic splines and Cox regression models were used to assess the associations between the TyG index and outcomes. Findings: In total, 3,524,459 participants with a median follow-up of 4.6 (IQR, 3.1-5.8) years were included. The associations of the TyG index with all-cause and cardiovascular mortality were reverse L-shaped, with cut-off values of 9.75 for all-cause mortality and 9.85 for cardiovascular mortality. For each 1-unit increase in the TyG index, when below the cut-off values, the TyG index was not significantly associated with all-cause mortality (HR = 1.02, 95% CI: 1.00-1.03) and was only modestly associated with cardiovascular mortality (HR = 1.09, 95% CI: 1.06-1.11). Conversely, when the cut-off values were exceeded, the HRs (95% CI) were 2.10 (1.94-2.29) for all-cause mortality and 1.99 (1.72-2.30) for cardiovascular mortality. However, the association between the TyG index and cancer mortality was linearly negative (HR = 0.97, 95% CI: 0.94-0.99). Interpretation: The associations of the TyG index with all-cause and cardiovascular mortality displayed reverse L-shaped patterns, while an elevated TyG index showed a slight negative association with cancer mortality. We suggest that <9.75 could be the optimal TyG index cut-off value among the Chinese general population. Individuals at high risk of mortality might benefit from proper management of a high TyG index. Funding: The National High Level Hospital Clinical Research Funding (2023-GSP-ZD-2, 2023-GSP-RC-01), the Ministry of Finance of China and National Health Commission of China.

Off-label use of Baricitinib improves moderate and severe atopic dermatitis in China through inhibiting MAPK and PI3K/Akt/mTOR pathway via targeting JAK-STAT signaling of CD4+ cells.

As an inflammatory disease with a disrupted immune system, cytokine disorders in atopic dermatitis (AD) are closely related to the abnormal activation of JAK-STAT signal pathway. The critical relevance of the JAK-STAT signaling pathway to the pathogenesis of AD provides a strong rationale for JAK inhibitor research. Baricitinib, a small-molecule oral JAK inhibitor, has been proven to inhibit JAK-STAT signaling in a variety of diseases, including AD. It is currently available in China for off-label use. However, its efficacy in China and its mechanism are rarely reported. In our study, we found that the immune status of patients with moderate and severe AD was hyperactive. Among the 49 known immunotherapy targets, JAK1 and JAK2 genes on lymphocytes of AD patients were significantly upregulated, which was closely related to the symptom severity in moderate and severe AD patients. Baricitinib can improve immune hyperresponsiveness and clinical symptoms in moderate and severe AD by inhibiting the activation of Th2 cell subsets and the secretion of Th2-type cytokines through MAPK, mTOR and PI3K-Akt signaling pathways, providing an important theoretical basis for clinical off-label use of Baricitinib to treat moderate and severe AD.

APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE-/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

Healthy lifestyle, statin, and mortality in people with high CVD risk: A nationwide population-based cohort study.

Objective: To examine the joint association of healthy lifestyles and statin use with all-cause and cardiovascular mortality in high-risk individuals, and evaluate the survival benefits by life expectancy. Methods: During 2015-2021, participants aged 35-75 years were recruited by the China Health Evaluation And risk Reduction through nationwide Teamwork. Based on number of healthy lifestyles related to smoking, alcohol drinking, physical activity, and diet, we categorized them into: very healthy (3-4), healthy (2), and unhealthy (0-1). Statin use was determined by self-report taking statin in last two weeks. Results: Among the 265,209 included participants at high risk, 6979 deaths were observed, including 3236 CVD deaths during a median 3.6 years of follow-up. Individuals taking statin and with a very healthy lifestyle had the lowest risk of all-cause (HR: 0.70; 95 %CI: 0.57-0.87) and cardiovascular mortality (0.56; 0.40-0.79), compared with statin non-users with an unhealthy lifestyle. High-risk participants taking statin and with a very healthy lifestyle had the highest years of life gained (5.90 years at 35-year-old [4.14-7.67; P < 0.001]) compared with statin non-users with an unhealthy lifestyle among high-risk people. And their life expectancy was comparable with those without high risk but with a very healthy lifestyle (4.49 vs. 4.68 years). Conclusion: The combination of preventive medication and multiple healthy lifestyles was associated with lower risk of all-cause and cardiovascular mortality and largest survival benefits. Integrated strategy to improve long-term health for high-risk people was urgently needed.

Association of high-density lipoprotein cholesterol with all-cause and cause-specific mortality in a Chinese population of 3.3 million adults: a prospective cohort study.

Background: High-density lipoprotein cholesterol (HDL-C) has been inversely associated with cardiovascular disease (CVD) risk, but recent evidence suggests that extremely high levels of HDL-C are paradoxically related to increased CVD incidence and mortality. This study aimed to comprehensively examine the associations of HDL-C with all-cause and cause-specific mortality in a Chinese population. Methods: The China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) project included 3,397,547 participants aged 35-75 years with a median follow-up of 3.9 years. Baseline HDL-C levels were measured, and mortality data was ascertained from the National Mortality Surveillance System and Vital Registration of Chinese Center for Disease Control and Prevention. Findings: This study found U-shaped associations of HDL-C with all-cause, cardiovascular and cancer mortality. When compared with the groups with the lowest risk, the adjusted hazard ratios (95% CIs) for HDL-C <30 mg/dL was 1.23 (1.17-1.29), 1.33 (1.23-1.45) and 1.18 (1.09-1.28) for all-cause, CVD and cancer mortality, respectively. For HDL-C >90 mg/dL, the corresponding HR (95% CIs) was 1.10 (1.05-1.15), 1.09 (1.01-1.18) and 1.11 (1.03-1.19). Similar U-shaped patterns were also found in associations of HDL-C with ischemic heart disease, ischemic stroke, and liver cancer. About 3.25% of all-cause mortality could be attributed to abnormal levels of HDL-C. The major contributor to mortality was ischemic heart disease (16.06 deaths per 100,000 persons, 95% UI: 10.30-22.67) for HDL-C <40 mg/dL and esophageal cancer (2.29 deaths per 100,000 persons, 95% UI: 0.57-4.77) for HDL-C >70 mg/dL. Interpretation: Both low and high HDL-C were associated with increased mortality risk. We recommended 50-79 mg/dL as the optimal range of HDL-C among Chinese adults. Individuals with dyslipidemia might benefit from proper management of both low and high HDL-C. Funding: The CAMS Innovation Fund for Medical Science (2021-1-I2M-011), the National High Level Hospital Clinical Research Funding (2022-GSP-GG-4), the Ministry of Finance of China and National Health Commission of China, and the 111 Project from the Ministry of Education of China (B16005), the Program for Guangdong Introducing Innovative and Enterpreneurial Teams (2019ZT08Y481), Sanming Project of Medicine in Shenzhen (SZSM201811096), the Young Talent Program of the Academician Fund, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen (YS-2022-006) and Guangdong Basic and Applied Basic Research Foundation (2023A1515010076 & 2021A1515220173).

Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression.

Neural stem cells (NSCs) are critical for brain development and maintenance of neurogenesis. However, the molecular mechanisms that regulate NSC proliferation and differentiation remain unclear. Mysm1 is a deubiquitinase and is essential for the self-renewal and differentiation of several stem cells. It is unknown whether Mysm1 plays an important role in NSCs. Here, we found that Mysm1 was expressed in NSCs and its expression was increased with age in mice. Mice with Mysm1 knockdown by crossing Mysm1 floxed mice with Nestin-Cre mice exhibited abnormal brain development with microcephaly. Mysm1 deletion promoted NSC proliferation and apoptosis, resulting in depletion of the stem cell pool. In addition, Mysm1-deficient NSCs skewed toward neurogenesis instead of astrogliogenesis. Mechanistic investigations with RNA sequencing and genome-wide CUT&Tag analysis revealed that Mysm1 epigenetically regulated Id4 transcription by regulating histone modification at the promoter region. After rescuing the expression of Id4, the hyperproliferation and imbalance differentiation of Mysm1-deficient NSCs was reversed. Additionally, knockdown Mysm1 in aged mice could promote NSC proliferation. Collectively, the present study identified a new factor Mysm1 which is essential for NSC homeostasis and Mysm1-Id4 axis may be an ideal target for proper NSC proliferation and differentiation.

Associations between Chinese visceral adiposity index and risks of all-cause and cause-specific mortality: A population-based cohort study.

AIM: To determine the associations between the Chinese visceral adiposity index (CVAI) and the risks of all-cause and cause-specific mortality. MATERIALS AND METHODS: A total of 3 916 214 Chinese adults were enrolled in a nationwide population cohort covering all 31 provinces of mainland China. The CVAI was calculated based on age, body mass index, waist circumference, and triglyceride and high-density lipoprotein cholesterol concentrations. We used a Cox proportional hazards regression model to determine the hazard ratios and 95% confidence intervals (CIs) for risk of mortality associated with different CVAI levels. RESULTS: The median follow-up duration was 3.8 years. A total of 86 158 deaths (34 867 cardiovascular disease [CVD] deaths, 29 884 cancer deaths, and 21 407 deaths due to other causes) were identified. In general, after adjusting for potential confounding factors, a U-shaped relationship between CVAI and all-cause mortality was observed by restricted cubic spline (RCS). Compared with participants in CVAI quartile 1, those in CVAI quartile 4 had a 23.0% (95% CI 20.0%-25.0%) lower risk of cancer death, but a 23.0% (95% CI 19.0-27.0) higher risk of CVD death. In subgroup analysis, a J-shaped and inverted U-shaped relationship for all-cause mortality and cancer mortality was observed in the group aged < 60 years. CONCLUSIONS: The CVAI, an accessible indicator reflecting visceral obesity among Chinese adults, has predictive value for all-cause, CVD, and cancer mortality risks. Moreover, the CVAI carries significance in the field of health economics and secondary prevention. In the future, it could be used for early screening purposes.

Associations of remnant cholesterol with cardiovascular and cancer mortality in a nationwide cohort.

The health significance of triglyceride-rich lipoproteins, also known as remnant cholesterol, has been increasingly recognized. However, evidence of their associations with cause-specific mortality in the general population was previously insufficient. To explore these associations and their heterogeneities across subgroups, a prospective cohort study was conducted including 3,403,414 community-based participants from ChinaHEART, an ongoing government-funded public health program throughout China, from November 2014 through December 2022. The study assessed mortality risk of all-cause mortality, cardiovascular disease (CVD) mortality (including mortality from ischemic heart diseases (IHD), ischemic stroke (IS), and hemorrhagic stroke (HS), separately), and cancer mortality (including lung cancer, stomach cancer, and liver cancer, separately). During the 4-year follow-up, 23,646 individuals died from CVD (including 8807 from IHD, 3067 from IS, and 5190 from HS), and 20,318 from cancer (including 6208 from lung cancer, 3013 from liver cancer, and 2174 from stomach cancer). Compared with individuals with remnant cholesterol <17.9 mg/dL, multivariable-adjusted mortality hazard ratios (HRs) for individuals with remnant cholesterol ≥27.7 mg/dL were 1.03 (1.00-1.05) for all-cause mortality, 1.17 (1.12-1.21) for CVD (1.19 (1.12-1.27) for IHD mortality, and 1.22 (1.09-1.36) for IS mortality), and 0.90 (0.87-0.94) for all-cancer mortality (0.94 (0.87-1.02) for lung cancer, 0.59 (0.53-0.66) for liver cancer, and 0.73 (0.64-0.83) for stomach cancer). In summary, this study revealed a correlation between increased remnant cholesterol levels and an elevated risk of cardiovascular disease mortality, as well as a reduced risk of mortality for certain types of cancer.

Time-Varying Effect of Physical Activity on Mortality Among Myocardial Infarction Survivors: A Nationwide Population-Based Cohort Study.

Background: Physical activity (PA) is an important component of secondary prevention after myocardial infarction (MI). The mortality risk of MI survivors varies at different post-MI periods, yet the time-varying effect of total PA is unclear. We aimed to investigate the association between different volumes and patterns of total PA and mortality at different post-MI periods. Methods: Using data from the China Patient-centered Evaluative Assessment of Cardiac Events Million Persons Project, we divided the screened MI survivors into within-1-year and beyond-1-year groups based on the duration between their baseline interview and MI onset. Total PA was divided into insufficient ( < 3000 metabolic equivalent of task [MET] minutes/week) and sufficient PA. Sufficient PA was further categorized as moderate and high (3000-4500 and > 4500 MET minutes/week) volumes; leisure ( ≥ 50%) and non-leisure ( > 50%) patterns. Data on mortality were derived from the National Mortality Surveillance System and Vital Registration of the Chinese Center for Disease Control and Prevention. Cox proportional hazard models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline regression analyses were performed to examine the dose-response association between PA and mortality. Results: During the follow-up (median 3.7 years) of the 20,653 post-MI patients, 751 patients died. In the within-1-year group, moderate (HR: 0.59, 95% CI: 0.40 to 0.88) and high (0.63, 0.45 to 0.88) volumes and both patterns (leisure: 0.52, 0.29 to 0.94; non-leisure: 0.64, 0.46 to 0.88) of PA were all associated with significantly lower risk of mortality, compared with insufficient PA. In the beyond-1-year group, the association was observed in high volume (0.69, 0.56 to 0.86) and both patterns (leisure: 0.64, 0.48 to 0.87; non-leisure: 0.79, 0.65 to 0.97). A non-linear relationship between PA and mortality was found in the within-1-year group (p for non-linearity < 0.001), while a linear relationship was demonstrated in the beyond-1-year group (p for non-linearity = 0.107). Conclusions: Sufficient total PA was associated with mortality risk reduction after MI, either leisure or non-leisure pattern. Different dose-response associations between PA and mortality were found at different post-MI periods. These results could promote individualized and scientifically derived secondary prevention strategies for MI.

Predictors of HBeAg seroconversion after long-term nucleos(t)ide analogues treatment for chronic hepatitis B: a multicenter study in real clinical setting

ABSTRACT Aims: To evaluate the HBeAg seroconversion rate in real clinical setting and explore its predictors in long-term nucleos(t)ide analogues (NAs) treatment for chronic hepatitis B (CHB). Methods: 251 patients were recruited from January 2001 to September 2009 in four hospitals in Hebei province, China, for this retrospective study. Clinical and laboratory data before and after treatment with lamivudine (LAM, 100 mg daily), adefovir (ADV, 10 mg daily), telbivudine (LDT, 600 mg daily), entecavir (ETV, 0.5 mg daily), and LAM/ADV combination were compared among three groups according to treatment outcomes: synchronous HBeAg loss and HBeAg seroconversion, anti-HBe development after treatment, and no anti-HBe. Adherence was also evaluated. Results: In real clinical setting, cumulative HBeAg seroconversion rates were 14.3%, 32.7%, 43.0%, 46.9%, and 50.5% after 1, 2, 3, 5, and 8 years, respectively. 45 patients (17.9%) were non-adherent. Adherence (p < 0.001, Hazard Ratio (HR) = 2.203), elevated alanine aminotransferase (ALT) levels (p < 0.001, HR = 2.049), and non-vertical transmission (p = 0.006, HR = 1.656) were predictors of HBeAg seroconversion. Conclusion: Adherence, elevated ALT, and non-vertical transmission are predictors of HBeAg seroconversion in CHB patients treated with NAs.