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Background and Aims: Flavonoids are widely distributed polyphenolic compounds in the diet that possess various health-promoting effects. This study aimed to investigate the association between dietary flavonoid intake and all-cause and cardiovascular mortality in adults., Methods and Results: The data on the six main subclasses of flavonoids, including isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, and flavonols, were obtained from the 2007-2010 National Health and Nutrition Examination Survey (NHANES) dataset of adults. The participants were followed up until December 30, 2019. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for dietary flavonoid intake and mortality. The study included a total of 8758 adults (mean age 44.00 years; 47.40% men). A median follow-up of 10.7 years yielded 1113 all-cause deaths and 261 cardiovascular deaths were recorded. In comparison to category 1, category 4 of flavan-3-ols, flavonols, and total flavonoids were associated with lower risks of all-cause mortality, with multivariable-adjusted HRs of 0.71 (95% CI: 0.55-0.92, P trend  = 0.021), 0.58 (95% CI: 0.45-0.74, P trend <0.001), and 0.63 (95% CI: 0.50-0.80, P trend  = 0.010), respectively. Similarly, higher intake of category 4 flavonoids was associated with a reduced risk of cardiovascular mortality, with HRs of 0.68 (95% CI: 0.29-0.89, P trend  = 0.035) for flavones, 0.41 (95% CI: 0.22-0.78, P trend  = 0.001) for flavonols, and 0.54 (95% CI: 0.36-0.80, P trend  = 0.021) for total flavonoids., Conclusion: Dietary flavonoid intake is associated with all-cause and cardiovascular mortality. Increasing dietary flavonoid intake may reduce the risk of death in adults., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Aim: The information assessing sex differences in outcomes of patients with three-vessel coronary disease (TVD) after different treatment strategies is sparse. This study aimed to investigate long-term outcomes of TVD among women compared with men after medical therapy (MT) alone, percutaneous coronary intervention (PCI), or coronary artery bypass grafting surgery (CABG)., Methods: Consecutive 8943 patients with TVD were enrolled. Associations between sex and all-cause death and major adverse cardiac and cerebrovascular events (MACCE) (all-cause death, myocardial infarction, or stroke) were assessed., Results: Of the 8943 patients, 1821 (20.4%) were women. During a median follow-up of 6.6 years, women had comparable incidences of all-cause death (16.6% vs. 14.9%, P = 0.079) and MACCE (27.2% vs. 26.1%, P = 0.320) to men. After multivariable analysis, women showed lower adjusted risks of all-cause death (HR: 0.777; P = 0.001) and MACCE (HR: 0.870; P = 0.016) than men in the entire cohort. Subgroup analysis revealed that the less all-cause death risk of women relative to men was significant in PCI (HR: 0.702; P = 0.009), and CABG groups (HR: 0.708; P = 0.047), but not in MT alone group. Lower MACCE risk for women vs. men was significant only in PCI group (HR: 0.821; P = 0.037). However, no significant interaction between sex and three strategies was observed for all-cause death ( P for interaction = 0.312) or MACCE ( P for interaction = 0.228)., Conclusions: The cardiovascular prognosis of TVD female patients is better than that of men, which has no interaction with the treatment strategies received (MT alone, PCI, or CABG)., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Aim: Our study aimed to investigate the correlation between glycated hemoglobin (HbA1c) and adverse prognostic events in patients with diabetes and triple-vessel coronary disease (TVD)., Methods: This study ultimately included 2051 patients with TVD and diabetes. Patients were categorized into five groups based on their HbA1c levels: < 6.0 %, 6.0-6.4 %, 6.5-6.9 %, 7.0-7.9 %, and ≥ 8.0 %. The primary endpoint was all-cause death, and the secondary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE)., Results: The median follow-up time was 5.88 years. During this period, a total of 323 (15.7 %) all-cause deaths and 537 (26.2 %) MACCEs were recorded. The relationship between HbA1c and the risk of endpoint events showed a J-shaped pattern, with the lowest risk observed between 6.0 % and 6.4 %. Further analysis revealed a significant interaction between HbA1c and age. In the subgroup with age < 70 years, as HbA1c increased, the risk of endpoint events gradually rose. While in the subgroup with age ≥70 years, there was an L-shaped relationship between HbA1c and endpoint events, with the highest risk observed in patients with HbA1c < 6.0 %., Conclusion: Our study revealed variations in the relationship between HbA1c levels and endpoint events among patients with TVD and diabetes of different ages. In younger patients, elevated HbA1c levels were associated with a higher risk of death and MACCE, while in older patients, excessively low HbA1c levels (HbA1c < 6 %) were linked to a higher risk of death and MACCE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium. It is characterized by acute onset, rapid progress and high risk of death. Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm. According to China's practical experience, the adoption of the "life support-based comprehensive treatment regimen" (with mechanical circulation support and immunomodulation therapy as the core) can significantly improve the survival rate and long-term prognosis. Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment., (© 2024. Science China Press.)

Aims: Risk assessment for triple-vessel disease (TVD) remain challenging. Stress hyperglycemia represents the regulation of glucose metabolism in response to stress, and stress hyperglycemia ratio (SHR) is recently found to reflect true acute hyperglycemic status. This study aimed to evaluate the prognostic value of SHR and its role in risk stratification in TVD patients with acute coronary syndrome (ACS)., Methods: A total of 3812 TVD patients with ACS with available baseline SHR measurement were enrolled from two independent centers. The endpoint was cardiovascular mortality. Cox regression was used to evaluate the association between SHR and cardiovascular mortality. The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) II (SSII) was used as the reference model in the model improvement analysis., Results: During a median follow-up of 5.1 years, 219 (5.8%) TVD patients with ACS suffered cardiovascular mortality. TVD patients with ACS with high SHR had an increased risk of cardiovascular mortality after robust adjustment for confounding (high vs. median SHR: adjusted hazard ratio 1.809, 95% confidence interval 1.160-2.822, P = 0.009), which was fitted as a J-shaped pattern. The prognostic value of the SHR was found exclusively among patients with diabetes instead of those without diabetes. Moreover, addition of SHR improved the reclassification abilities of the SSII model for predicting cardiovascular mortality in TVD patients with ACS., Conclusions: The high level of SHR is associated with the long-term risk of cardiovascular mortality in TVD patients with ACS, and is confirmed to have incremental prediction value beyond standard SSII. Assessment of SHR may help to improve the risk stratification strategy in TVD patients who are under acute stress., (© 2024. The Author(s).)

Background: The public health burden of cardiomyopathies and competency in their management by health agencies in China are not well understood., Methods: This study adopted a multi-stage sampling method for hospital selection. In the first stage, nationwide tertiary hospital recruitment was performed. As a result, 88 hospitals with the consent of the director of cardiology and access to an established electronic medical records system, were recruited. In the second stage, we sampled 66 hospitals within each geographic-economic stratification through a random sampling process. Data on (1) the outpatient and inpatient visits for cardiomyopathies between 2017 and 2021 and (2) the competency in the management of patients with cardiomyopathies, were collected. The competency of a hospital to provide cardiomyopathy care was evaluated using a specifically devised scale., Findings: The outpatient and inpatient visits for cardiomyopathies increased between 2017 and 2021 by 38.6% and 33.0%, respectively. Most hospitals had basic facilities for cardiomyopathy assessment. However, access to more complex procedures was limited, and the integrated management pathway needs improvement. Only 4 (6.1%) of the 66 participating hospitals met the criteria for being designated as a comprehensive cardiomyopathy center, and only 29 (43.9%) could be classified as a primary cardiomyopathy center. There were significant variations in competency between hospitals with different administrative and economic levels., Interpretation: The health burden of cardiomyopathies has increased significantly between 2017 and 2021 in China. Although most tertiary hospitals in China can offer basic cardiomyopathy care, more advanced facilities are not yet universally available. Moreover, inconsistencies in the management of cardiomyopathies across hospitals due to differing administrative and economic levels warrants a review of the nation allocation of medical resources., Funding: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2023-I2M-1-001) and the National High Level Hospital Clinical Research Funding (2022-GSP-GG-17)., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Authors.)

This study was to estimate the associations of volatile organic compounds (VOCs) exposure with the prevalence of total and specific cardiovascular disease (CVD) among the general adult population. This cross-sectional study analyzed 15 urinary VOC metabolites in the general population using the 2011-2016 National Health and Nutrition Examination Survey ( n  = 5,213). The weighted study population with 47.0 years median age, was primarily female (51.2%). The prevalence of total CVD in the overall population was 7.9%. The single-exposure analyzes of AAMA, ATCA, CEMA, CYMA, DHBMA, 3HPMA, and 3MHA +4MHA were significantly associated with increased prevalence of total CVD. Qgcomp regression consistently showed that urinary VOCs-mixed exposure was positively correlated with the prevalence of total and specific CVDs (chronic heart failure, angina, and stroke), and highlighted each VOCs metabolite weights and direction. The similar results were observed for the WQS regression using mixed analysis methods. In conclusion, exposure to VOCs increases CVD prevalence and advances the identification of risk factors for CVD for environmental study.

Background: Risk assessment and treatment stratification for three-vessel coronary disease (TVD) remain challenging. This study aimed to investigate the prognostic value of left atrial volume index (LAVI) with the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score II, and its association with the long-term prognosis after three strategies (percutaneous coronary intervention [PCI], coronary artery bypass grafting [CABG], and medical therapy [MT]) in patients with TVD., Methods: This study was a post hoc analysis of a large, prospective cohort of patients with TVD in China, that aimed to determine the long-term outcomes after PCI, CABG, or optimal MT alone. A total of 8943 patients with TVD were consecutively enrolled between 2004 and 2011 at Fuwai Hospital. A total of 7818 patients with available baseline LAVI data were included in the study. Baseline, procedural, and follow-up data were collected. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), which was a composite of all-cause death, myocardial infarction (MI), and stroke. Secondary endpoints included all-cause death, cardiac death, MI, revascularization, and stroke. Long-term outcomes were evaluated among LAVI quartile groups., Results: During a median follow-up of 6.6 years, a higher LAVI was strongly associated with increased risk of MACCE (Q3: hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.06-1.37, P = 0.005; Q4: HR 1.85, 95%CI 1.64-2.09, P <0.001), all-cause death (Q3: HR 1.41, 95% CI 1.17-1.69, P <0.001; Q4: HR 2.54, 95%CI 2.16-3.00, P <0.001), and cardiac death (Q3: HR 1.81, 95% CI 1.39-2.37, P <0.001; Q4: HR 3.47, 95%CI 2.71-4.43, P <0.001). Moreover, LAVI significantly improved discrimination and reclassification of the SYNTAX score II. Notably, there was a significant interaction between LAVI quartiles and treatment strategies for MACCE. CABG was associated with lower risk of MACCE than MT alone, regardless of LAVI quartiles. Among patients in the fourth quartile, PCI was associated with significantly increased risk of cardiac death compared with CABG (HR: 5.25, 95% CI: 1.97-14.03, P = 0.001)., Conclusions: LAVI is a potential index for risk stratification and therapeutic decision-making in patients with three-vessel coronary disease. CABG is associated with improved long-term outcomes compared with MT alone, regardless of LAVI quartiles. When LAVI is severely elevated, PCI is associated with higher risk of cardiac death than CABG., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Metabolic syndrome combines major risk factors for cardiovascular disease, making deeper insight into its pathogenesis important. We here explore the mechanistic basis of metabolic syndrome by recruiting an essential patient cohort and performing extensive gene expression profiling. The mitochondrial fatty acid metabolism enzyme acyl-CoA synthetase medium-chain family member 3 (ACSM3) was identified to be significantly lower expressed in the peripheral blood of metabolic syndrome patients. In line, hepatic ACSM3 expression was decreased in mice with metabolic syndrome. Furthermore, Acsm3 knockout mice showed glucose and lipid metabolic abnormalities, and hepatic accumulation of the ACSM3 fatty acid substrate lauric acid. Acsm3 depletion markedly decreased mitochondrial function and stimulated signaling via the p38 MAPK pathway cascade. Consistently, Acsm3 knockout mouse exhibited abnormal mitochondrial morphology, decreased ATP contents, and enhanced ROS levels in their livers. Mechanistically, Acsm3 deficiency, and lauric acid accumulation activated nuclear receptor Hnf4α-p38 MAPK signaling. In line, the p38 inhibitor Adezmapimod effectively rescued the Acsm3 depletion phenotype. Together, these findings show that disease-associated loss of ACSM3 facilitates mitochondrial dysfunction via a lauric acid-HNF4a-p38 MAPK axis, suggesting a novel therapeutic vulnerability in systemic metabolic dysfunction., (© 2024. The Author(s).)

Background: Coronary artery calcification (CAC) is a highly specific marker of atherosclerosis. Niemann-Pick C1-like 1 (NPC1L1) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are the therapeutic targets of ezetimibe and statins, respectively, which are important for the progression of atherosclerosis. However, CAC's genetic susceptibility with above targets is still unknown. We aimed to investigate the association of NPC1L1 and HMGCR gene polymorphisms with CAC in patients with premature triple-vessel disease (PTVD)., Methods: Four single nucleotide polymorphisms (SNPs) (rs11763759, rs4720470, rs2072183, rs2073547) of NPC1L1, and three SNPs (rs12916, rs2303151, rs4629571) of HMGCR were genotyped in 872 PTVD patients. According to the coronary angiography results, patients were divided into low-degree CAC group and high-degree CAC group., Results: A total of 872 PTVD patients (mean age, 47.71 ± 6.12; male, 72.8%) were finally included for analysis. Multivariate logistic regression analysis showed no significant association between the SNPs of NPC1L1 and HMGCR genes and high-degree CAC in the total population (P > 0.05). Subgroup analysis by gender revealed that the variant genotype (TT/CT) of rs4720470 on NPC1L1 gene was associated with increased risk for high-degree CAC in male patients only (OR = 1.505, 95% CI: 1.008-2.249, P = 0.046) in dominant model, but no significant association was found in female population, other SNPs of NPC1L1 and HMGCR genes (all P > 0.05)., Conclusions: We reported for the first time that the rs4720470 on NPC1L1 gene was associated with high-degree CAC in male patients with PTVD. In the future, whether therapies related to this target could reduce CAC and cardiovascular events deserves further investigation., (© 2024. The Author(s).)

Background: Insulin resistance is a pivotal risk factor for cardiovascular diseases, and the triglyceride-glucose (TyG) index is a well-established surrogate of insulin resistance. This study aimed to investigate the prognostic value of the TyG index and its ability in therapy guidance in patients with three-vessel disease (TVD)., Methods: A total of 8862 patients with TVD with available baseline TyG index data were included in the study. The endpoint was major adverse cardiac events (MACE). All patients received coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or medical therapy (MT) alone reasonably., Results: An elevated TyG index was defined as the TyG index greater than 9.51. During a median follow-up of 7.5 years, an elevated TyG index was significantly associated with an increased risk of MACE (adjusted hazard ratio 1.161, 95% confidence interval 1.026-1.314, p = 0.018). The elevated TyG index was shown to have a more pronounced predictive value for MACE in patients with diabetes, but failed to predict MACE among those without diabetes, whether they presented with stable angina pectoris (SAP) or acute coronary syndrome (ACS). Meanwhile, the association between an elevated TyG index and MACE was also found in patients with left main involvement. Notably, CABG conferred a significant survival advantage over PCI in patients with a normal TyG index, but was not observed to be superior to PCI in patients with an elevated TyG index unless the patients had both ACS and diabetes. In addition, the benefit was shown to be similar between MT and revascularisation among patients with SAP and an elevated TyG index., Conclusions: The TyG index is a potential indicator for risk stratification and therapeutic decision-making in patients with TVD., (© 2023. The Author(s).)

White adipose tissue browning can promote lipid burning to increase energy expenditure and improve adiposity. Here, we show that Slc35d3 expression is significantly lower in adipose tissues of obese mice. While adipocyte-specific Slc35d3 knockin is protected against diet-induced obesity, adipocyte-specific Slc35d3 knockout inhibits white adipose tissue browning and causes decreased energy expenditure and impaired insulin sensitivity in mice. Mechanistically, we confirm that SLC35D3 interacts with the NOTCH1 extracellular domain, which leads to the accumulation of NOTCH1 in the endoplasmic reticulum and thus inhibits the NOTCH1 signaling pathway. In addition, knockdown of Notch1 in mouse inguinal white adipose tissue mediated by orthotopic injection of AAV8-adiponectin-shNotch1 shows considerable improvement in obesity and glucolipid metabolism, which is more pronounced in adipocyte-specific Slc35d3 knockout mice than in knockin mice. Overall, in this study, we reveal that SLC35D3 is involved in obesity via NOTCH1 signaling, and low adipose SLC35D3 expression in obesity might be a therapeutic target for obesity and associated metabolic disorders., (© 2023. The Author(s).)

Insulin resistance is associated with many pathological conditions, and an in-depth understanding of the mechanisms involved is necessary to improve insulin sensitivity. Here, we show that ZFYVE28 expression is decreased in insulin-sensitive obese individuals but increased in insulin-resistant individuals. Insulin signaling inhibits ZFYVE28 expression by inhibiting NOTCH1 via the RAS/ERK pathway, whereas ZFYVE28 expression is elevated due to impaired insulin signaling in insulin resistance. While Zfyve28 overexpression impairs insulin sensitivity and causes lipid accumulation, Zfyve28 knockout in mice can significantly improve insulin sensitivity and other indicators associated with insulin resistance. Mechanistically, ZFYVE28 colocalizes with early endosomes via the FYVE domain, which inhibits the generation of recycling endosomes but promotes the conversion of early to late endosomes, ultimately promoting phosphorylated insulin receptor degradation. This effect disappears with deletion of the FYVE domain. Overall, in this study, we reveal that ZFYVE28 is involved in insulin resistance by promoting phosphorylated insulin receptor degradation, and ZFYVE28 may be a potential therapeutic target to improve insulin sensitivity., (© 2023. The Author(s).)

Background: N,N-diethyl-m-toluamide (DEET) is a widely used active ingredient in insect repellents, and its effects on human health have been a matter of debate. This study aims to investigate the relationship between DEET exposure and hyperuricemia in the adult population., Methods: Our study utilized a cross-sectional design and analyzed data from adult participants of the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2016. 3-diethyl-carbamoyl benzoic acid (DCBA) was used as a specific indicator of DEET exposure. DCBA was categorized using quartiles based on its distribution within the study population. Multiple linear regression models were employed to examine the association between DCBA exposure and serum uric acid (SUA) levels in adults. The relationship between DCBA and the prevalence of hyperuricemia in adults was assessed using multiple logistic regression models. Dose-response relationships were analyzed using restricted cubic spline regression., Results: A total of 8708 participants were included in the study. The mean age of the participants was 46.49 years, and the total number of male participants was 50.93%. The median levels of DCBA and SUA were 2.07 ng/mL and 5.40 mg/dL, respectively. Hyperuricemia was found in 19.99% of the participants. In multivariate-adjusted linear regression models, it was found that higher SUA levels were associated with the highest quartile of DCBA compared with the lowest quartile of DCBA (β [95% CI]: 0.19 [0.08, 0.30], P trend <0.001). After adjusting for confounders, a positive association was found between the prevalence of hyperuricemia and DCBA levels (OR [95% CI] quartile 4 vs. 1 : 1.41 [1.14-1.74], P trend <0.001). Furthermore, linear associations were observed between DCBA concentrations and SUA levels (P for nonlinearity = 0.479) and the prevalence of hyperuricemia (P for nonlinearity = 0.755)., Conclusion: Higher DCBA concentrations were found to have a positive association with the prevalence of hyperuricemia in the general adult population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Previous studies have shown that hypertension and depression are associated with worse cardiovascular outcomes and reduced quality of life. Left ventricular hypertrophy (LVH) is strongly linked to increased mortality and cardiovascular disease, and depression may be one of the key factors contributing to hypertensive LVH. The authors consecutively enrolled 353 patients with uncomplicated hypertension between November 2017 and May 2021. All participants completed the Hamilton Depression Scale (HAM-D) to assess their depression status, with depression defined as a HAM-D score of 20 or higher. Linear regression analysis revealed a positive association between HAM-D and LVMI (adjusted β, 1.51, 95% CI, 1.19-1.83, p < .001). Logistic regression models showed that individuals with hypertension and depression had a higher risk of LVH than those with hypertension alone (adjusted OR, 2.51, 95% CI, 1.14-5.52, p = .022). The association between depression and LVH significantly interacted with age, sex, education levels, but not BMI and household income. Following age, sex, and education levels stratification, an independent association of depression and LVH was observed only in age <60 years (age <60 years: OR, 7.36, 95% CI, 2.25-24.13, p < .001), male (male: OR, 16.16, 95% CI, 3.80-68.73, p < .001), and higher education levels (high school and above: OR, 11.09, 95% CI, 2.91-42.22, p < .001). Our findings suggest that depression is a significant risk factor for LVH in hypertensive patients, particularly in those who are under 60 years of age, male, and have higher education levels., (© 2023 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: To investigate the association of HMGCR and NPC1L1 gene polymorphisms with residual cholesterol risk (RCR) in patients with premature triple-vessel disease (PTVD)., Methods: Three SNPs within HMGCR including rs12916, rs2303151, and rs4629571, and four SNPs within NPC1L1 including rs11763759, rs4720470, rs2072183, and rs2073547 were genotyped. RCR was defined as achieved low-density lipoprotein cholesterol (LDL-C) concentrations after statins higher than 1.8 mmol/L (70 mg/dL)., Results: Finally, a total of 609 PTVD patients treated with moderate-intensity statins were included who were divided into two groups: non-RCR group (n = 88) and RCR group (n = 521) according to LDL-C concentrations. Multivariate logistic regression showed the homozygotes for the minor allele of rs12916 within HMGCR gene (CC) were associated with a 2.08 times higher risk of RCR in recessive model [odds ratio (OR): 2.08, 95% confidence interval (CI): 1.16-3.75]. In codominant model, the individuals homozygous for the minor allele of rs12916 (CC) were associated with a 2.26 times higher risk of RCR (OR: 2.26, 95% CI: 1.16-4.43) while the heterozygous individuals (CT) were not, compared with the individuals homozygous for the major allele of rs12916 (TT). There was no significant association between the SNPs within NPC1L1 gene and RCR in various models., Conclusions: We first reported that the variant homozygous CC of rs12916 within HMGCR gene may incur a significantly higher risk of RCR in PTVD patients treated with statins, providing new insights into early individualized guidance of precise lipid-lowering treatment., (© 2023. The Author(s).)

This study aims to assess the associations of serum and red blood cell (RBC) folate with cardiovascular and all-cause mortality in hypertensive adults. Data on serum and RBC folate from the 1999-2014 National Health and Nutrition Examination Survey were included. Through December 31, 2015, cardiovascular and all-cause mortality were identified from the National Death Index. Multiple Cox regression and restricted cubic spline analyses were used to determine the relationship between folate concentrations and outcomes. A total of 13,986 hypertensive adults were included in the analysis (mean age, 58.5 ± 16.1 years; 6898 [49.3%] men). At a median of 7.0 years of follow-up, 548 cardiovascular deaths and 2726 all-cause deaths were identified. After multivariable adjustment, the fourth quartile of serum folate was associated with cardiovascular (HR = 1.32 [1.02-1.70]) and all-cause (HR = 1.20 [1.07-1.35]) mortality compared to the second quartile, whereas the first quartile was only linked with increased all-cause (HR = 1.29 [1.15-1.46]) mortality. The inflection points for the non-linear associations of serum folate with cardiovascular and all-cause mortality were 12.3 ng/mL and 20.5 ng/mL, respectively. In addition, the highest quartile of RBC folate was associated with cardiovascular (HR = 1.68 [1.30-2.16]) and all-cause (HR = 1.30 [1.16-1.46]) mortality compared to the second quartile, but the lowest quartile was not associated with either outcome. The inflection points for the non-linear associations of RBC folate with cardiovascular and all-cause mortality were 819.7 and 760.1 ng/mL, respectively. The findings suggest non-linear associations between serum and RBC folate levels and the risk of cardiovascular and all-cause mortality in hypertensive adults., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background and Aim: This study was to assess the association between vitamin B6 turnover rate and mortality in hypertensive adults., Methods and Results: Vitamin B6 status including serum pyridoxal-5'-phosphate (PLP) levels, serum 4-pyridoxal acid (4-PA) levels, and vitamin B6 turnover rate (4-PA/PLP) were obtained from the 2005-2010 National Health and Nutrition Examination Survey (NHANES) dataset of hypertensive adults with follow-up through December 30, 2019. Using Cox proportional risk regression models, Hazard ratios (HRs) and 95% confidence intervals (CIs) were analyzed for PLP, 4-PA and 4-PA/PLP quartiles in relation to cardiovascular and all-cause mortality. A total of 5434 participants were included in this study (mean age, 58.48 years; 50.4% men), and the median 4-PA/PLP was 0.75. The median follow-up time was 11.0 years, with 375 and 1387 cardiovascular and all-cause deaths, respectively. In multivariate COX regression models, PLP was negatively associated with cardiovascular mortality (HR [95% CI] quartile 4 vs. 1: 0.66 [0.47-0.94], P trend  = 0.03) and 4-PA/PLP was positively associated with cardiovascular mortality (HR [95% CI] quartile 4 vs.1: 1.80 [1.21-2.67], P trend  = 0.01). Similarly, the higher the quartile of PLP, the lower the risk of all-cause mortality (HR [95% CI] quartile 4 vs. 1: 0.67 [0.56-0.80], P trend  < 0.01). The higher the quartile of 4-PA and 4-PA/PLP, the higher the risk of all-cause mortality (HR [95% CI] quartile 4 vs. 1: 1.22 [1.01-1.48], P trend  < 0.01; and 2.09 [1.71-2.55], P trend  < 0.01)., Conclusion: The findings suggested that higher vitamin B6 turnover rate was associated with an increased risk of cardiovascular and all-cause mortality in hypertensive adults., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. All rights reserved.)

Changes in kidney function and the progression of chronic kidney disease (CKD) are associated with the risk of cardiovascular disease (CVD) and influenced by genetic factors. However, the association between genetic variants and kidney function in patients treated with antihypertensive drugs remains uncertain. This study aimed to examine the association between 30 variants locating at the 22 genes and the risk of kidney function evaluated by the estimated glomerular filtration rate (eGFR) in 1911 patients with hypertension from a Chinese community-based longitudinal cohort (including 1220 participants with CKD and 691 without CKD at baseline). By using multivariate linear regression analysis after adjustment for age, sex, traditional cardiovascular risk factors, and the use of antihypertensive drugs, as well as after correction for multiple comparison, patients with rs10767873T allele of the metallophosphoesterase domain containing 2 (MPPED2) gene were associated with higher level of eGFR (β = 0.041, p = 0.01) and lower levels of serum creatinine (β = -0.068, p = 0.001) and serum uric acid (β = -0.047, p = 0.02). But variant rs10767873 was not found to be associated with the risk of CKD, regardless of the types of antihypertensive drugs used. During a median 2.25-year follow-up, 152 CVD events were documented. Interestingly, patients with the rs10767873TT genotype had an increased risk of CVD events (hazard ratio, 1.74, 95% confidence interval, 1.11 to 2.73; p = 0.02) compared with patients carrying the wild-type genotype of rs10767873CC. In conclusion, our findings suggest variant rs10767873 of the MPPED2 gene is associated with kidney function and risk of CVD in Chinese hypertensive patients., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: The genetic factors in assessing therapeutic efficacy and predicting antihypertensive drug response are unclear. Therefore, this study aims to identify the associations between variants and antihypertensive drug response. Methods: A longitudinal study including 1837 hypertensive patients was conducted in Northern China and followed up for a median 2.24 years. The associations of 11 candidate variants with blood pressure changes in response to antihypertensive drugs and with the risk of cardiovascular events during the follow-up were examined. The dual-luciferase assay was carried out to assess the effect of genetic variants on gene transcriptional activity. Results: The variant rs11039149A>G in the promoter of nuclear receptor subfamily 1 group H member 3 ( NR1H3 ) was associated with the change in systolic blood pressure (ΔSBP) in response to calcium channel blockers (CCBs) monotherapy. Patients carrying rs11039149AG genotype showed a significant increase of systolic blood pressure (SBP) at follow-up compared with AA carriers, and the difference of ΔSBP between AG and AA carriers was 5.94 mm Hg (95%CI: 2.09-9.78, p = 0.002). In 1,184 patients with CCBs therapy, SBP levels decreased in AA carriers, but increased in AG carriers, the difference of ΔSBP between AG and AA carriers was 8.04 mm Hg (95%CI: 3.28-12.81, p = 0.001). Further analysis in 359 patients with CCBs monotherapy, the difference of ΔSBP between AG and AA carriers was 15.25 mm Hg (95%CI: 6.48-24.02, p = 0.001). However, there was no significant difference in ΔSBP between AG and AA carriers with CCBs multitherapy. The rs11039149A>G was not associated with the cardiovascular events incidence during the follow-up. Additionally, transcriptional factor forkhead box C1 ( FOXC1 ) bound to the NR1H3 promoter containing rs11039149A and significantly increased the transcriptional activity, while rs11039149 A to G change led to a loss-of-function and disabled FOXC1 binding. For the other 10 variants, associations with blood pressure changes or risk of cardiovascular events were not observed. Conclusion: Hypertensive patients with rs11039149AG genotype in the NR1H3 gene have a significant worse SBP control in response to CCBs monotherapy compared with AA carriers. Our findings suggest that the NR1H3 gene might act as a promising genetic factor to affect individual sensitivity to antihypertensive drugs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Han, Wu, Hui, Yang, Zhong, Zhang and Zhang.)

Background and Aims: Risk stratification for three-vessel coronary artery disease (3VD) remains an important clinical challenge. In this study, we utilized machine learning (ML), which can address the limitations of traditional regression-based models, to develop a novel model to assess mortality risk in patients with 3VD., Methods: This study was based on a prospective cohort of 8943 participants with 3VD consecutively enrolled between 2004 and 2011. An ML-derived random forest model was trained and tested to predict 4-year mortality. The predictability of the model was compared with that of an established model, the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery score II (SSII), among 3VD patients undergoing percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), and medical therapy (MT) alone., Results: The all-cause mortality was 7.5% (667 patients) over the 4-year follow-up period. The correlation-based feature selection algorithm selected 18 of the 94 features to develop the ML model. In the testing dataset, the ML-derived model achieved an area under the curve of 0.81 for 4-year mortality prediction. Its predictability was significantly better than that of the SSII among patients undergoing PCI (0.80 vs. 0.70, p < 0.001) or CABG (0.80 vs. 0.67, p < 0.001). The model also outperformed the SSII in patients receiving MT alone (ML: 0.75 vs. SSII for PCI: 0.70 or SSII for CABG: 0.66, p < 0.001)., Conclusions: This ML-based approach exhibited better performance in risk stratification for 3VD compared with the conventional method. Further validation studies are needed to confirm these findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Limited data are available on the long-term impact of mild renal dysfunction (estimated glomerular filtration rate [eGFR] 60-89 mL/min/1.73 m2) in patients with three-vessel coronary disease (3VD)., Methods: A total of 5,272 patients with 3VD undergoing revascularization were included and were categorized into 3 groups: normal renal function (eGFR ≥90 mL/min/1.73 m2, n = 2,352), mild renal dysfunction (eGFR 60-89, n = 2,501), and moderate renal dysfunction (eGFR 30-59, n = 419). Primary endpoint was all-cause death. Secondary endpoints included cardiac death and major adverse cardiac and cerebrovascular events (MACCE), a composite of death, myocardial infarction, and stroke., Results: During the median 7.6-year follow-up period, 555 (10.5%) deaths occurred. After multivariable adjustment, patients with mild and moderate renal dysfunction had significantly higher risks of all-cause death (adjusted hazard ratio [HR]: 1.36, 95% confidence interval [CI]: 1.07-1.70; adjusted HR: 2.06, 95% CI: 1.53-2.78, respectively) compared with patients with normal renal function. Patients after coronary artery bypass grafting (CABG) had a lower rate of all-cause death and MACCE than those undergoing percutaneous coronary intervention (PCI) in the normal and mild renal dysfunction group but not in the moderate renal dysfunction group. Results were similar after propensity score matching., Conclusions: In patients with 3VD, even mild renal impairment was significantly associated with a higher risk of all-cause death. The superiority of CABG over PCI diminished in those with moderate renal dysfunction. Our study alerts clinicians to the early screening of mild renal impairment in patients with 3VD and provides real-world evidence on the optimal revascularization strategy in patients with renal impairment., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Epidemiological evidence of the associations between metal exposure and gout-related outcomes (including serum uric acid [SUA], hyperuricemia and gout) is scarce. The aim of the study is to investigate the associations of metal exposure with SUA, hyperuricemia and gout in general adults., Methods: In this study, the exposure to five blood metals (mercury, manganese, lead, cadmium and selenium) of general adults was analyzed based on the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018 (n = 14,871). Linear, logistic and weighted quantile sum (WQS) regression models were applied to examine the associations of blood metals with gout-related outcomes. Possible dose-response relationships were analyzed through restricted cubic spline regression., Results: Compared with the lowest quartile of blood metals, mercury (quartile 2 and 4), lead (quartile 2, 3, and 4) and selenium (quartile 2 and 4) were found to be positively correlated with SUA and hyperuricemia. Higher levels of mercury and lead were associated with gout, but only those in the fourth quartile had statistical significance (OR [95%CI]: 1.39 [1.10-1.75] and 1.905 [1.41-2.57]) respectively). The WQS index of the blood metals was independently correlated with SUA (β [95%CI]: 0.17 [0.13-0.20]), hyperuricemia (OR [95%CI]: 1.29 [1.16-1.42]) and gout (OR [95%CI]: 1.35 [1.15-1.58]). Among them, lead was the most heavily weighted component (weight = 0.589 for SUA, 0.482 for hyperuricemia, and 0.527 for gout). In addition, restricted cubic spline regression models showed a linear association of lead with the prevalence of hyperuricemia and gout., Conclusion: Our results suggested that blood metal mixtures were positively associated with gout-related outcomes, with the greatest effect coming from lead., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Zhu, Hui, Xing, Wang, Shi, Zhang and Zhu.)

Background: Compared with patients who require fewer antihypertensive agents, those with apparent treatment-resistant hypertension (aTRH) are at increased risk for cardiovascular and all-cause mortality, independent of blood pressure control. However, the etiopathogenesis of aTRH is still poorly elucidated., Methods: We performed a genome-wide association study (GWAS) in first cohort including 586 aTRHs and 871 healthy controls. Next, expression quantitative trait locus (eQTL) analysis was used to identify genes that are regulated by single nucleotide polymorphisms (SNPs) derived from the GWAS. Then, we verified the genes obtained from the eQTL analysis in the validation cohort including 65 aTRHs, 96 hypertensives, and 100 healthy controls through gene expression profiling analysis and real-time quantitative polymerase chain reaction (RT-qPCR) assay., Results: The GWAS in first cohort revealed four suggestive loci (1p35, 4q13.2-21.1, 5q22-23.2, and 15q11.1-q12) represented by 23 SNPs. The 23 significant SNPs were in or near LAPTM5, SDC3, UGT2A1, FTMT, and NIPA1. eQTL analysis uncovered 14 SNPs in 1p35 locus all had same regulation directions for SDC3 and LAPTM5. The disease susceptible alleles of SNPs in 1p35 locus were associated with lower gene expression for SDC3 and higher gene expression for LAPTM5. The disease susceptible alleles of SNPs in 4q13.2-21.1 were associated with higher gene expression for UGT2B4. GTEx database did not show any statistically significant eQTLs between the SNPs in 5q22-23.2 and 15q11.1-q12 loci and their influenced genes. Then, gene expression profiling analysis in the validation cohort confirmed lower expression of SDC3 in aTRH but no significant differences on LAPTM5 and UGT2B4, when compared with controls and hypertensives, respectively. RT-qPCR assay further verified the lower expression of SDC3 in aTRH., Conclusions: Our study identified a novel association of SDC3 with aTRH, which contributes to the elucidation of its etiopathogenesis and provides a promising therapeutic target., (© 2022. The Author(s).)

Background: The purpose of this study was to examine the relationship between N,N-diethyl-m-toluamide (DEET) exposure and obesity-related outcomes in the general adult population using the data from the National Health and Nutrition Examination Survey (NHANES)., Methods: This cross-sectional study examined the data from the NHANES from 2007 to 2016 and totally evaluated 8,770 individuals. DEET's primary oxidative metabolite, 3-(diethylcarbamoyl) benzoic acid (DCBA), is a sensitive and specific indicator of DEET exposure. DCBA was divided into three groups based on the interquartile range. Body mass index (BMI) and waist circumference (WC) were used to define obesity and abdominal obesity, respectively. The association among DCBA and obesity-related outcomes was evaluated using a multivariable linear and logistic regression model., Results: Overall, median age of participants was 46.0 (IQR 31.0, 59.0) years, with 4295 (49.2%) men, while median BMI and WC were 27.8 (24.0, 32.0) and 29.6 (86.6, 108.1) kg/m 2 , respectively. Approximately 3,251 (35.9%) cases of obesity and 4,778 cases (54.4%) of abdominal obesity were observed. In multivariable-adjusted linear regression models, as the tertiles of DCBA increased, BMI and WC monotonically increased regardless of the adjustments (all p for trend <0.01). By referring the lowest tertile of DCBA, the highest tertile was associated with a higher BMI (β = 0.83, 95% confidence intervals [CI] [0.45, 1.21]; p < 0.001) and WC (β = 1.59, 95% CI [0.59, 2.60]; p = 0.002). The multivariate odds ratios (95% CI) for obesity increased monotonically as 1.18 (0.97-1.44) and 1.36 (1.15-1.61) (p for trend 0.001). Similar associations between DCBA and the prevalence of abdominal obesity were observed across increasing DCBA tertiles compared with the reference tertile (OR = 1.22, 95% CI [1.02, 1.44]; OR = 1.28, 95% CI [1.08-1.54]; p for trend = 0.002)., Conclusions: These findings suggested that higher DCBA concentrations are positively associated with the prevalence of obesity and abdominal obesity in the general adult population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Hypertension is a common cardiovascular disease that is related to genetic and environmental factors, but its mechanisms remain unclear. DNA methylation, a classic epigenetic modification, not only regulates gene expression but is also susceptible to environmental factors, linking environmental factors to genetic modification. Therefore, globally screening differential genomic DNA methylation in patients with hypertension is important for investigating hypertension mechanisms., Methods: Differential genomic DNA methylation in patients with hypertension, individuals with prehypertension, and healthy control individuals was screened using Illumina 450K BeadChip and verified by pyrosequencing. Plasma OVGP1 (oviduct glycoprotein 1) levels were determined using an enzyme-linked immunosorbent assay. Ovgp1 transgenic and knockout mice were generated to analyze the function of OVGP1. The blood pressure levels of the mouse models were measured using the tail-cuff system and radiotelemetry methods. The role of OVGP1 in vascular remodeling was determined by vascular relaxation studies. Protein-protein interactions were investigated using a pull-down/mass spectrometry assay and verified with coimmunoprecipitation and pull-down assays., Results: We found a hypomethylated site at cg20823859 in the promoter region of OVGP1 and plasma OVGP1 levels were significantly increased in patients with hypertension. This finding indicates that OVGP1 is associated with hypertension. In Ovgp1 transgenic mice, OVGP1 overexpression caused an increase in blood pressure, dysfunctional vasoconstriction and vasodilation, remodeling of arterial walls, and increased vascular superoxide stress and inflammation, and these phenomena were exacerbated by angiotensin II infusion. In contrast, OVGP1 deficiency attenuated angiotensin II-induced vascular oxidase stress, inflammation, and collagen deposition. These findings indicate that OVGP1 is a prohypertensive factor that directly promotes vascular remodeling. Pull-down and coimmunoprecipitation assays showed that MYH9 (nonmuscle myosin heavy chain IIA) interacted with OVGP1, whereas inhibition of MYH9 attenuated OVGP1-induced hypertension and vascular remodeling., Conclusions: Hypomethylation at cg20823859 in the promoter region of OVGP1 is associated with hypertension and induces upregulation of OVGP1. The interaction between OVGP1 and MYH9 contributes to vascular remodeling and dysfunction. Therefore, OVGP1 is a prohypertensive factor that promotes vascular remodeling by binding with MYH9.

Background: Coronary heart disease and diabetes are highly interrelated and complex diseases. We proposed to investigate the association of genetic polymorphisms of the lipoprotein important regulatory genes Niemann-Pick C1-like 1 (NPC1L1) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with premature triple-vessel coronary disease (PTVD) with diabetes, blood glucose and body mass index., Methods: Four single-nucleotide polymorphisms (SNPs) (rs11763759, rs4720470, rs2072183 and rs2073547) of NPC1L1 and three SNPs (rs12916, rs2303151 and rs4629571) of HMGCR were genotyped in 872 PTVD patients., Results: After performing logistic regression analysis adjusted for age and sex, rs2303151 of HMGCR was related to the risk of diabetes in the dominance model (odds ratio = 1.35, 95% confidence interval = 1.01-1.80, p = 0.04). However, the four SNPs of NPC1L1 were not associated with the risk of diabetes. Further analyses showed that neither the above SNPs of NPC1L1, nor the SNPs of HMGCR were related to blood glucose and body mass index (all p > 0.05)., Conclusions: We report that rs2303151 is a novel polymorphism of the HMGCR gene related to the risk of diabetes in PTVD patients, which suggests HMGCR may be a potential common targeted pathogenic pathways between coronary heart disease and diabetes., (© 2022 John Wiley & Sons Ltd.)

Aims: To explore the effects of age and sex on the outcomes of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients with the three-vessel disease (TVD)., Methods and Results: The study is a subanalysis of data from a prospective cohort of 8,943 patients with angiographically confirmed TVD at Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China. The primary end point was major adverse cardiac and cerebrovascular events (MACCEs), a composite of all-cause death, myocardial infarction, and stroke. In total, 2,819 patients with NSTE-ACS who received CABG (43.6%) or PCI (56.4%) were included, among whom 32.7% were of 65-74 years, 7.2% were ≥75 years, and 22.6% were women. The median follow-up duration was 6.8 years. The superiority of CABG relative to PCI in terms of MACCE was decreased with age (adjusted hazard ratio [HR] [95% confidence interval (CI)]: <65 years: 0.662 [0.495-0.885], p = 0.005; 65-74 years: 0.700 [0.512-0.956], p = 0.025; ≥75 years: 0.884 [0.529-1.479], p = 0.640) and was only seen in men (adjusted HR [95% CI]: men: 0.668 [0.526-0.848], p = 0.001; women: 0.713 [0.505-1.006], p = 0.054). Significant treatment-by-sex and treatment-by-age interactions were observed in patients ≥ 75 years and women, respectively, ( p interaction with sex = 0.001; p interaction with age = 0.002)., Conclusion: Coronary artery bypass grafting is favorable for most NSTE-ACS patients with TVD. The preponderance of CABG over PCI disappeared in patients ≥ 75 years and women. PCI is superior in women ≥ 75 years., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Jiang, Xu, Tian, Zhao, Feng, Wang, Zhang, Sun, Xu, Liu, Xu, Zhao, Hui, Gao, Song and Yuan.)

Background: DNA methylation plays a key role in establishing cell type-specific gene expression profiles and patterns in atherosclerosis. The underlying mechanism remains unclear. Previous studies have shown that DNA methyltransferase 3b (DNMT3b) may play an important role in atherosclerosis. This study aimed to establish the regulatory role of DNMT3b in the development of atherosclerosis., Methods: We constructed a viral vector carrying Dnmt3b shRNA to transduce ApoE -/- mice. Meanwhile, healthy human peripheral blood Treg cells were treated with inhibitor of DNMT3b (AZA and EGCG) or transduced with DNMT3b shRNA., Results: It showed that Dnmt3b silencing attenuated atherosclerosis, including decreased lesion size and macrophage content and increased collagen and smooth muscle cells content in ApoE -/- mice. To further investigate the possible mechanisms, combined with previous studies by our group, we showed that Foxp3 -TSDR methylation level was significantly reduced Foxp3 expression and peripheral blood Treg levels were significantly increased by Dnmt3b shRNA vector transduction in animals committed to western diet for 12 and 18 weeks. Consistently, inhibition of DNMT3b (AZA and EGCG) decreased the expression levels of DNMT3b, which can increase the expression levels of FOXP3, and increase the levels of TGF- β and IL-10 and decrease the levels of IL- β and IFN- γ . After transduction with DNMT3b shRNA, the effect was more obvious., Conclusions: DNMT3b accelerated atherosclerosis, and may be associated with FOXP3 hypermethylation status in regulatory T cells., Competing Interests: All the authors declare there is no conflict of interest., (Copyright © 2022 Ling Zhu et al.)

Elevated serum uric acid (UA) level has been shown to be influenced by multiple genetic variants, but it remains uncertain how UA-associated variants differ in their influence on hyperuricemia risk in people taking antihypertensive drugs. We examined a total of 43 UA-related variants at 29 genes in 1840 patients with hypertension from a community-based longitudinal cohort during a median 2.25-year follow-up (including 1031 participants with normal UA, 440 prevalent hyperuricemia at baseline, and 369 new-onset hyperuricemia). Compared with the wild-type genotypes, patients carrying the SLC2A9 rs3775948G allele or the rs13129697G allele had decreased risk of hyperuricemia, while patients carrying the SLC2A9 rs11722228T allele had increased risk of hyperuricemia, after adjustment for cardiovascular risk factors and correction for multiple comparisons; moreover, these associations were modified by the use of diuretics, β-blockers, or angiotensin converting enzyme inhibitors. The rs10821905A allele of A1CF gene was associated with increased risk of hyperuricemia, and this risk was enhanced by diuretics use. The studied variants were not observed to confer risk for incident cardiovascular events during the follow-up. In conclusion, the genes SLC2A9 and A1CF may serve as potential genetic markers for hyperuricemia risk in relation to antihypertensive drugs therapy in Chinese hypertensive patients., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

The prognostic value of high-sensitivity C-reactive protein (hsCRP) in complex coronary artery disease has not been fully established. We aimed to determine the association between hsCRP and long-term outcomes in elderly patients with 3-vessel disease (TVD). From April 2004 to February 2011, 3069 patients aged ≥65 years with TVD were consecutively enrolled and received medical treatment alone, percutaneous coronary intervention, or coronary artery bypass grafting. The patients were divided into 2 groups according to their hsCRP levels: <3.00 mg/L (62.1%) and ≥3.00 mg/L (37.9%). The mean age was 71 ± 4 years. The high hsCRP group had more risk factors and more frequently received conservative treatment than the low hsCRP group. During a median follow-up period of 6.2 years, elevated hsCRP was significantly associated with increased all-cause death (19.5% vs 29.6%, P < .001), cardiac death (9.4% vs 15.2%, P = .001), and major adverse cardiovascular and cerebrovascular events (34.1% vs 42.5%, P = .001). Multivariable Cox regression analyses revealed that hsCRP was an independent predictor for all of these events. Combining hsCRP with Synergy between PCI with TAXUS and Cardiac Surgery score II further improved the predictive power of the score. The relationship between hsCRP and mortality was relatively consistent across subgroups. Overall, hsCRP could prove useful for risk prediction in elderly patients.

Biomarker-assisted diagnosis of acute aortic dissection (AAD) is important for initiation of treatment and improved survival. However, identification of biomarkers for AAD in blood is a challenging task. The present study aims to find the potential AAD biomarkers using a transcriptomic strategy. Arrays based genome-wide gene expression profiling were performed using ascending aortic tissues which were collected from AAD patients and healthy donors. The differentially expressed genes were validated using quantitative reverse transcriptase PCR (qRT-PCR) and western blot. The plasma levels of a potential biomarker, angiopoietin 2 (ANGPT2) were determined in case-control cohort (77 AAD patients and 82 healthy controls) by enzyme linked immunosorbent assay. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic power of ANGPT2 for AAD. Transcriptome data demonstrated that a total of 18 genes were significantly up-regulated and 28 genes were significantly down-regulated among AAD tissues (foldchange>3.0, p < 0.01). By bioinformatic analysis, we identified ANGPT2 as a candidate biomarker for blood-based detection of AAD. The qRT-PCR and protein expression demonstrated that ANGPT2 increased 2.4- and 4.2 folds, respectively in aortic tissue of AAD patients. Immunohistochemical staining demonstrated that ANGPT2 was markedly increased in intima of the aortic wall in AAD. Furthermore, ANGPT2 was significantly elevated in AAD patients as compared with controls (median 1625 vs. 383 pg/ml, p < 1E-6). ROC curve analysis showed that ANGPT2 was highly predictive of a diagnosis of type A AAD (area under curve 0.93, p < 1E-6). Sensitivity and specificity were 81 and 90%, respectively at the cutoff value of 833 pg/ml. In conclusion, ANGPT2 could be a promising biomarker for diagnosis of AAD; however, more studies are still needed to verify its specificity in diagnosing of AAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Tian, Chen, Zhang, Su, Lu, Yang, Hui, Wang and Fan.)

Background: Both Niemann-Pick C1-like 1 (NPC1L1) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) play a key role on dyslipidaemia. We aim to evaluate whether NPC1L1 and HMGCR genetic variants are associated with susceptibility of premature triple-vessel disease (PTVD). Methods: Four single-nucleotide polymorphisms (SNPs) (rs11763759, rs4720470, rs2072183, and rs2073547) of NPC1L1; and three SNPs (rs12916, rs2303151, and rs4629571) of HMGCR were genotyped in 872 PTVD patients (males ≤ 50 years old and females ≤ 60 years old), and 401 healthy controls. Results: After adjusting for age and sex, rs12916 of HMGCR was associated with the risk of PTVD in dominance model [odds ratio (OR) = 1.68, 95% confidence intervals (CI): 1.29-2.18, P < 0.001], recessive model (OR = 1.43, 95% CI: 1.08-1.90, P = 0.013) and codominant model (OR = 1.38, 95% CI: 1.17-1.63, P < 0.001); meanwhile, rs4720470 of NPC1L1 was related to increased risk of PTVD in recessive model (OR = 1.74, 95% CI: 1.14-2.74, P = 0.013). Patients who carried both variant rs4720470 and rs12916 also had the risk of PTVD ( P < 0.001); however, there were no correlation between these SNPs and the SNYTAX score (all P > 0.05). Conclusions: This is the first report that rs4720470 is a novel polymorphism of the NPC1L1 gene associated with PTVD, and rs12916 of HMGCR gene appears to be a strong genetic marker of PTVD. Our study may improve the early warning, therapeutic strategies and drug development of PTVD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Xu, Tang, Huang, Li, Liu, Jiang, Zhang, Wang, Sun, Xu, Zhao, Hui, Gao, Song and Yuan.)

To investigate the optimal blood pressure (BP) levels and relative importance of BP and BP variability in the early phase of acute ischemic stroke (AIS) for hypertensive patients with carotid artery stenosis (CAS). A single-center cohort study included 750 AIS patients with hypertension and tests were performed for CAS. Participants were categorized to Group 1 (SBP < 140 mm Hg and DBP < 90 mm Hg), Group 2: (SBP: 140-159 mm Hg and or DBP: 90-99 mm Hg), and Group 3: (SBP ≥160 mm Hg and/or DBP ≥100 mm Hg) according to the guidelines. The associations of mean BP levels and variability with outcomes (recurrent stroke, all-cause death and the composite cardiovascular events) at 6 months were analyzed by Cox proportional hazard models. The associations of BP variability with BP levels and cerebral blood flow (CBF) were analyzed by linear regression and generalized additive models. Both for primary and secondary outcome, more events occurred in Group 1 compared with Group 2, while no significant difference was found in Group 3 with higher BP levels. Lower systolic BP variability showed better prognosis and higher CBF. The associations were more significant in patients with CAS ≥50%. BP variability exhibited a linear negative relationship with BP levels. In the early phase of AIS with hypertension and CAS, maintaining low blood pressure variability may be important to improve outcomes while low BP levels (SBP/DBP < 140/90 mm Hg) were harmful, especially in those patients with CAS ≥ 50%., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

[Figure: see text].

[Figure: see text].

Cavernous malformations affecting the CNS occur in ∼0.16-0.4% of the general population. The majority (85%) of cavernous malformations are in a sporadic form, but the genetic background of sporadic cavernous malformations remains enigmatic. Of the 81 patients, 73 (90.1%) patients were detected carrying somatic missense variants in two genes: MAP3K3 and PIK3CA by whole-exome sequencing. The mutation spectrum correlated with lesion size (P = 0.001), anatomical distribution (P < 0.001), MRI appearance (P = 0.004) and haemorrhage events (P = 0.006). PIK3CA mutation was a significant predictor of overt haemorrhage events (P = 0.003, odds ratio = 11.252, 95% confidence interval = 2.275-55.648). Enrichment of endothelial cell population was associated with a higher fractional abundance of the somatic mutations. Overexpression of the MAP3K3 mutation perturbed angiogenesis of endothelial cell models in vitro and zebrafish embryos in vivo. Distinct transcriptional signatures between different genetic subgroups of sporadic cavernous malformations were identified by single cell RNA sequencing and verified by pathological staining. Significant apoptosis in MAP3K3 mutation carriers and overexpression of GDF15 and SERPINA5 in PIK3CA mutation carriers contributed to their phenotype. We identified activating MAP3K3 and PIK3CA somatic mutations in the majority (90.1%) of sporadic cavernous malformations and PIK3CA mutations could confer a higher risk for overt haemorrhage. Our data provide insights into genomic landscapes, propose a mechanistic explanation and underscore the possibility of a molecular classification for sporadic cavernous malformations., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with heart failure-related death in hypertrophic cardiomyopathy (HCM), but the relationship between NT-proBNP level and sudden cardiac death (SCD) in HCM remains undefined., Methods: The study prospectively enrolled 977 unrelated patients with HCM with available NT-proBNP results who were prospectively enrolled and followed for 3.0±2.1 years. The Harrell's C-statistic under the receiver operating characteristic curve was calculated to evaluate discrimination performance. A combination model was constructed by adding NT-proBNP tertiles to the HCM Risk-SCD model. The correlation between log NT-proBNP level and cardiac fibrosis as measured by late gadolinium enhancement (LGE) or Masson's staining was analysed., Results: During follow-up, 29 patients had SCD. Increased log NT-proBNP levels were associated with an increased risk of SCD events (adjusted HR 22.27, 95% CI 10.93 to 65.63, p<0.001). The C-statistic of NT-proBNP in predicting SCD events was 0.80 (p<0.001). The combined model significantly improved the predictive efficiency of the HCM Risk-SCD model from 0.72 to 0.81 (p<0.05), with a relative integrated discrimination improvement of 0.002 (p<0.001) and net reclassification improvement of 0.67 (p<0.001). Furthermore, log NT-proBNP levels were significantly correlated with cardiac fibrosis as detected either by LGE (r=0.257, p<0.001) or by Masson's trichrome staining in the myocardium (r=0.198, p<0.05)., Conclusion: NT-proBNP is an independent predictor of SCD in patients with HCM and may help with risk stratification of this disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

[Figure: see text].

Background and Purpose: This study aimed to test the hypothesis that long noncoding RNA (lncRNA) AL110200 exerts a proinflammatory effect on atherosclerosis and that the variant rs901681 contributes to ischaemic stroke incidence and recurrence., Methods: The expression of AL110200 was analyzed in THP-1 cells treated with oxidized low-density lipoprotein and in human peripheral blood in a coronary heart disease and control population to determine the role of AL110200 in atherosclerosis. The effect of AL110200 on cell adhesion and invasion was tested. The plasma level of leukotriene B4 and rs901681 genotype distribution were assessed in 220 participants. In 1004 ischaemic stroke patients and 1434 controls, the association between rs901681 and stroke incidence was analyzed by logistic regression, and the association of rs901681 and stroke prognosis was analyzed using Kaplan-Meier analysis and the Cox proportional hazards model., Results: Increased expression of AL110200 was observed in THP-1 cells under oxidized low-density lipoprotein treatment. Knockdown of AL110200 reduced the adhesive and invasive ability of THP-1 cells. AL110200 expression in peripheral blood was significantly higher in the coronary heart disease group than in the controls. The GG genotype of rs901681 is associated with reduced plasma leukotriene B4. In the ischaemic stroke population, rs901681 was not associated with ischaemic stroke incidence (p = 0.686). Patients carrying rs901681 GG had a lower risk for stroke recurrence at age ≥60 years (p = 0.001), cardiovascular stroke death (p = 0.022) and all-cause mortality (p = 0.034) in the all-age group., Conclusions: AL110200 might exert a proinflammatory effect on atherosclerosis, and the variant rs901681 might be a strong predictor of stroke prognosis in ischaemic stroke patients., (© 2021 European Academy of Neurology.)

Background: Dramatic changes of blood pressure (BP) were observed in the peripheral thrombolysis period, however, there is no consensus about BP control targets in the different phases., Methods: We retrospectively studied a consecutive sample of 510 patients treated with intravenous thrombolysis and followed-up for 3 months. The peripheral thrombolysis period was divided into these phases: Phase 1 (from onset to thrombolysis), Phase 2 (thrombolysis), Phase 3 (from thrombolysis to 24 h after thrombolysis), and Phase 4 (from 24 h to 7 days after thrombolysis). Patients were divided into quintiles according to mean blood pressure in these phases, respectively. Neurological improvement was evaluated using the modified Rankin Scale score at 3-month after thrombolysis., Results: Lower risk of intracerebral hemorrhage within 7 days was found in lower quintiles of SBP (OR = 0.100, 95% CI 0.011-0.887, P = 0.039 in Phase 1 quintile Q1, OR = 0.110, 95% CI 0.012-0.974, P = 0.047 in Phase 2-3 quintile Q1, and OR, 0.175, 95% CI, 0.035-0.872; P = 0.033 in Phase 4 quintile Q2, respectively). Better neurological improvement was found in SBP quintiles: Q2-Q4 (127.3-155.7 mmHg) in Phase 4 (OR = 3.095, 95% CI 1.524-6.286, P = 0.002 for Q2; OR = 2.697, 95% CI 1.354-5.370, P = 0.005 for Q3; and OR = 2.491, 95% CI 1.263-4.913, P = 0.008 for Q4, respectively). Our results also showed higher average real variability of SBP was negatively associated with better neurological outcome in Phase 1 and Phase 2-3., Conclusions: Maintaining SBP levels (≤148 mmHg) from admission to the first 24 h after thrombolysis, then keeping SBP levels (127-138 mmHg) would be beneficial., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There are relatively limited data regarding real-world outcomes in very old patients with three-vessel disease (3VD) receiving different therapeutic strategies. This study aimed to perform analysis of long-term clinical outcomes of medical therapy (MT), coronary artery bypass grafting (CABG), and percutaneous coronary intervention (PCI) in this population., Methods: We included 711 patients aged ≥ 75 years from a prospective cohort of patients with 3VD. Consecutive enrollment of these patients began from April 2004 to February 2011 at Fu Wai Hospital. Patients were categorized into three groups (MT, n = 296; CABG, n = 129; PCI, n = 286) on the basis of different treatment strategies., Results: During a median follow-up of 7.25 years, 262 deaths and 354 major adverse cardiac and cerebrovascular events (MACCE) occurred. Multivariate Cox analysis showed that the risk of cardiac death was significantly lower for CABG compared with PCI (adjusted hazard ratio [HR] = 0.475, 95% confidence interval [CI] 0.232-0.974, P = 0.042). Additionally, MACCE appeared to show a trend towards a better outcome for CABG (adjusted HR = 0.759, 95% CI 0.536-1.074, P = 0.119). Furthermore, CABG was significantly superior in terms of unplanned revascularization (adjusted HR = 0.279, 95% CI 0.079-0.982, P = 0.047) and myocardial infarction (adjusted HR = 0.196, 95% CI 0.043-0.892, P = 0.035). No significant difference in all-cause death between CABG and PCI was observed. MT had a higher risk of cardiac death than PCI (adjusted HR = 1.636, 95% CI 1.092-2.449, P = 0.017). Subgroup analysis showed that there was a significant interaction between treatment strategy (PCI vs. CABG) and sex for MACCE (P = 0.026), with a lower risk in men for CABG compared with that of PCI, but not in women., Conclusions: CABG can be performed with reasonable results in very old patients with 3VD. Sex should be taken into consideration in therapeutic decision-making in this population.

Three-vessel disease (TVD) is a severe coronary heart disease (CHD) with poor prognosis. Niemann-Pick C1-like 1 ( NPC1L1 ) is a transporter protein for exogenous cholesterol absorption, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase ( HMGCR ) is a rate-limiting enzyme for cholesterol synthesis. We aimed to investigate the association between NPC1L1 and HMGCR gene polymorphisms and major adverse cardiac and cerebrovascular events (MACCE) in patients with TVD. A total of 342 TVD patients were consecutively enrolled and followed up for 1-year MACCE (a composite of all-cause death, myocardial infarction, revascularization, readmission, and stroke) as TVD event group, and 344 patients without CHD were control group. Four single-nucleotide polymorphisms (SNPs), rs11763759, rs4720470, rs2072183, and rs2073547, on NPC1L1 gene and four SNPs, rs12916, rs2303151, rs2303152, and rs4629571, on HMGCR gene were genotyped. Multivariate logistic regression analysis showed that rs4720470 of NPC1L1 was associated with higher risk of TVD with MACCE in codominant model (odds ratio [OR]: 1.315; 95% confidence intervals [CI]: 1.007-1.716, p  = 0.044), and that rs2303151 of HMGCR was associated with higher in recessive (OR: 3.383; 95% CI: 1.040-10.998, p  = 0.043) and codominant (OR: 1.458; 95% CI: 1.038-2.047, p  = 0.030) model, respectively. Patients with both variant rs4720470 in codominant model and variant rs2303151 in recessive model related to a higher risk (OR: 6.772, CI: 1.338-34.280; p  = 0.021). We reported for the first time that the rs4720470 on NPC1L1 gene and rs2303151 on HMGCR gene were associated with risk of 1-year MACCE in TVD.

Aims/introduction: Whether detection of prediabetes by routinely testing hemoglobin A 1c and fasting plasma glucose in three-vessel disease patients could identify individuals at high risk of future cardiovascular disease events remains unclear. This study evaluated the relationship between different glycemic status and clinical outcomes in this specific population., Materials and Methods: This study included 8,891 Chinese patients with three-vessel disease. Patients were categorized according to their glycemic status (normoglycemia [NG], n = 3,195; prediabetes, n = 1,978; diabetes mellitus, n = 3,718)., Results: The median follow-up time was 7.5 years, during which 1,354 deaths and 2,340 major adverse cardiac and cerebrovascular events occurred. Compared with the NG group, patients in the prediabetes and diabetes mellitus groups had more comorbidities. After adjusting for confounders, the diabetes mellitus group had a higher risk of all-cause death (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.20-1.53; P < 0.001), cardiac death (HR 1.35, 95% CI 1.14-1.61; P = 0.001) and major adverse cardiac and cerebrovascular events (HR 1.22, 95% CI 1.11-1.34; P < 0.001) compared with the NG group, whereas the prediabetes and NG groups had no significant difference. The diabetes mellitus group also had a higher risk of stroke compared with the NG group (HR 1.22, 95% CI 1.02-1.46; P = 0.031)., Conclusions: In the context of three-vessel disease, prediabetes patients have comparable long-term outcomes in terms of major adverse cardiac and cerebrovascular events, cardiac death and all-cause death to those with NG. Routine screening of glycemic metabolism based on hemoglobin A 1c and fasting plasma glucose might be valuable to identify individuals with diabetes mellitus who are at high risk of future cardiovascular disease events and individuals with prediabetes who are at high risk of progressing to diabetes mellitus., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background and Aims: It is still controversial whether obesity and overweight increase the risk of mortality for patients with coronary artery disease. The current study aimed to investigate the relationship between body mass index (BMI) and mortality in patients with triple-vessel disease (TVD)., Methods and Results: From April 2004 to February 2011, 8943 patients with angiographically confirmed TVD were consecutively enrolled. Patients were divided into five groups according to BMI: underweight (<18.5 kg/m 2 ), normal weight (18.5-23.9 kg/m 2 ), overweight: (24-27.9 kg/m 2 ), mild obesity (28-31.9 kg/m 2 ), and severe obesity (≥32 kg/m 2 ). The primary end point was all-cause death. Subgroup analysis was performed for treatment strategies: revascularization and medical treatment alone. During a median follow-up of 7.5 years, lower risks of mortality were observed in patients with overweight (adjusted HR 0.85, 95% CI 0.75-0.97) and mild obesity (adjusted HR 0.83, 95% CI 0.69-1.00) compared to those with normal weight. Polynomial Cox regression suggested a U-shape association between BMI and adjusted mortality risk. In the revascularization subgroup, there was a significantly higher mortality risk in patients with severe obesity (adjusted HR 1.57, 95% CI 1.03-2.40) than in those with normal weight. While in the medical treatment subgroup, mortality risk decreased as BMI increased, with the lowest risk being observed in patients with severe obesity., Conclusion: There is a U-shape relationship between BMI and all-cause death in patients with TVD, with increased risks among both underweight and severely obese patients. This relationship may be influenced by treatment strategies., Competing Interests: Declaration of Competing Interest The authors have nothing to disclose., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Whether routine assessment of FT3/FT4 ratio in euthyroid patients with three-vessel disease (3VD) could help identify high-risk individuals remains unclear. This study evaluated the relationship between FT3/FT4 ratio and long-term clinical outcomes in this specific population., Methods and Results: This study included 2106 euthyroid patients with 3VD (stenoses of ≥50% in right coronary artery, left circumflex and left anterior descending). Patients were categorized into three groups according to tertiles of FT3/FT4 ratio (Q1>2.58,n = 704; 2.2 ≤ Q2<2.58, n = 706; Q3<2.22, n = 696). The median follow-up time was 5.3 years, during which 206 deaths and 332 MACCEs (consisting of all-cause death, myocardial infarction, and stroke) occurred. Compared with the other two groups, patients with low level of FT3/FT4 ratio tended to be female, older, diabetic, and had significantly higher incidences of all-cause death, cardiac death and MACCE (all P < 0.05). Cox regression analysis showed that patients with low level of FT3/FT4 ratio had higher risks of long-term cardiac death (adjusted HR = 1.87, 95% CI 1.06-3.28, P = 0.030) and MACCE (adjusted HR = 1.43, 95% CI 1.07-1.93, P = 0.017) than those with high level of FT3/FT4 ratio. Subgroup analysis showed there was a significant interaction between FT3/FT4 ratio and age (≥65 years vs.<65 years) for MACCE (P = 0.029)., Conclusion: Low level of FT3/FT4 ratio is independently associated with an increased risk of long-term cardiac death and MACCE in euthyroid patients with 3VD. Routine assessment of FT3/FT4 ratio might be helpful to identify high-risk individuals in this specific population., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Patients with diabetes and triple-vessel disease (TVD) are associated with a high risk of events. The choice of treatment strategies remains a subject of discussion. In the real-world, we aim to compare the outcomes of medical therapy (MT), coronary artery bypass grafting (CABG), and percutaneous coronary intervention (PCI) treatment strategies in patients with diabetes and TVD., Methods: A total of 3117 consecutive patients with diabetes and TVD were enrolled. The primary endpoint was all-cause death and the secondary endpoint was major adverse cardiac and cerebrovascular events (MACCE, composite of all-cause death, myocardial infarction, or stroke)., Results: During the mean follow-up of 6.3 ± 2.6 years, 573 (18.4%) deaths and 1094 (35.1%) MACCE occurred. Multivariate analysis showed that PCI (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.32-0.51) and CABG (HR 0.33, 95% CI 0.26-0.44) were associated with a lower risk of death compared with MT, with no difference between the PCI and CABG groups. When MACCE was the endpoint, PCI (HR 0.71, 95% CI 0.60-0.84) and CABG (HR 0.48, 95% CI 0.39-0.57) had a lower risk than MT. CABG was associated with a significantly lower risk of MACCE compared with PCI (HR 0.67, 95% CI 0.55-0.81), which was mainly attributed a lower risk in myocardial infarction, but a higher risk of stroke., Conclusions: In this big real-world data and intermediate-term follow-up study, for patients with diabetes and TVD, PCI and CABG were associated with a lower risk of death and MACCE more than MT. The results suggest the importance of appropriate revascularization for diabetic patients with TVD. However, CABG was not associated with a lower risk of death, but with a lower risk of MACCE, compared with PCI. In the future, we perhaps should strengthen comprehensive treatment in addition to PCI or CABG.

Background: The endothelium is the first line of defence against harmful microenvironment risks, and microRNAs (miRNAs) involved in vascular inflammation may be promising therapeutic targets to modulate atherosclerosis progression. In this study, we aimed to investigate the mechanism by which microRNA-216a (miR-216a) modulated inflammation activation of endothelial cells . Methods . A replicative senescence model of human umbilical vein endothelial cells (HUVECs) was established, and population-doubling levels (PDLs) were defined during passages. PDL8 HUVECs were transfected with miR-216a mimics/inhibitor or small interfering RNA (siRNA) of SMAD family member 7 (Smad7). Real-time PCR and Western blot assays were performed to detect the regulatory role of miR-216a on Smad7 and NF- κ B inhibitor alpha (I κ B α ) expression. The effect of miR-216a on adhesive capability of HUVECs to THP-1 cells was examined. MiR-216a and Smad7 expression in vivo were measured using human carotid atherosclerotic plaques of the patients who underwent carotid endarterectomy ( n = 41)., Results: Luciferase assays showed that Smad7 was a direct target of miR-216a. Smad7 mRNA expression, negatively correlated with miR-216a during endothelial aging, was downregulated in senescent PDL44 cells, compared with young PDL8 HUVECs. MiR-216a markedly increased endothelial inflammation and adhesive capability to monocytes in PDL8 cells by promoting the phosphorylation and degradation of I κ B α and then activating NF- κ B signalling pathway. The effect of miR-216a on endothelial cells was consistent with that blocked Smad7 by siRNAs. When inhibiting endogenous miR-216a, the Smad7/I κ B α expression was rescued, which led to decreased endothelial inflammation and monocytes recruitment. In human carotid atherosclerotic plaques, Smad7 level was remarkably decreased in high miR-216a group compared with low miR-216a group. Moreover, miR-216a was negatively correlated with Smad7 and I κ B α levels and positively correlated with interleukin 1 beta (IL1 β ) expression in vivo ., Conclusion: In summary, our findings suggest a new mechanism of vascular endothelial inflammation involving Smad7/I κ B α signalling pathway in atherosclerosis., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Shujun Yang et al.)