Associations of dietary flavonoid intake with the risk of all-cause and cardiovascular mortality in adults.

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, Ptrend = 0.021), 0.58 (95% CI: 0.45-0.74, Ptrend<0.001), and 0.63 (95% CI: 0.50-0.80, Ptrend = 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, Ptrend = 0.035) for flavones, 0.41 (95% CI: 0.22-0.78, Ptrend = 0.001) for flavonols, and 0.54 (95% CI: 0.36-0.80, Ptrend = 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.

Associations of urinary volatile organic compounds with cardiovascular disease among the general adult population.

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.

Palmitic acid in type 2 diabetes mellitus promotes atherosclerotic plaque vulnerability via macrophage Dll4 signaling.

Patients with Type 2 Diabetes Mellitus are increasingly susceptible to atherosclerotic plaque vulnerability, leading to severe cardiovascular events. In this study, we demonstrate that elevated serum levels of palmitic acid, a type of saturated fatty acid, are significantly linked to this enhanced vulnerability in patients with Type 2 Diabetes Mellitus. Through a combination of human cohort studies and animal models, our research identifies a key mechanistic pathway: palmitic acid induces macrophage Delta-like ligand 4 signaling, which in turn triggers senescence in vascular smooth muscle cells. This process is critical for plaque instability due to reduced collagen synthesis and deposition. Importantly, our findings reveal that macrophage-specific knockout of Delta-like ligand 4 in atherosclerotic mice leads to reduced plaque burden and improved stability, highlighting the potential of targeting this pathway. These insights offer a promising direction for developing therapeutic strategies to mitigate cardiovascular risks in patients with Type 2 Diabetes Mellitus.

Association of dietary flavonoid intakes with prevalence of chronic respiratory diseases in adults.

BACKGROUND AND AIMS: Flavonoids are a class of secondary plant metabolites that have been shown to have multiple health benefits, including antioxidant and anti-inflammatory. This study was to explore the association between dietary flavonoid consumption and the prevalence of chronic respiratory diseases (CRDs) in adults. METHODS AND RESULTS: The six main types of flavonoids, including isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, and flavonols, were obtained from the National Health and Nutrition Examination Survey (NHANES) 2007-2010 and 2017-2018 by the two 24-h recall interviews. The prevalence of CRDs, including asthma, emphysema, and chronic bronchitis, was determined through a self-administered questionnaire. The analysis included 15,753 participants aged 18 years or older who had completed a diet history interview. After adjustment for potential confounders, the inverse link was found with total flavonoids, anthocyanidins, flavanones, and flavones, with an OR (95%CI) of 0.86 (0.75-0.98), 0.84 (0.72-0.97), 0.80(0.69-0.92), and 0.85(0.73-0.98) for the highest group compared to the lowest group. WQS regression revealed that the mixture of flavonoids was negatively linked with the prevalence of CRDs (OR = 0.88 [0.82-0.95], P < 0.01), and the largest effect was mainly from flavanones (weight = 0.41). In addition, we found that flavonoid intake was negatively linked with inflammatory markers, and systemic inflammation significantly mediated the associations of flavonoids with CRDs, with a mediation rate of 12.64% for CRP (P < 0.01). CONCLUSION: Higher flavonoid intake was related with a lower prevalence of CRDs in adults, and this relationship may be mediated through systemic inflammation.

Association of depression with hypertensive left ventricular hypertrophy in age, sex, and education level-specific differences.

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 ß, 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.

Association of N, N-diethyl-m-toluamide (DEET) with hyperuricemia among adult participants.

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 (ß [95% CI]: 0.19 [0.08, 0.30], Ptrend<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], Ptrend<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.

Comparison of outcomes between transcatheter tricuspid valve repair and surgical tricuspid valve replacement or repair in patients with tricuspid insufficiency.

BACKGROUND: Tricuspid regurgitation is associated with significant morbidity and mortality, but with limited treatment options. The objective of this study is to compare the demographic characteristics, complications, and outcomes of transcatheter tricuspid valve repair (TTVr) versus surgical tricuspid valve replacement (STVR) or surgical tricuspid valve repair (STVr), using real-world data from the National Inpatient Sample (NIS) database. METHODS AND RESULTS: Our study analyzed data from the National Inpatient Sample (NIS) database from 2016 to 2018 and identified 92, 86, and 84 patients with tricuspid insufficiency who underwent STVr, STVR, and TTVr, respectively. The mean ages of patients who received STVr, STVR, and TTVr were 65.03 years, 66.3 years, and 71.09 years, respectively, with TTVr patients significantly older than those who received STVr (P < 0.05). Patients who received STVr or STVR had higher mortality rates (8.7% and 3.5%, respectively) compared to those who received TTVr (1.2%). Patients who underwent STVr or STVR were also more likely to experience perioperative complications, including third-degree atrioventricular block (8.7% STVr vs. 1.2% TTVr, P = 0.329; 38.4% STVR vs. 1.2% TTVr, P < 0.05), respiratory failure (5.4% STVr vs. 1.2% TTVr, P = 0.369; 15.1% STVR vs. 1.2% TTVr, P < 0.05), respiratory complications (6.5% STVr vs. 1.2% TTVr, P = 0.372; 19.8% STVR vs. 1.2% TTVr, P < 0.05), acute kidney injury (40.2% STVr vs. 27.4% TTVr, P = 0.367; 34.9% STVR vs. 27.4% TTVr, P = 0.617), and fluid and electrolyte disorders (44.6% STVr vs. 22.6% TTVr, P = 0.1332; 50% STVR vs. 22.6% TTVr, P < 0.05). In addition, the average cost of care and the average length of hospital stay were higher for patients who underwent STVr or STVR than for those who received TTVr (USD$37995 ± 356008.523 STVr vs. USD$198397 ± 188943.082 TTVr, P < 0.05; USD$470948 ± 614177.568 STVR vs. USD$198397 ± 188943.082 TTVr, P < 0.05; 15.4 ± 15.19 STVr vs. 9.6 ± 10.21 days TTVr, P = 0.267; 24.7 ± 28.81 STVR vs. 9.6 ± 10.21 days TTVr, P < 0.05). CONCLUSION: TTVr has shown to have favorable outcomes compared to STVr or STVR, but more research and clinical trials are required to help formulate evidence-based guidelines for the role of catheter-based management in tricuspid valve disease.

Associations of vitamin B6 turnover rate with the risk of cardiovascular and all-cause mortality in hypertensive adults.

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], Ptrend = 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], Ptrend = 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], Ptrend < 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], Ptrend < 0.01; and 2.09 [1.71-2.55], Ptrend < 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.

Non-linear associations of serum and red blood cell folate with risk of cardiovascular and all-cause mortality in hypertensive adults.

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.

Transcatheter Mitral Valve Repair Versus Transcatheter Mitral Valve Replacement in Patients with Mitral insufficiency.

AIMS: Mitral regurgitation (MR) is the most prevalent form of valvular heart disease. Transcatheter mitral valve repair (TMVr) and transcatheter mitral valve replacement (TMVR) have recently emerged as alternatives to open heart surgical repair or replacement. However, studies on the comparative outcomes of TMVr and TMVR are limited. This study aims to compare the demographics, complications and outcomes of TMVr and TMVR based on a real-world investigation of the National Inpatient Sample (NIS) database. METHODS AND RESULTS: From 2016-2018 in the NIS database, a total of 210 and 3370 patients who underwent TMVR and TMVr, respectively, were selected. The mean age of the patients was 75.99 years (TMVr) and 69.6 years (TMVR) (p <0.01). The mortality of patients who received TMVR was higher compared to that of patients who were treated with TMVr (8.1 vs. 1.9%, p <0.01). The patients who underwent TMVR were more likely to suffer perioperative complications including blood transfusions (16.2 vs. 5.0%, p <0.01) and acute kidney injury (22.9 vs. 13.3%, p <0.01). The average cost of treatment was higher (USD $278864 vs. USD $216845, p <0.01), and the average duration of hospitalization was longer (8.73 vs. 4.17 d, p <0.01) for TMVR compared to TMVr. When taking into account perioperative comorbidities and other factors, TMVR was associated with a worse adjusted in-hospital mortality (odds ratio [OR], 3.307 [95% CI, 1.533-7.136]; p <0.01). CONCLUSION: TMVr is associated with lower mortality, peri-procedural morbidity, and resource use compared to TMVR. A patient-centered approach can help guide decision-making about the choice of intervention for the individual patient and more studies evaluating the long-term outcomes and durability of TMVR are needed at present.

Uric Acid Predicts Recovery of Left Ventricular Function and Adverse Events in Heart Failure With Reduced Ejection Fraction: Potential Mechanistic Insight From Network Analyses.

Background and Aims: Heart failure with reduced ejection fraction (HFrEF) still carries a high risk for a sustained decrease in left ventricular ejection fraction (LVEF) even with the optimal medical therapy. Currently, there is no effective tool to stratify these patients according to their recovery potential. We tested the hypothesis that uric acid (UA) could predict recovery of LVEF and prognosis of HFrEF patients and attempted to explore mechanistic relationship between hyperuricemia and HFrEF. Methods: HFrEF patients with hyperuricemia were selected from the National Inpatient Sample (NIS) 2016-2018 database and our Xianyang prospective cohort study. Demographics, cardiac risk factors, and cardiovascular events were identified. Network-based analysis was utilized to examine the relationship between recovery of LVEF and hyperuricemia, and we further elucidated the underlying mechanisms for the impact of hyperuricemia on HFrEF. Results: After adjusting confounding factors by propensity score matching, hyperuricemia was a determinant of HFrEF [OR 1.247 (1.172-1.328); P < 0.001] of NIS dataset. In Xianyang prospective cohort study, hyperuricemia is a significant and independent risk factor for all-cause death (adjusted HR 2.387, 95% CI 1.141-4.993; P = 0.021), heart failure readmission (adjusted HR 1.848, 95% CI 1.048-3.259; P = 0.034), and composite events (adjusted HR 1.706, 95% CI 1.001-2.906; P = 0.049) in HFrEF patients. UA value at baseline was negatively correlated to LVEF of follow-ups (r = -0.19; P = 0.046). Cutoff UA value of 312.5 µmmol/L at baseline can work as a predictor of LVEF recovery during follow-up, with the sensitivity of 66.7%, the specificity of 35.1%, and the accuracy of 0.668 (95% CI, 0.561-0.775; P = 0.006). Moreover, gene overlap analysis and network proximity analysis demonstrated a strong correlation between HFrEF and Hyperuricemia. Conclusion: Lower baseline UA value predicted the LVEF recovery and less long-term adverse events in HFrEF patients. Our results provide new insights into underlying mechanistic relationship between hyperuricemia and HFrEF.

Model Embraced Electromechanical Coupling Time for Estimation of Heart Failure in Patients With Hypertrophic Cardiomyopathy.

Objective: This study aimed to establish a model embraced electromechanical coupling time (EMC-T) and assess the value of the model for the prediction of heart failure (HF) in patients with hypertrophic cardiomyopathy (HCM). Materials and Methods: Data on 82 patients with HCM at Shaanxi Provincial People's Hospital between February 2019 and November 2021 were collected and then formed the training dataset (n = 82). Data were used to screen predictors of HF using univariate and multivariate analyses. Predictors were implemented to discover the optimal cut-off value, were incorporated into a model, and shown as a nomogram. The cumulative HF curve was calculated using the Kaplan-Meier method. Additionally, patients with HCM at other hospitals collected from March 2019 to March 2021 formed the validation dataset. The model's performance was confirmed both in training and validation sets. Results: During a median of 22.91 months, 19 (13.38%) patients experienced HF. Cox analysis showed that EMC-T courses in the lateral wall, myoglobin, PR interval, and left atrial volume index were independent predictors of HF in patients with HCM. Five factors were incorporated into the model and shown as a nomogram. Stratification of patients into two risk subgroups by applying risk score (<230.65, ≥230.65) allowed significant distinction between Kaplan-Meier curves for cumulative incidence of HF events. In training dataset, the model had an AUC of 0.948 (95% CI: 0.885-1.000, p < 0.001) and achieved a good C-index of 0.918 (95% CI: 0.867-0.969). In validation dataset, the model had an AUC of 0.991 (95% CI: 0.848-1.000, p < 0.001) and achieved a strong C-index of 0.941 (95% CI: 0.923-1.000). Calibration plots showed high agreement between predicted and observed outcomes in both two datasets. Conclusion: We established and validated a novel model incorporating electromechanical coupling time courses for predicting HF in patients with HCM.

Association of N,N-diethyl-m-toluamide (DEET) with obesity among adult participants: Results from NHANES 2007-2016.

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/m2, 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 (ß = 0.83, 95% confidence intervals [CI] [0.45, 1.21]; p < 0.001) and WC (ß = 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.

DNA Methyltransferase 3b Accelerates the Process of Atherosclerosis.

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-ß and IL-10 and decrease the levels of IL-ß 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.

Outcomes of transcatheter edge-to-edge mitral valve repair with percutaneous coronary intervention vs. surgical mitral valve repair with coronary artery bypass grafting.

Aims: Patients with severe ischemic mitral regurgitation (IMR) may receive concurrent coronary artery bypass graft (CABG) with surgical mitral valve repair (SMVr) or percutaneous coronary stent implantation (PCI) with transcatheter edge-to-edge mitral valve repair (TMVr). However, there is no consensus on the management of severe IMR in this setting. We aimed to compare the outcomes of combined SMVr with CABG to concurrent TMVr with PCI among patients with IMR in the National Inpatient Sample (NIS) database. Methods and results: The National Inpatient Sample was queried for all patients diagnosed with IMR who underwent SMVr with CABG or TMVr with PCI during the years 2016-2018. Study outcomes included all-cause in-hospital mortality, periprocedural complications, and resources used. A total of 1,360 potentially eligible patients were included in the study. After 1:5 propensity score matching, 133 patients were classified in the SMVr + CABG group and 29 patients in the TMVr + PCI group. Adjusted mortality was higher in the TMVr + PCI group compared with the SMVr + CABG group (13.8% vs. 4.5%, P = 0.034). Perioperative complications were higher among patients who underwent SMVr + CABG including blood transfusions (29.3% vs. 6.9%, P = 0.01) and post-procedural cardiogenic shock (11.3% vs. 0%, P = 0.044). The cost of care was higher (USD$783548.80 vs. USD$331846.523, P = 0.001) and the length of stay was longer (17.9 vs. 15.44 days, P < 0.001) in the TMVr + PCI group. On multivariable analysis, age (OR, 1.039 [95% CI, 1.006-1.072]; P = 0.032), renal failure (OR, 3.465 [95% CI, 1.867-6.433]; P < 0.001), and liver disease (OR, 5.012 [95% CI, 2.578-9.686]; P < 0.001) were associated with in-hospital mortality. Conclusion: TMVr + PCI was associated with higher resource use and in-hospital mortality but with improved perioperative complications compared with SMVr + CABG.

Nicorandil attenuates high glucose-induced insulin resistance by suppressing oxidative stress-mediated ER stress PERK signaling pathway.

INTRODUCTION: Glucose-induced insulin resistance is a typical character of diabetes. Nicorandil is now widely used in ischemic heart disease. Nicorandil shows protective effects against oxidative and endoplasmic reticulum (ER) stress, which are involved in insulin resistance. Here, we investigated mechanisms of nicorandil's novel pharmacological activity on insulin resistance in diabetes. RESEARCH DESIGN AND METHODS: Nicorandil was administrated to streptozotocin-induced animals with diabetes and high glucose exposed skeletal muscle cells. Insulin resistance and glucose tolerance were evaluated. Molecular mechanisms concerning oxidative stress, ER stress signaling activation and glucose uptake were assessed. RESULTS: Nicorandil attenuated high glucose-induced insulin resistance without affecting fasting blood glucose and glucose tolerance in whole body and skeletal muscle in rats with diabetes. Nicorandil treatment suppressed protein kinase C/nicotinamide adenine dinucleotide phosphate oxidases system activities by reducing cytoplasmic free calcium level in skeletal muscle cells exposed to high glucose. As a result, the oxidative stress-mediated ER stress protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α/activating transcription factor 4/CEBP homologous protein/tribbles homolog (TRB)3 signaling pathway activation was inhibited. Nicorandil downregulated expression of TRB3 and thus facilitated Akt phosphorylation in response to insulin stimulation, leading to glucose transporter4 plasma membrane translocation which promoted glucose uptake capability of skeletal muscle cells. CONCLUSIONS: By reducing cytoplasmic calcium, nicorandil alleviated high glucose-induced insulin resistance by inhibiting oxidative stress-mediated ER stress PERK pathway.

Diabetes mellitus exacerbates post-myocardial infarction heart failure by reducing sarcolipin promoter methylation.

AIMS: Sarcolipin (SLN) is a key regulator of sarcoplasmic reticulum calcium-ATPase (SERCA)2a, which handles intracellular calcium re-uptake. This study was aimed to investigate the involvement of SLN in post-myocardial infarction (MI) heart failure (HF) in diabetes. METHODS AND RESULTS: Diabetes/MI rat models were established. Altered SLN expression in diabetic hearts was screened out by microarray. A myocardiotropic viral vector was used to deliver siRNA to silence SLN. DNA methylation was evaluated by bisulfite sequencing. Cardiac functions were evaluated by invasive haemodynamic examinations. The SERCA2a activity, cytoplasmic calcium concentration ([Ca2+ ]i ), calcium spark, and myocyte contraction were detected. Correlation between HF and diabetes was analysed in a cohort consisted of 101 ST-segment elevated myocardial infarction (STEMI) patients between 2017 and 2019 [53.54 ± 4.64 years old; 61.4% male gender; HbA1c% 6.15 ± 2.00; and left ventricular ejection fraction (LVEF%) 40.64 ± 3.20%]. SLN expression was evaluated in left ventricular tissue sample from six STEMI patients complicated with diabetes and six STEMI patients without diabetes. Expressions of DNA methyltransferase 1a and DNA methyltransferase 3 were reduced in diabetic hearts, leading to down-regulation of SLN promoter methylation, resulting in increased SLN expression in rats. Impaired heart systolic functions were found in experimental diabetic MI rats, which were attenuated by SLN silencing. SERCA2a activity reduction and [Ca2+ ]i elevation were attenuated by SLN silencing in diabetic animal hearts and high-glucose incubated primary myocytes. SLN silencing suppressed calcium sparks and improved contraction and sarcoplasmic reticulum calcium re-uptake in high-glucose incubated primary myocytes. Expression of SLN was up-regulated in LV sampled from STEMI patients complicated with diabetes compared with non-diabetic ones (P < 0.05). LVEF% was reduced in STEMI patients complicated with diabetes compared with non-diabetic ones (P < 0.01). HbA1c% and LVEF% was related (r = -0.218, P = 0.028). Increased HbA1c% was correlated with reduced LVEF% after adjustment for age, sex, body mass index, cigarette smoking, creatinine, UA, low density lipoprotein, K+ , Na+ , and troponin I (adjusted odds ration = 0.75, 95% confidence interval 0.62-0.90, P = 0.002). CONCLUSIONS: Diabetes increases the vulnerability of STEMI patients to post-MI HF by down-regulating SLN promoter methylation, which further regulates SERCA2a activity via increasing cardiac SLN expression.

Ear Crease Features Are Associated with Complexity of Coronary Lesions.

BACKGROUND The presence of a Frank's sign ear crease is closely correlated with coronary artery disease (CAD). The SYNTAX score indicates the complexity of coronary lesions. This present investigation sought to identify the correlation between SYNTAX score and several specific ear creases. MATERIAL AND METHODS Four specific types of ear creases - crossing crease not originated from ear hole (CC-NEH), crossing crease originated from ear hole (CC-EH), vertical creases on the face side (VC-F), and vertical creases dividing earlobe and face (VC-EF) - were investigated in patients undergoing coronary angiography. A Frank's sign score system was introduced based on the 4 creases. Demographic data, clinical data, and SYNTAX score were also documented. The association between ear creases and SYNTAX score, as well as the correlation between Frank's score and SYNTAX score, were statistically analyzed. RESULTS CC-NEH had the highest positive predictive value (positive predictive value=0.439), and VC-F had the highest negative predictive value for the detection of intermediate and high SYNTAX score (negative predictive value=1.000). VC-EF and CC-NEH were associated with intermediate and high SYNTAX scores (OR=2.913-7.694, all P<0.05). Only 2.9% of patients with Frank's score=0 had intermediate or high SYNTAX scores, and 52.2% and 50.0% of patients with Frank's sign score=3 and 4 had intermediate or high SYNTAX scores, respectively. The Frank's sign score was significantly and positively correlated with SYNTAX score (r=0.457, P<0.001). CONCLUSIONS Features of specific ear creases and Frank's sign scores were associated with intermediate and high complexity of coronary lesions.

Matrine blocks AGEs- induced HCSMCs phenotypic conversion via suppressing Dll4-Notch pathway.

Vascular smooth muscle cells (VSMCs) contractile- synthetic phenotypic conversion takes responsibility in the atherosclerotic plaque formation by abnormal synthesis, secretion and deposition of extracellular matrix (ECM). Matrine exerts therapeutic effects on both cardiovascular diseases and organ fibrosis. In this study, we investigated matrine's inhibitory effect and mechanisms on AGEs- induced VSMC contractile- synthetic phenotypic conversion. Cultured human coronary smooth muscle cells (HCSMCs) were exposed to AGEs. Matrine at serially diluted concentrations were used to treat the cells. HCSMCs phenotype was identified by immunofluorescent staining of contractile phenotypic markers including mooth muscle myosin heavy chain (MYH11) and smooth muscle α-actin (ACTA2). Sircol collagen assay was used to assess the collagen secretion level. Notch signaling activation was determined by luciferase assay. Western blotting was used to evaluate expression levels of collagen I, collagen VIII, Delta-like (Dll)1, Dll3, Dll4, Jagged1, Jagged2, Notch intracellular domain (NICD)1 and Hes family basic helix-loop-helix (bHLH) transcription factor1 (HES1). Matrine pre-treatment recovered the AGEs- induced contractile- synthetic phenotypic conversion by increasing MYH11 and ACTA2 in HCSMCs. Matrine reduced AGEs- mediated activation of Notch signaling, down-regulated expression levels of NICD1, HES1, collagen I and collagen VIII and collagen secretion contents in HCSMCs. Matrine inhibited expression level of Dll4 without affecting other Notch ligands including Dll1, Dll3, Jagged1 and Jagged2 in HCSMCs exposed to AGEs. These results suggested that AGEs exposure facilitated the contractile- synthetic phenotypic conversion of HCSMCs. Matrine blocked this phenotypic conversion by suppressing Dll4- Notch signaling pathway activation.

Enhanced MiR-711 transcription by PPARγ induces endoplasmic reticulum stress-mediated apoptosis targeting calnexin in rat cardiomyocytes after myocardial infarction.

MicroRNA 711 (miR-711) levels in the heart change dynamically after myocardial infarction (MI). As peroxisome proliferator-activated receptor gamma (PPARγ) can upregulate miR-711 in adipocytes and cardiac fibroblasts, this study examined the precise mechanism of PPARγ-mediated miR-711 upregulation and its role in the heart in the early stages after MI. In a rat model of MI induced by left anterior descending coronary artery ligation, immunohistochemical and western blot analyses revealed increased PPARγ expression in cardiomyocyte nuclei after MI. PPARγ modulated miR-711 levels in neonatal rat cardiomyocytes, and chromatin immunoprecipitation and luciferase assays revealed that it bound the premiR-711 promoter to upregulate miR-711. Bioinformatics analysis identified calnexin as a putative miR-711 target; this was confirmed by luciferase, western blot, and real-time polymerase chain reaction analyses. Additionally, the transfection of a miR-711 mimic into cardiomyocytes induced the endoplasmic reticulum (ER) stress-induced apoptosis response by upregulating glucose-regulated protein 78 (GRP78), activating transcription factor (ATF6), spliced X-box binding protein 1 (XBP1), apoptotic signal-regulating kinase 1 (ASK1), CCAAT-enhancer binding protein homologous protein (CHOP), caspase-12, and endoplasmic reticulum oxidoreductase 1 alpha (ERO1a). Similarly, on day 2 after MI, increased miR-711 levels in the heart were accompanied by increased cardiomyocyte apoptosis, decreased calnexin levels, and increased levels of GRP78, ATF6, spliced XBP1, ASK1, CHOP, and caspase-12, as well as cardiomyocytes apoptosis. The mechanism underlying these effects may involve the direct binding of PPARγ to the pre-miR-711 promoter for the upregulation of miR-711, which may induce ER stress-mediated cardiomyocyte apoptosis via calnexin. These findings augment the general knowledge of the post-MI pathological process and suggest a therapeutic strategy for cardiac remodelling in the early stages after MI.