Associations of Flavonoid Intakes with Mortality among Populations with Hypertension: A Prospective Cohort Study.

BACKGROUND: The effect of flavonoid consumption on all-cause and special-cause mortality remains unclear among populations with hypertension. METHODS: A total of 6110 people with hypertension from three NHANES survey cycles (2007-2008, 2009-2010, and 2017-2018) were enrolled in this study. Cox proportional hazard models were conducted to estimate the association between the intake of total flavonoids and flavonoid subclasses and all-cause, cancer-related, and cardiovascular disease (CVD)-related mortality. Nonlinear relationships were identified using restricted cubic splines (RCS). RESULTS: During 43,977 person-years of follow-up, 1155 participants died from any cause, 282 participants died from CVD, and 265 participants died from cancer. After adjusting for relevant confounders, including demographic, lifestyle, and dietary intake, a higher intake of total flavonoids was significantly associated with lower all-cause mortality but not CVD-related and cancer-related mortality among the population with hypertension. Compared with extreme quartiles, the hazard ratio (HR) and 95% confidence interval (CI) were 0.74 (0.56-0.97) for all-cause mortality, 0.77 (0.40-1.46) for CVD-related mortality, and 0.62 (0.35-1.08) for cancer-related mortality. In terms of all-cause mortality, this inverse association was optimized at total flavonoid consumption of approximately 375 mg/day. In addition, the negative association between total flavonoid consumption and all-cause mortality was more pronounced in non-obese (BMI < 30 kg/m2) compared to obese (BMI ≥ 30 kg/m2) populations. Higher intakes of anthocyanidin, flavan-3-ol, flavonol, and isoflavone were significantly associated with lower all-cause mortality (HR (95%CI): 0.70 (0.55-0.89); 0.76 (0.59-0.96); 0.66 (0.46-0.94); 0.79 (0.67-0.93), respectively). Higher intakes of anthocyanidin, flavan-3-ol, and flavonol were significantly associated with lower cancer-related mortality (HR (95%CI): 0.55 (0.32-0.93); 0.51 (0.31-0.82); 0.52 (0.28-0.96), respectively). CONCLUSION: This study suggests that a heightened consumption of total flavonoids and some flavonoid subclasses was linked to lower mortality, which supports the proposal of increasing flavonoid intake as part of healthy diets in patients with hypertension.

GLP-1 receptor agonists and myocardial metabolism in atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Many medical conditions, including hypertension, diabetes, obesity, sleep apnea, and heart failure (HF), increase the risk for AF. Cardiomyocytes have unique metabolic characteristics to maintain adenosine triphosphate production. Significant changes occur in myocardial metabolism in AF. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been used to control blood glucose fluctuations and weight in the treatment of type 2 diabetes mellitus (T2DM) and obesity. GLP-1RAs have also been shown to reduce oxidative stress, inflammation, autonomic nervous system modulation, and mitochondrial function. This article reviews the changes in metabolic characteristics in cardiomyocytes in AF. Although the clinical trial outcomes are unsatisfactory, the findings demonstrate that GLP-1 RAs can improve myocardial metabolism in the presence of various risk factors, lowering the incidence of AF.

Changes in Life's Essential 8 and risk of cardiovascular disease in Chinese people.

BACKGROUND: The American Heart Association recently released an updated algorithm for evaluating cardiovascular health-Life's Essential 8 (LE8). However, the associations between changes in LE8 score over time and risk of cardiovascular disease (CVD) remain unclear. METHODS: We investigated associations between 6-year changes (2006-12) in LE8 score and risk of subsequent CVD events (2012-20) among 53 363 Chinese men and women from the Kailuan Study, who were free from CVD in 2012. The LE8 score was calculated based on eight components: diet quality, physical activity, smoking status, sleep health, body mass index, blood lipids, blood glucose and blood pressure. Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We documented 4281 incident CVD cases during a median of 7.7 years of follow-up. Compared with participants whose LE8 scores remained stable in a 6-year period, those with the large increases of LE8 score over the 6-year period had a lower risk of CVD, heart disease and stroke in the subsequent 8 years [HRs and 95% CIs: 0.67 (0.64, 0.70) for CVD, 0.65 (0.61, 0.69) for heart disease, 0.71 (0.67, 0.76) for stroke, all Ptrend < 0.001]. Conversely, those with the large decreases of LE8 score had 47%, 51% and 41% higher risk for CVD, heart disease and stroke, respectively. These associations were consistent across the subgroups stratified by risk factors. CONCLUSIONS: Improving LE8 score in a short- and moderate-term was associated with a lower CVD risk, whereas decreased LE8 score over time was associated with a higher risk.

CD4+ T-Cell Legumain Deficiency Attenuates Hypertensive Damage via Preservation of TRAF6.

BACKGROUND: T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear. METHODS: Peripheral blood samples were collected from patients with hypertension, and cluster of differentiation (CD)4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell-specific LGMN-knockout) mice (Lgmnf/f/CD4Cre), regulatory T cell (Treg)-specific LGMN-knockout mice (Lgmnf/f/Foxp3YFP Cre), and RR-11a (LGMN inhibitor)-treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development. RESULTS: LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II-induced or deoxycorticosterone acetate/salt-induced hypertension and target organ damage relative to wild-type (WT) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II-induced or deoxycorticosterone acetate/salt-induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II-induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II-induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor-associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II-induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects. CONCLUSIONS: LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.

Intensive Lipid-Lowering Therapy as per the Latest Dyslipidemia Management Guideline in Predicting Favorable Long-Term Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Grafting: A Retrospective Cohort Study.

Background There are limited data on low-density lipoprotein cholesterol (LDL-C) goal achievement per the 2019 European Society of Cardiology/European Atherosclerosis Society dyslipidemia management guidelines and its impact on long-term outcomes in patients undergoing coronary artery bypass grafting (CABG). We investigated the association between LDL-C levels attained 1 year after CABG and the long-term outcomes. Methods and Results A total of 2072 patients diagnosed with multivessel coronary artery disease and undergoing CABG between 2011 and 2020 were included. Patients were categorized by lipid levels at 1 year after CABG, and the occurrence of major adverse cardiovascular and cerebrovascular events (MACCEs) was evaluated. The goal of LDL-C <1.40 mmol/L was attained in only 310 patients (14.9%). During a mean follow-up of 4.2 years after the index 1-year assessment, 25.0% of the patients experienced MACCEs. Multivariable-adjusted hazard ratios (95% CIs) for MACCEs, cardiac death, nonfatal myocardial infarction, nonfatal stroke, revascularization, and cardiac rehospitalization were 1.94 (1.41-2.67), 2.27 (1.29-3.99), 2.45 (1.55-3.88), 1.17 (0.63-2.21), 2.47 (1.31-4.66), and 1.87 (1.19-2.95), respectively, in patients with LDL-C ≥2.60 mmol/L, compared with patients with LDL-C <1.40 mmol/L. The LDL-C levels at 1-year post-CABG were independently associated with long-term MACCEs. Conclusions This retrospective analysis demonstrates that lipid goals are not attained in the vast majority of patients at 1 year after CABG, which is independently associated with the increased risk of long-term MACCEs. Further prospective, multicenter studies are warranted to validate if intensive lipid management could improve the outcomes of patients undergoing CABG.

Changes of ubiquitylated proteins in atrial fibrillation associated with heart valve disease: proteomics in human left atrial appendage tissue.

Background: Correlations between posttranslational modifications and atrial fibrillation (AF) have been demonstrated in recent studies. However, it is still unclear whether and how ubiquitylated proteins relate to AF in the left atrial appendage of patients with AF and valvular heart disease. Methods: Through LC-MS/MS analyses, we performed a study on tissues from eighteen subjects (9 with sinus rhythm and 9 with AF) who underwent cardiac valvular surgery. Specifically, we explored the ubiquitination profiles of left atrial appendage samples. Results: In summary, after the quantification ratios for the upregulated and downregulated ubiquitination cutoff values were set at >1.5 and <1:1.5, respectively, a total of 271 sites in 162 proteins exhibiting upregulated ubiquitination and 467 sites in 156 proteins exhibiting downregulated ubiquitination were identified. The ubiquitylated proteins in the AF samples were enriched in proteins associated with ribosomes, hypertrophic cardiomyopathy (HCM), glycolysis, and endocytosis. Conclusions: Our findings can be used to clarify differences in the ubiquitination levels of ribosome-related and HCM-related proteins, especially titin (TTN) and myosin heavy chain 6 (MYH6), in patients with AF, and therefore, regulating ubiquitination may be a feasible strategy for AF.

Dietary fruits and vegetables and risk of cardiovascular diseases in elderly Chinese.

BACKGROUND: Evidence regarding the potential effect of fruit and vegetable consumption on cardiovascular diseases (CVD) was limited and inconsistent among Asian people. METHODS: We prospectively examined associations of fruit and vegetable consumption with the risk of CVD among 9740 participants aged 65 years and older (mean baseline age: 88 years) in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) (2008-2018). Dietary data were collected using a validated food frequency questionnaire. RESULTS: During 37 366 person-years of follow-up, a total of 3738 CVD cases were recorded. After adjusting for demographics, dietary, lifestyle and economical social factors, higher intakes of total fruits and vegetables were associated with lower risk of CVD [comparing with extreme quintiles, hazard ratio and 95% confidence interval: 0.84 (0.74, 0.95)]. The inverse association was mainly driven by vegetable consumption [0.86 (0.77, 0.95)]. Furthermore, the inverse association was stronger for the risk of hypertension [0.84 (0.72, 0.98)]. These associations were consistent across age, sex, body mass index, residence, exercise status, smoking, drinking, meat intake, modified hPDI and health status. CONCLUSIONS: This study suggests higher intakes of total fruits and vegetables are associated with a lower risk of CVD among elderly Chinese people, supporting the current recommendations of increasing fruit and vegetable consumption as part of a healthy diet for the prevention of CVD.

Septal radioablation therapy for patients with hypertrophic obstructive cardiomyopathy: first-in-human study.

Aims: There is still no non-invasive septal reduction therapy for patients with hypertrophic obstructive cardiomyopathy (HOCM). This study aimed to investigate the feasibility, safety, and efficacy of stereotactic body radiotherapy (SBRT) in patients with drug-refractory symptomatic HOCM. Methods and results: The radiation target of ventricular septum was determined by multiple anatomical imaging. Stereotactic body radiotherapy was performed with standard techniques. Patients were treated with a single fraction of 25 Gy, followed up at 1, 3, 6, and 12 months by clinical visit. Five patients were enrolled and completed the 12 months follow-up. The mean radioablation time was 21.6 min, and the mean target volume was 10.5 cm3. All five patients survived and showed improvements in symptoms after SBRT. At 12 months post-SBRT, the echocardiography-derived left ventricular outflow tract gradient decreased from 88 mmHg (range, 63-105) to 52 mmHg (range, 36-66) at rest and from 101 mmHg (range, 72-121) to 74 mmHg (range, 65-100) after Valsalva. The end-diastolic thickness of the targeted septum reduced from 23.7 mm (range, 20.3-29) to 22.4 mm (range, 19.7-26.5); 6 min walking distance increased from 190.4 m (range, 50-370) to 412.0 m (range, 320-480). All patients presented with new fibrosis in the irradiated septum area. No radiation-related complications were observed during SBRT and up to 12 months post procedure. Conclusion: The current study suggests that SBRT might be a feasible radioablation therapeutic option for patients with drug-refractory symptomatic HOCM. Trial registration: ClinicalTrials.gov Identifier: NCT04686487.

Polo-like kinase 4 inhibitor CFI-400945 inhibits carotid arterial neointima formation but increases atherosclerosis.

Neointima lesion and atherosclerosis are proliferative vascular diseases associated with deregulated proliferation of vascular smooth muscle cells (SMCs). CFI-400945 is a novel, highly effective anticancer drug that inhibits polo-like kinase 4 (PLK4) and targets mitosis. In this study, we aim to investigate how CFI-400945 affects the development of proliferative vascular diseases. In C57BL/6 mice, neointima formation was generated by complete carotid ligation. In apolipoprotein E knockout (ApoE-/-) mice fed a high-fat diet, atherosclerosis was induced by partial carotid ligation. CFI-400945 was directly applied to carotid arteries via a perivascular collar. Our results showed that CFI-400945 drastically inhibited neointima formation but significantly accelerated atherosclerosis. In vitro studies showed that CFI-400945 treatment induced SMC polyploidization and arrested cells in the G2/M phase. CFI-400945 treatment upregulated p53 and p27 expression but decreased p21 and cyclin B1 expression. CFI-400945 also induced SMC apoptosis, which was inhibited by hydroxyurea, a DNA synthesis inhibitor that inhibits polyploidization. Furthermore, CFI-400945 caused supernumerary centrosomes, leading to mitotic failure, resulting in polyploidization. In conclusion, CFI-400945 prevents carotid arterial neointima formation in C57BL/6 mice but accelerates atherosclerosis in ApoE-/- mice, likely through mitotic arrest and subsequent induction of polyploidization and apoptosis.

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Hypertrophic obstructive cardiomyopathy (HOCM) is a hereditary cardiac disorder characterized primarily by septal hypertrophy and left ventricular outflow tract obstruction. Traditional therapeutic modalities, such as medications and surgeries, do not yield satisfactory outcomes in a subset of patients. The advancements have been made in novel treatments, including new drugs and percutaneous intramyocardial septal radiofrequency ablation (PIMSRA), still need further observation to obtain long-term efficacy and safety. In recent years, stereotactic body radiation therapy (SBRT) has emerged as an innovative non-invasive approach for treating HOCM. Studies indicate that SBRT allows for precise targeting of the hypertrophied septal region, causing both direct and indirect damage to targeted myocardial cells. This can alleviate left ventricular outflow tract obstruction and myocardial ischemia, fulfilling the therapeutic objective. For those with HOCM who neither respond well to medications nor are surgical candidates, SBRT offers a potential new therapeutic alternative. However, the latent risks of radiation therapy persist, such as the onset of radiation-induced heart disease (RIHD). The preliminary investigations guarantee the safety and feasibility of SBRT in HOCM management, an increased volume of clinical studies and prolonged follow-up data are essential to evaluate its real efficacy and potential hazards. In addition, research regarding the therapeutic mechanisms of SBRT for HOCM, optimal dosages and treatment durations, indications and contraindications, prevention of complications, and enhancing the precision of radiation therapy, still needs to be further exploration, to determine the best therapeutic strategies.

Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux.

INTRODUCTION: Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin's impact on VSMC senescence is largely undefined. OBJECTIVES: To test the hypothesis that metformin exerts an anti-senescence role by restoring autophagic activity in VSMCs and vascular tissues. METHODS: Animal models established by angiotensin II (Ang II) induction and physiological aging and senescent primary VSMCs from the aortas of elderly patients were treated with metformin. Cellular and vascular senescence were assessed by measuring the amounts of senescence-associated ß-galactosidase and senescence markers, including p21 and p53. Autophagy levels were assessed by autophagy-related protein expression, transmission electron microscope, and autolysosome staining. In order to explore the underlying mechanism of the anti-senescence effects of metformin, 4D label-free quantitative proteomics and bioinformatic analyses were conducted, with subsequent experiments validating these findings. RESULTS: Ang II-dependent senescence was suppressed by metformin in VSMCs and vascular tissues. Metformin also significantly improved arterial stiffness and alleviated structural changes in aged arteries, reduced senescence-associated secretory phenotype (SASP), and improved proliferation and migration of senescent VSMCs. Mechanistically, the proteomic analysis indicated that autophagy might contribute to metformin's anti-senescence effects. Reduced autophagic flux was observed in Ang II-induced cellular and vascular senescence; this reduction was reversed by metformin. Specifically, metformin enhanced the autophagic flux at the autophagosome-lysosome fusion level, whereas blockade of autophagosome-lysosome fusion inhibited the anti-senescence effects of metformin. CONCLUSIONS: Metformin prevents VSMC and vascular senescence by promoting autolysosome formation.

Quantitative acetylated proteomics on left atrial appendage tissues revealed atrial energy metabolism and contraction status in patients with valvular heart disease with atrial fibrillation.

Background: Numerous basic studies have demonstrated critical roles of metabolic and contractile remodeling in pathophysiological changes of atrial fibrillation (AF), but acetylation changes underlying atrial remodeling have not been fully elucidated. Quantitative acetylated proteomics enables researchers to identify a comprehensive map of protein alterations responsible for pathological development and progression of AF in the heart of patients. Materials and methods: In this study, 18 samples (9 with chronic AF and 9 with sinus rhythm) of left atrial appendage (LAA) tissues were obtained during mitral valve replacement surgery. Changes in the quantitative acetylated proteome between the AF and sinus rhythm (SR) groups were studied by dimethyl labeling, acetylation affinity enrichment, and high-performance liquid chromatography-tandem mass spectrometry analysis. Results: We identified a total of 5,007 acetylated sites on 1,330 acetylated proteins, among which 352 acetylated sites on 193 acetylated proteins were differentially expressed between the AF and SR groups by setting a quantification ratio of 1.3 for threshold value and P < 0.05 for significant statistical difference. The bioinformatics analysis showed that the differentially expressed acetylated proteins were mainly involved in energy metabolism and cellular contraction and structure function-related biological processes and pathways. Among 87 differentially expressed energy metabolism acetylated proteins related to the processes of fatty acid, carbohydrate, ketone body metabolism, and oxidative phosphorylation, nearly 87.1% Kac sites were upregulated (148 Kac sites among 170) in the AF group. Besides, generally declining acetylation of cardiac muscle contraction-related proteins (88.9% Kac sites of myosin) was found in the LAA of patients with AF. Immune coprecipitation combined with Western blotting was conducted to validate the differential expression of acetylated proteins. Conclusion: Many differentially expressed energy metabolism and cellular contraction acetylated proteins were found in the LAA tissues of patients with chronic AF, and may reflect the impaired ATP production capacity and decreased atrial muscle contractility in the atrium during AF. Thus, acetylation may play an important regulatory role in metabolic and contractile remodeling of the atrium during AF. Moreover, the identified new acetylated sites and proteins may become promising targets for prevention and treatment of AF.

KMT2B-dependent RFK transcription activates the TNF-α/NOX2 pathway and enhances ferroptosis caused by myocardial ischemia-reperfusion.

Epigenetic regulation such as histone modification is implicated in the pathogenesis of myocardial ischemia/reperfusion injury (MIRI). Lysine-specific methyltransferase 2B (KMT2B) is a histone H3 lysine 4 (H3K4) methyltransferase. This study aims at exploring the role of KMT2B-mediated histone modification in MIRI. Peripheral blood samples were collected from 30 patients with acute myocardial infarction (AMI) and 30 healthy volunteers for analyses of the expression levels of KMT2B, riboflavin kinase (RFK), tumor necrosis factor (TNF)-α, and NADPH oxidase 2 (NOX2). H9C2 cardiomyocytes and Sprague-Dawley rats were utilized for developing in vitro and in vivo models. To evaluate the effects of the aforementioned molecules on cellular damage and MIRI, short hairpin RNAs or overexpression plasmids were introduced into cardiomyocytes for gene silencing or overexpression and also, they were packaged into adenovirus vectors for in vivo interventions. Immunoprecipitation assays were conducted to assess the interactions between KMT2B and RFK and among RFK, NOX2 sub-unit p22phox, and TNF receptor 1-associated death domain protein. KMT2B, RFK, TNF-α, and NOX2 were notably upregulated in AMI patients. KMT2B knockdown resulted in considerably attenuated cell apoptosis and reduced myocardial infarct area. Additionally, the release of pro-inflammatory proteins and ferroptosis were suppressed. Furthermore, KMT2B could promote RFK gene transcription by upregulating H3 methylation levels and consequently activate the TNF-α/NOX2 axis, which was the possible mechanism underlying the role of KMT2B in MIRI. KMT2B motivates MIRI-induced cellular injury and ferroptosis by inducing RFK transcription and mediating the TNF-α/NOX2 axis.

Bedside temporary transvenous cardiac pacing lead placement in patients with tricuspid valve surgery without guidance of X-ray: A single-center experience.

BACKGROUND: It is difficult to insert cardiac pacing leads in patient with tricuspid valve surgery (TVS). The aim of this study was to evaluate safety and effectiveness of a novel technique applied for bedside temporary pacemaker placement (TPP) in patients with TVS. METHODS: We investigated patients with TVS who required bedside TPP without X-ray guidance in cardiac intensive care unit between January 2019 and March 2022. They were divided into Novel pre-shaped group (N = 21) and Control group (routine pre-shaped group, N = 26). The ordinary bipolar electrodes were applied in both groups. In Novel pre-shaped group, electrodes were reshaped by a novel technique with three-curve with anterior tip method, while electrodes were shaped by traditional strategy in Control group. We evaluated the operation duration, first-attempt success rate of the lead placement, pacing threshold, success rate of lead placement, the rate of leads displacement, and complications. RESULTS: Compared with that in Control group, the procedure time was significantly shortened and the first-attempt success rate of lead placement was obviously increased in Novel pre-shaped group (both p < 0.05). Although there was a slight reduction in complications in Novel pre-shaped group when compared with that in Control group. However, there were no statistical significance in pacing threshold, the success rate of lead placement, the rate of leads displacement, and complications when compared between two groups. CONCLUSIONS: We propose a novel technique, three-curve with anterior tip method, is a feasible and effective bedside method to insert emergency temporary pacing leads in patients with TVS.

N-acetylcysteine attenuates atherosclerosis progression in aging LDL receptor deficient mice with preserved M2 macrophages and increased CD146.

BACKGROUND AND AIMS: Inflammation and reactive oxygen species (ROS) are important to the pathogenesis of atherosclerosis. The effect of antioxidants on atherosclerosis is inconsistent, and sometimes controversial. We aimed to test the hypothesis that attenuation of atherosclerosis by N-acetylcysteine (NAC) depends on NAC treatment timing and duration. METHODS: Male LDL receptor deficient (LDLR-/-) mice were fed a normal diet (ND) and divided into controls (on ND for 24 months), models 1-2 (at age of 9 months, starting NAC treatment for 3 or 6 months), and model 3 (at age of 18 months, starting NAC treatment for 6 months). To determine if hyperlipidemia compromises NAC treatment outcome, mice were fed a high fat diet (HFD) starting at age of 6 weeks and treated with NAC starting at 9 months of age for 6 months. RESULTS: NAC treatment for 6 months, not for 3 months, significantly attenuated atherosclerosis progression, but did not reverse atherosclerotic lesions, in aging LDLR-/- mice on ND. NAC had no effect on atherosclerotic lesions in mice on HFD. NAC treatment significantly decreased aortic ROS production, and the levels of inflammatory cytokines in serum and aorta of aging LDLR-/- mice with increased CD146 level. Bone marrow transplantation study with GFP-positive bone marrow cells showed that NAC treatment preserved M2 population and M2 polarization in the aorta of LDLR-/- mice. CONCLUSIONS: Early and adequate NAC treatment could effectively attenuate inflammation and atherosclerosis progression with preserved M2 population and increased CD146 level in aging LDLR-/- mice without extreme hyperlipidemia.

Clinical characteristics of severe aortic stenosis patients combined with diabetes mellitus after transcatheter aortic valve replacement and short-term outcome. / ç»å¯¼ç®¡ä¸»åŠ¨è„‰ç“£ç½®æ¢æœ¯åŽé‡åº¦ä¸»åŠ¨è„‰ç“£ç‹­çª„æ‚£è€ åˆå¹¶ç³–å°¿ç— çš„ä¸´åºŠç‰¹å¾åŠå ¶çŸ­æœŸé¢„åŽ.

OBJECTIVES: Type 2 diabetes (T2DM) is a common comorbidity in patients with degenerative aortic stenosis (AS).As a key item of the American Society of Thoracic Surgeons (STS) score, it has a vital impact on the clinical prognosis of traditional thoracic surgery. T2DM has an adverse effect on the morbidity and mortality of cardiovascular diseases. At the same time, studies have shown that T2DM are associated with myocardial hypertrophy and remodeling, decreased left ventricular function, and worsening heart failure symptoms in the AS patients. Transcatheter aortic valve replacement (TAVR) as an interventional method to replace the aortic valve has better safety for middle and high risk patients in surgery, but the impact of T2DM on the clinical outcome of TAVR in AS patients is not clear.By analyzing the clinical and image characteristics of patients with AS and T2DM who received TAVR treatment, so as to explore the effect of T2DM on the perioperative complications and prognosis of TAVR. METHODS: A total of 100 consecutive patients with severe AS, who underwent TAVR treatment and were followed up for more than 1 month, were selectedin the Second Xiangya Hospital of Central South University from January 2016 to December 2020.Among them, 5 patients who were treated with TAVR due to simple severe aortic regurgitation were not included, therefore a total of 95 patients with severe aortic stenosis were enrolled in this study.The age of the patients was (72.7±4.8) years old, and there were 58 males (61.1%), and the patients with moderate or above aortic regurgitation had 30 cases (31.6%). The patients were divided into a diabetic group and a non-diabetic group according to whether they were combined with T2DM.There was no statistical difference in age, gender, body mass index (BMI), STS score, and New York Heart Association (NYHA) cardiac function classification between the 2 groups (all P>0.05). The primary end point was defined as a composite event consisting of all-cause death and stroke one month after surgery, and the secondary end point was defined as TAVR-related complications immediately after surgery and one month after surgery.The preoperative clinical data, cardiac ultrasound data, CT data, postoperative medication and the incidence of each endpoint event were compared between the 2 groups.The predictive model of adverse events was constructed by single factor and multivariate logistic regression. RESULTS: Compared with the non-diabetic group, the diabetic group had high blood pressure and chronic renal insufficiency.There was no significant difference in preoperative ultrasound echocardiography between the 2 groups. Preoperative CT evaluation found that the anatomical structure of the aortic root in the diabetic group was smaller than that in the non-diabetic group, and there was no significant difference in the incidence of bicuspid aortic valve between the 2 groups (all P<0.05). In terms of postoperative medication, the use of statins in the diabetes group was significantly higher than that in the non-diabetic group. In the diabetes group, 6 patients (37.5%) received insulin therapy, and 9 patients (56.3%) received oral medication alone.Univariate logistic regression analysis showed that the all-cause death and stroke compound events was increased in the diabetes group in 30 days after TAVR (OR=6.86; 95% CI: 2.14 to 21.79; P<0.01). Heart disease (OR=2.80; 95% CI: 0.99 to 7.88; P<0.05) and chronic renal insufficiency (OR=3.75; 95% CI: 1.24 to 11.34; P<0.05) were also risk factors for all-cause death and stroke compound events.In a multivariate analysis, after adjusting for age, gender, BMI, comorbidities, N-terminal pro-B type natriuretic peptide (NT-proBNP), total calcification score, ejection fraction, and degree of aortic regurgitation, T2DM was still a risk factor for all-cause death and stroke compound events in 30 days after TAVR (OR=12.68; 95% CI: 1.76 to 91.41; P<0.05). CONCLUSIONS: T2DM is a risk factor for short-term poor prognosis in patients with symptomatic severe AS after TAVR treatment. T2DM should play an important role in the future construction of the TAVR surgical risk assessment system, but the conclusions still need to be further verified by long-term follow-up of large-scale clinical studies.

Dietary ω-3 fatty acids reduced atrial fibrillation vulnerability via attenuating myocardial endoplasmic reticulum stress and inflammation in a canine model of atrial fibrillation.

BACKGROUND: Dietary consumption of ω-3 fatty acids is correlated with a reduced incidence of cardiovascular events. Here, we investigated the effect of dietary ω-3 fatty acids on atrial fibrillation (AF) vulnerability in a canine model of AF and explored the related mechanisms. METHODS: Twenty four male beagle dogs (weight, 8-10 kg) were randomly divided into four groups: (a) sham-operated group (normal chow); (b) AF+FO [AF and normal chow supplemented with fish oil (FO): 0.6 g n-3 polyunsaturated fatty acids (ω-3 PUFA) /kg/day]; (c) AF group (normal chow); (d) sham-operated FO group (chow supplemented with FO: 0.6 g ω-3 PUFA/kg/day). AF was induced by rapid atrial pacing (RAP: 400 bpm for 4 weeks). Daily oral administration of FO was initiated 1 week before surgery and continued for 4 weeks post operation. RESULTS: Atrial electric remodeling was significantly attenuated and AF vulnerability were significantly reduced in AF+FO group compared to AF group. Endoplasmic reticulum (ER) stress-related protein expression levels of glucose-regulated protein78, C/EBP homologous protein, cleaved-Caspase12, and phosphorylation of protein kinase R-like ER kinase as well as inflammatory cytokines interleukin-1ß, interleukin-6, tumor necrosis factor-α in left atrium (LA) were significantly downregulated in AF+FO group than in AF group (all p<0.05). In addition, Masson staining revealed lower extent of LA interstitial fibrosis in AF+FO group than in AF group (p<0.01). Myocardial apoptosis was also significantly reduced in AF+FO group than in AF group (p<0.05). CONCLUSIONS: Dietary ω-3 fatty acids could significantly reduce RAP-induced AF vulnerability, possibly via attenuating myocardial ER stress, inflammation, and apoptosis in this canine model of AF.

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Triggers Vascular Smooth Muscle Cell Senescence and Apoptosis: Implication of Its Direct Role in Degenerative Vascular Disease.

OBJECTIVE: PCSK9 (proprotein convertase subtilisin/kexin type 9) plays a critical role in cholesterol metabolism via the PCSK9-LDLR (low-density lipoprotein receptor) axis in the liver; however, evidence indicates that PCSK9 directly contributes to the pathogenesis of various diseases through mechanisms independent of its LDL-cholesterol regulation. The objective of this study was to determine how PCSK9 directly acts on vascular smooth muscle cells (SMCs), contributing to degenerative vascular disease. Approach and Results: We first examined the effects of PCSK9 on cultured human aortic SMCs. Overexpression of PCSK9 downregulated the expression of ApoER2 (apolipoprotein E receptor 2), a known target of PCSK9. Treatment with soluble recombinant human ApoER2 or the DNA synthesis inhibitor, hydroxyurea, inhibited PCSK9-induced polyploidization and other cellular responses of human SMCs. Treatment with antibodies against ApoER2 resulted in similar effects to those observed with PCSK9 overexpression. Inducible, SMC-specific knockout of Pcsk9 accelerated neointima formation in mouse carotid arteries and reduced age-related arterial stiffness. PCSK9 was expressed in SMCs of human atherosclerotic lesions and abundant in the "shoulder" regions of vulnerable atherosclerotic plaques. PCSK9 was also expressed in SMCs of abdominal aortic aneurysm, which was inversely related to the expression of smooth muscle α-actin. CONCLUSIONS: Our findings demonstrate that PCSK9 inhibits proliferation and induces polyploidization, senescence, and apoptosis, which may be relevant to various degenerative vascular diseases.

Combination of Antioxidant Enzyme Overexpression and N-Acetylcysteine Treatment Enhances the Survival of Bone Marrow Mesenchymal Stromal Cells in Ischemic Limb in Mice With Type 2 Diabetes.

Background Therapy with mesenchymal stem cells remains a promising but challenging approach to critical limb ischemia in diabetes because of the dismal cell survival. Methods and Results Critical limb ischemia in type 2 diabetes mouse model was used to explore the impact of diabetic limb ischemia on the survival of bone marrow mesenchymal stromal cells (bMSCs). Inhibition of intracellular reactive oxygen species was achieved with concomitant overexpression of superoxide dismutase (SOD)-1 and glutathione peroxidase-1 in the transplanted bMSCs, and extracellular reactive oxygen species was attenuated using SOD-3 overexpression and N-acetylcysteine treatment. In vivo optical fluorescence imaging and laser Doppler perfusion imaging were used to track cell retention and determine blood flow in diabetic ischemic limb, respectively. Survival of the transplanted bMSCs was significantly decreased in diabetic ischemic limb compared with the control. In vitro study indicated that advanced glycation end products, not high glucose, significantly decreased the proliferation of bMSCs and increased their apoptosis associated with increased reactive oxygen species production and selective reduction of SOD-1 and SOD-3. In vivo study demonstrated that concomitant overexpression of SOD-1, SOD-3, and glutathione peroxidase-1, or host treatment with N-acetylcysteine, significantly enhanced in vivo survival of transplanted bMSCs, and improved critical limb ischemia in diabetic mice. Combination of triple antioxidant enzyme overexpression in bMSCs with host N-acetylcysteine treatment further improved bMSC survival with enhanced circulatory and functional recovery from diabetic critical limb ischemia. Conclusions Simultaneous suppression of reactive oxygen species from transplanted bMSCs and host tissue could additively enhance bMSC survival in diabetic ischemic limb with increased therapeutic efficacy in diabetes.

N-acetyl cysteine ameliorates aortic fibrosis by promoting M2 macrophage polarization in aging mice.

Background: Vascular fibrosis is a universal phenomenon associated with aging, and oxidative stress plays an important role in the genesis of vascular damage in line with the aging process. However, whether antioxidants can ameliorate vascular fibrosis remains unclear.Objectives: The present study was to determine antioxidant N-acetylcysteine (NAC) could ameliorates aortic fibrosis in aging wild-type C57BL/6 mice.Methods: The aortas were harvested from both 12-week and 60-week wild-type mice. The 60-week mice were treated with and without the NAC for 12 weeks starting at the age of 48 weeks. Hematoxylin and eosin (H&E) staining and Masson's trichrome staining of aortic samples were performed, and the levels of reactive oxygen species (ROS), RNA expression of GAPDH, TNF-α, MCP-1, IL-6, IL-10, IL-4, SIRT-1, SIRT-3, FOXO-1, and macrophage polarization were determined.Results: There is a positive relationship between collagen deposition and the M1/M2 macrophage ratio in the aortic wall of aged wild-type C57BL/6 mice. The higher collagen area percentage in the aortas of 60-week-old mice than in 12-week-old mice was reversed by NAC. NAC could not impact the total number of macrophages, but partly promoted M2 macrophage polarization. By performing qRT-PCR using aortic samples from these mice, we identified that SIRT-1, SIRT-3, FOXO-1 could be somehow responsible for aging-related fibrosis.Conclusions: NAC ameliorates aortic fibrosis in aging wild type mice partly by promoting M2 macrophage polarization.