Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia.

BACKGROUND: The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents. METHODS: We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant. Arterial ligation or wire injury was used to induce neointima in mice, whereas ApoE-/- and LDLR-/- (LDLR [low-density lipoprotein receptor]) mice fed a high-fat diet were applied to assess atherosclerosis. In addition, coronary stent implantation was performed on vaccine-immunized Bama miniature pigs, followed by optical coherence tomography to evaluate coronary intimal hyperplasia. RESULTS: A vaccine, ATS7vac, was screened out from 3 candidates to effectively inhibit intimal thickening in murine carotid artery ligation models after vaccination. As well, immunization with ATS7vac alleviated neointima formation in murine wire injury models and mitigated atherosclerotic lesions in both hyperlipidemic ApoE-/- and LDLR-/- mice without lowering lipid levels. Preclinically, ATS7vac markedly impeded intimal hyperplasia in swine stented coronary arteries, but without significant immune-related organ injuries. Mechanistically, ATS7vac vaccination produced specific antibodies against ADAMTS-7, which markedly repressed ADAMTS-7-mediated COMP (cartilage oligomeric matrix protein) and TSP-1 (thrombospondin-1) degradation and subsequently inhibited vascular smooth muscle cell migration but promoted re-endothelialization. CONCLUSIONS: ATS7vac is a novel atherosclerosis vaccine that also alleviates in-stent restenosis. The application of ATS7vac would be a complementary therapeutic avenue to the current lipid-lowering strategy for atherosclerotic disease.

Insulin resistance, coronary artery lesion complexity and adverse cardiovascular outcomes in patients with acute coronary syndrome.

BACKGROUND: Insulin resistance (IR) is linked to both the complexity of coronary artery lesions and the prognosis of acute coronary syndrome (ACS). However, the precise extent of this correlation and its impact on adverse cardiovascular outcomes in ACS patients remain unclear. Therefore, this study aims to investigate the intricate relationship between IR, coronary artery lesion complexity, and the prognosis of ACS through a cohort design analysis. METHOD: A total of 986 patients with ACS who underwent percutaneous coronary intervention (PCI) were included in this analysis. IR was assessed using the triglyceride-glucose (TyG) index, while coronary artery lesion complexity was evaluated using the SYNTAX score. Pearson's correlation coefficients were utilized to analyze the correlations between variables. The association of the TyG index and SYNTAX score with major adverse cardiovascular events (MACEs) in ACS was investigated using the Kaplan-Meier method, restricted cubic splines (RCS), and adjusted Cox regression. Additionally, a novel 2-stage regression method for survival data was employed in mediation analysis to explore the mediating impact of the SYNTAX score on the association between the TyG index and adverse cardiovascular outcomes, including MACEs and unplanned revascularization. RESULTS: During a median follow-up of 30.72 months, 167 cases of MACEs were documented, including 66 all-cause deaths (6.69%), 26 nonfatal myocardial infarctions (MIs) (2.64%), and 99 unplanned revascularizations (10.04%). The incidence of MACEs, all-cause death, and unplanned revascularization increased with elevated TyG index and SYNTAX score. Both the TyG index (non-linear, P = 0.119) and SYNTAX score (non-linear, P = 0.004) displayed a positive dose-response relationship with MACEs, as illustrated by the RCS curve. Following adjustment for multiple factors, both the TyG index and SYNTAX score emerged as significant predictors of MACEs across the total population and various subgroups. Mediation analysis indicated that the SYNTAX score mediated 25.03%, 18.00%, 14.93%, and 11.53% of the correlation between the TyG index and MACEs in different adjusted models, respectively. Similar mediating effects were observed when endpoint was defined as unplanned revascularization. CONCLUSION: Elevated baseline TyG index and SYNTAX score were associated with a higher risk of MACEs in ACS. Furthermore, the SYNTAX score partially mediated the relationship between the TyG index and adverse cardiovascular outcomes.

Association between the triglyceride glucose index and in-hospital and 1-year mortality in patients with chronic kidney disease and coronary artery disease in the intensive care unit.

OBJECTIVE: This study aimed to explore the association between the triglyceride glucose index (TyG) and the risk of in-hospital and one-year mortality in patients with chronic kidney disease (CKD) and cardiovascular disease (CAD) admitted to the intensive care unit (ICU). METHODS: The data for the study were taken from the Medical Information Mart for Intensive Care-IV database which contained over 50,000 ICU admissions from 2008 to 2019. The Boruta algorithm was used for feature selection. The study used univariable and multivariable logistic regression analysis, Cox regression analysis, and 3-knotted multivariate restricted cubic spline regression to evaluate the association between the TyG index and mortality risk. RESULTS: After applying inclusion and exclusion criteria, 639 CKD patients with CAD were included in the study with a median TyG index of 9.1 [8.6,9.5]. The TyG index was nonlinearly associated with in-hospital and one-year mortality risk in populations within the specified range. CONCLUSION: This study shows that TyG is a predictor of one-year mortality and in-hospital mortality in ICU patients with CAD and CKD and inform the development of new interventions to improve outcomes. In the high-risk group, TyG might be a valuable tool for risk categorization and management. Further research is required to confirm these results and identify the mechanisms behind the link between TyG and mortality in CAD and CKD patients.

Predictive value of the stress hyperglycemia ratio in dialysis patients with acute coronary syndrome: insights from a multi-center observational study.

BACKGROUND: Various studies have indicated that stress hyperglycemia ratio (SHR) can reflect true acute hyperglycemic status and is associated with poor outcomes in patients with acute coronary syndrome (ACS). However, data on dialysis patients with ACS are limited. The Global Registry of Acute Coronary Events (GRACE) risk score is a well-validated risk prediction tool for ACS patients, yet it underestimates the risk of major events in patients receiving dialysis. This study aimed to evaluate the association between SHR and adverse cardiovascular events in dialysis patients with ACS and explore the potential incremental prognostic value of incorporating SHR into the GRACE risk score. METHODS: This study enrolled 714 dialysis patients with ACS from January 2015 to June 2021 at 30 tertiary medical centers in China. Patients were stratified into three groups based on the tertiles of SHR. The primary outcome was major adverse cardiovascular events (MACE), and the secondary outcomes were all-cause mortality and cardiovascular mortality. RESULTS: After a median follow-up of 20.9 months, 345 (48.3%) MACE and 280 (39.2%) all-cause mortality occurred, comprising 205 cases of cardiovascular death. When the highest SHR tertile was compared to the second SHR tertile, a significantly increased risk of MACE (adjusted hazard ratio, 1.92; 95% CI, 1.48-2.49), all-cause mortality (adjusted hazard ratio, 2.19; 95% CI, 1.64-2.93), and cardiovascular mortality (adjusted hazard ratio, 2.70; 95% CI, 1.90-3.83) was identified in the multivariable Cox regression model. A similar association was observed in both diabetic and nondiabetic patients. Further restricted cubic spline analysis identified a J-shaped association between the SHR and primary and secondary outcomes, with hazard ratios for MACE and mortality significantly increasing when SHR was > 1.08. Furthermore, adding SHR to the GRACE score led to a significant improvement in its predictive accuracy for MACE and mortality, as measured by the C-statistic, net reclassification improvement, and integrated discrimination improvement, especially for those with diabetes. CONCLUSIONS: In dialysis patients with ACS, SHR was independently associated with increased risks of MACE and mortality. Furthermore, SHR may aid in improving the predictive efficiency of the GRACE score, especially for those with diabetes. These results indicated that SHR might be a valuable tool for risk stratification and management of dialysis patients with ACS.

The triglyceride-glucose index predicts 1-year major adverse cardiovascular events in end-stage renal disease patients with coronary artery disease.

BACKGROUND: The triglyceride-glucose (TyG) index has been suggested as a dependable indicator for predicting major adverse cardiovascular events (MACE) in individuals with cardiovascular conditions. Nevertheless, there is insufficient data on the predictive significance of the TyG index in end-stage renal disease (ESRD) patients with coronary artery disease (CAD). METHODS: This study, conducted at multiple centers in China, included 959 patients diagnosed with dialysis and CAD from January 2015 to June 2021. Based on the TyG index, the participants were categorized into three distinct groups. The study's primary endpoint was the combination of MACE occurring within one year of follow-up, including death from any cause, non-fatal myocardial infarction, and non-fatal stroke. We assessed the association between the TyG index and MACE using Cox proportional hazard models and restricted cubic spline analysis. The TyG index value was evaluated for prediction incrementally using C-statistics, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: The three groups showed notable variations in the risk of MACE (16.3% in tertile 1, 23.5% in tertile 2, and 27.2% in tertile 3; log-rank P = 0.003). Following complete adjustment, patients with the highest TyG index exhibited a notably elevated risk of MACE in comparison to those in the lowest tertile (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.14-2.35, P = 0.007). Likewise, each unit increase in the TyG index correlated with a 1.37-fold higher risk of MACE (HR 1.37, 95% CI 1.13-1.66, P = 0.001). Restricted cubic spline analysis revealed a connection between the TyG index and MACE (P for nonlinearity > 0.05). Furthermore, incorporating the TyG index to the Global Registry of Acute Coronary Events risk score or baseline risk model with fully adjusted factors considerably enhanced the forecast of MACE, as demonstrated by the C-statistic, continuous NRI, and IDI. CONCLUSIONS: The TyG index might serve as a valuable and dependable indicator of MACE risk in individuals with dialysis and CAD, indicating its potential significance in enhancing risk categorization in clinical settings.

Triglyceride-glucose index is associated with recurrent revascularization in patients with type 2 diabetes mellitus after percutaneous coronary intervention.

BACKGROUND: The Triglyceride-glucose (TyG) index, as a surrogate marker of insulin resistance, is independently associated with the severity of coronary artery lesions and the prognosis of coronary heart disease. The investigation aimed to explore the relationship between the TyG index and recurrent revascularization in individuals with type 2 diabetes mellitus (T2DM) resulting from the progression of lesions or in-stent restenosis (ISR) after percutaneous coronary intervention (PCI). METHOD: A total of 633 patients who met the inclusion and exclusion criteria were enrolled and divided into three groups based on the tertiles of the TyG index. The primary endpoint was recurrent revascularization resulting from the progression of lesions or ISR. All-cause death was considered as the competing risk event. Competing risk analysis and Cox regression analysis for predicting recurrent revascularization after PCI were conducted stepwise. Variables were standardized to make the hazard ratio (HR), subdistribution hazard ratio (SHR) and corresponding 95% CI more consistent prior to being used for fitting the multivariate risk model. The predictive ability of the TyG index was evaluated using several measures, including the ROC curve, likelihood ratio test, Akaike's information criteria, category-free continuous net reclassification improvement (cNRI > 0), and integrated discrimination improvement (IDI). Internal validation was conducted through bootstrapping with 1000 resamples. RESULTS: During a median follow-up period of 18.33 months, a total of 64 (10.11%) patients experienced recurrent revascularization, including 55 cases of lesion progression and 9 cases of in-stent restenosis. After controlling for competitive risk events, the TyG index was independently associated with a higher risk of recurrent revascularization [SHR:1.4345, (95% CI 1.1458-1.7959), P = 0.002]. The likelihood ratio test and Akaike's information criteria showed that the TyG index significantly improves the prognostic ability. Additionally, adding the TyG index improved the ability of the established risk model in predicting recurrent revascularization, indicated by a C-index of 0.759 (95% CI 0.724-0.792, P < 0.01), with a cNRI > 0 of 0.170 (95% CI 0.023-0.287, P < 0.05), and an IDI of 0.024 (95% CI 0.009-0.039, P = 0.002). These results remained consistent when the models containing TyG index were confirmed using an internal bootstrap validation method. CONCLUSION: The findings highlight the potential of the TyG index as a predictor of recurrent revascularization. Lesion progression emerged as the primary contributor to recurrent revascularization instead of in-stent restenosis. The incorporation of the TyG index into risk prediction models is likely to be beneficial for accurate risk stratification in order to improve prognosis.

Ischemia preconditioning alleviates ischemia/reperfusion injury-induced coronary no-reflow and contraction of microvascular pericytes in rats.

BACKGROUND: Ischemia preconditioning (IPC) ameliorates coronary no-reflow induced by ischemia/reperfusion (I/R) injury, and pericytes play an important role in microvascular function. However, it is unclear whether IPC exerts a protective effect on coronary microcirculation and regulates the pericytes. OBJECTIVE: The purpose of this study was to assess whether IPC improves coronary microvascular perfusion and reduces pericyte constriction after myocardial I/R injury. METHODS: Rats were randomly divided into three groups: the sham group, the I/R group, and the IPC + I/R group. The left anterior descending artery (LAD) of rats in the I/R group were ligated for 45 min, and the rats in the IPC + I/R group received 4 episodes of 6min occlusion followed by 6min reperfusion before the LAD was ligated. After 24 h of reperfusion, the area of no-reflow, and area at risk were evaluated with thioflavin-S and Evens blue staining, and infarct size with triphenyl tetrazolium chloride staining, respectively. Besides, fluorescent microspheres were perfused to enable visualization of the non-obstructed coronary vessels. Cardiac pericytes and microvascular were observed by immunofluorescence, and the diameter of microvascular at the site of the pericyte somata was analyzed. RESULTS: The infarct size, and area of no-reflow in the IPC + I/R group were significantly reduced compared with the I/R group (infarct size, 33.5% ± 11.9% vs. 49.2% ± 9.4%, p = 0.021；no-reflow, 12.7% ± 5.2% vs. 26.6% ± 5.0%, p < 0.001). IPC improved microvascular perfusion and reduced the percentage of the blocked coronary capillary. Moreover, we found that cardiac pericytes were widely distributed around the microvascular in various regions of the heart, and expressed the contractile protein α-smooth muscle actin. The microvascular lumen diameter at pericyte somata was reduced after I/R (4.3 ± 1.0 µm vs. 6.5 ± 1.2 µm, p < 0.001), which was relieved in IPC + I/R group compared with the I/R group (5.2 ± 1.0 µm vs. 4.3 ± 1.0 µm, p < 0.001). Besides, IPC could reduce the proportion of apoptotic pericytes compared to the I/R group (22.1% ± 8.4% vs. 38.5% ± 7.5%, p < 0.001). CONCLUSION: IPC reduced no-reflow and inhibited the contraction of microvascular pericytes induced by cardiac I/R injury, suggesting that IPC might play a protective role by regulating the pericyte function.

The triglyceride glucose index is associated with future cardiovascular disease nonlinearly in middle-aged and elderly Chinese adults.

OBJECTIVE: We aimed to investigate the association between triglyceride glucose index and cardiovascular disease (CVD) development in the Chinese middle-aged and elderly population using the China Health and Retirement Longitudinal Study dataset 2011-2018. METHODS: Basic characteristics of participants, including sociodemographic information, and health conditions, were acquired. Logistic regression analyses and restricted cubic spline regression analyses were conducted to investigate the association between the triglyceride glucose index and future CVD risks. Subgroup analyses were performed to evaluate potential interaction. RESULTS: Seven hundred fifty-three of 6114 (12.3%) participants have developed CVD in 2018 over an approximately 7-year follow-up. The logistic regression analysis exhibited that compared to the lowest triglyceride glucose index group, the multivariable OR for future CVD was 0.985 (95%CI 0.811-1.198) in the T2 triglyceride glucose index group and 1.288 (95%CI 1.068-1.555) in the T3 TyG index (P for trend 0.006). The restricted cubic spline regression analysis showed the nonlinear association between triglyceride glucose index and CVD incidence; the cut-off values were 8.07 and 8.57, respectively, after total adjustment. Gender, fast blood glucose, and triglycerides interacted with triglyceride glucose index and CVD except for BMI. CONCLUSION: The triglyceride glucose index was nonlinearly related to the risk of future cardiovascular disease in the middle-aged and elderly Chinese population.

Triglyceride glucose index exacerbates the risk of future cardiovascular disease due to diabetes: evidence from the China Health and Retirement Longitudinal Survey (CHARLS).

OBJECTIVE: We aimed to investigate the effect of the triglyceride glucose (TyG) index on the association between diabetes and cardiovascular disease (CVD). METHODS: Data from 6,114 individuals were extracted and analyzed from the China Health and Retirement Longitudinal Survey (CHARLS) from 2011 to 2018. Logistic regression analyses were conducted to assess the relationship between diabetes and CVD across the various TyG index groups. The statistical method of subgroup analysis was used to determine the correlation between diabetes and CVD for each TyG index group by sex, history of hypertension and dyslipidemia, smoking, and drinking. RESULTS: Diabetes was positively associated with CVD risk after adjustment in 2011(odds ratio (OR) 1.475, 95% CI 1.243-1.752, P < 0.001). There was a gradient increase in the OR for new-onset CVD in 2018 due to diabetes at baseline across the value of the TyG index based on a fully adjusted model (P for trend < 0.05). The ORs of diabetes at baseline for CVD in 2018 were 1.657 (95% CI 0.928-2.983, P = 0.098), 1.834(95% CI 1.064-3.188, P = 0.037) and 2.234(95% CI 1.349-3.673, P = 0.006) for T1, T2 and T3 of the TyG index respectively. The gradient of increasing risk of CVD still existed among those with hypertension and nondrinkers in the subgroup analysis. CONCLUSION: Elevated TyG index strengthens the correlation between diabetes mellitus and CVD in middle-aged and elderly Chinese adults.

Association between serum alpha-Klotho and severe abdominal aortic calcification among civilians in the United States.

BACKGROUND AND AIMS: Abdominal aortic calcification (AAC) has been recognized as an independent predictor of cardiovascular disease (CVD) incidence and mortality. The aim of this cross-sectional study is to investigate the relationship between serum α-Klotho, an anti-aging hormone, and severe AAC in United States (US) civilians, which was not documented before. METHODS AND RESULTS: The data were obtained from the 2013-2014 National Health and Nutrition Examination Survey (NHANES), which included 2267 individuals aged 40-79 years. Serum α-Klotho concentration, categorized into four quartiles, was examined by enzyme linked immunosorbent assay (ELISA). AAC was quantified by the Kauppila score system based on dual-energy X-ray absorptiometry. The association between serum α-Klotho and severe AAC was determined by multivariable logistic regression models. After adjusting for multiple covariates, the odds ratios (OR) (95% CI) of severe AAC for participants in serum α-Klotho quartiles 2-4 were 0.83 (0.52, 1.32), 0.56 (0.34, 0.94), and 0.54 (0.32, 0.92), respectively, compared with those in quartile 1 (P for trend = 0.007). The association between serum α-Klotho and severe AAC was stable in the different subgroups (all P for interaction＞0.05). CONCLUSION: In a sample of US adults, serum α-Klotho levels were negatively related to the risk of severe AAC. Our findings indicated that serum α-Klotho may become a promising tool to predict the incidence and prognosis of CVD.

Interleukin-7 aggravates myocardial ischaemia/reperfusion injury by regulating macrophage infiltration and polarization.

Interleukin (IL)-7 is known to enhance the macrophages cytotoxic activity and that macrophages play a pivotal role in the development and progression of myocardial ischaemia/reperfusion (I/R) injury. However, the effects of IL-7 on macrophages infiltration and polarization in myocardial I/R injury are currently unclear. This study aimed to evaluate the effects of the IL-7 expression on myocardial I/R injury and their relationship with macrophages. The data showed that IL-7 expression in mouse heart tissue increases following I/R injury and that IL-7 knockout or anti-IL-7 antibody treatment significantly improve I/R injury, including reduction in myocardial infarction area, a serum troponin T level decreases and an improvement in cardiac function. On the other hand, recombinant IL-7 (rIL-7) supplementation induces opposite effects and the anti-IL-7 antibody significantly reduces the cardiomyocyte apoptosis and macrophage infiltration. rIL-7 cannot directly cause apoptosis, but it can induce cardiomyocyte apoptosis through macrophages, in addition to increase the macrophages migration in vitro. Anti-IL-7 antibody affects the cytokine production in T helper (Th) 1 and Th2 cells and also promotes the macrophages differentiation to M2 macrophages. However, anti-IL-7 antibody does not reduce the M1 macrophage number, and it only increases the ratio of M2/M1 macrophages in mice heart tissues after I/R injury. Taking together, these data reveal that IL-7 plays an intensifying role in myocardial I/R injury by promoting cardiomyocyte apoptosis through the regulation of macrophage infiltration and polarization.

Double Ionic-Electronic Transfer Interface Layers for All-Solid-State Lithium Batteries.

Large-scale implementation of all-solid-state lithium batteries is impeded by the physical limitations of the interface between the electrode and solid electrolyte; specifically, high resistance and poor stability, as well as poor compatibility with Li+ migration. We report double ionic-electronic transfer interface layers grown at electrode-electrolyte interfaces by in situ polymerization of 2,2'-bithiophene in polyethylene oxide (PEO) electrolyte. For all-solid-state LiFePO4 ∥PT-PEO-PT∥Li cells, the formation of a conductive polythiophene (PT) layer at the cathode-electrolyte interface resulted in an at least sevenfold decrease in interface resistance, and realized a capacity retention of about 94 % after 1000 cycles along with a lower polarization voltage under a rate of 2 C. The mixed ionic-electronic conductive layers imparted superior interface stability and contact while keeping good compatibility with the Li anode.

Impact of Prior Ischemic Stroke on Outcomes in Patients With Heart Failure　- A Propensity-Matched Study.

BACKGROUND: Whether ischemic stroke per se, rather than older age or additional comorbidities, accounts for the adverse prognosis of heart failure (HF) is uncertain. The present study examineed the intrinsic association of ischemic stroke with outcomes in a propensity-matched cohort.Methods and Results:Of 1,351 patients hospitalized with HF, 388 (28.7%) had prior ischemic stroke. Using propensity score for prior ischemic stroke, estimated for each patient, a matched cohort of 379 pairs of HF patients with and without prior ischemic stroke, balanced on 32 baseline characteristics was assembled. At 30 days, prior ischemic stroke was associated with significantly higher risks of the combined endpoint of all-cause death or readmission (hazard ratio [HR]: 1.91; 95% confidence interval [CI]: 1.38 to 2.65; P<0.001), all-cause death (HR: 2.08; 95% CI: 1.28 to 3.38; P=0.003), all-cause readmission (HR: 2.67; 95% CI: 1.78 to 4.01; P<0.001), and HF readmission (HR: 2.11; 95% CI: 1.19 to 3.72; P=0.010). Prior ischemic stroke was associated with a significantly higher risk of all 4 outcomes at both 6 months and 1 year. CONCLUSIONS: Prior ischemic stroke was a potent and persistent risk predictor of death and readmission among patients with HF after accounting for clinical characteristics.

Smooth Muscle Sirtuin 1 Blocks Thoracic Aortic Aneurysm/Dissection Development in Mice.

PURPOSE: Advancing age is the major risk factor for thoracic aortic aneurysm/dissection (TAAD). However, the causative link between age-related molecules and TAAD remains elusive. Here, we investigated the role of Sirtuin 1 (SIRT1, also known as class III histone deacetylase), the best studied member of the longevity-related Sirtuin family, in TAAD development in vivo. METHODS: We used male smooth muscle-specific SIRT1 transgenic (ST-Tg) mice, smooth muscle-specific SIRT1 knockout (ST-KO) mice, and their wild-type (WT) littermates on a C57BL/6J background to establish a TAAD model induced by oral administration of 3-aminopropionitrile fumarate (BAPN). We analyzed the incidence and fatality rates of TAAD in the groups. We examined matrix metallopeptidase 2 (MMP2) and MMP9 expression in aortas or cultured A7r5 cells via western blotting and real-time polymerase chain reaction (PCR). We performed chromatin immunoprecipitation (ChIP) to clarify the epigenetic mechanism of SIRT1-regulated MMP2 expression in vascular smooth muscle cells (VSMCs). RESULTS: BAPN treatment markedly increased the incidence of TAAD in WT mice but caused less disease in ST-Tg mice. Moreover, ST-KO mice had the highest BAPN-induced TAAD fatality rate of all the groups. Mechanistically, SIRT1 overexpression resulted in lower MMP2 and MMP9 expression after BAPN treatment in both mouse aortas and cultured A7r5 cells. The downregulation of BAPN-induced MMP2 expression by SIRT1 was mediated by deacetylation of histone H3 lysine 9 (H3K9) on the Mmp2 promoter in the A7r5 cells. CONCLUSION: Our findings suggest that SIRT1 expression in SMCs protects against TAAD and could be a novel therapeutic target for TAAD management.

Naringenin Ameliorates Renovascular Hypertensive Renal Damage by Normalizing the Balance of Renin-Angiotensin System Components in Rats.

Background: Naringenin, a member of the dihydroflavone family, has been shown to have a protective function in multiple diseases. We previously demonstrated that naringenin played a protective role in hypertensive myocardial hypertrophy by decreasing angiotensin-converting enzyme (ACE) expression. The kidney is a primary target organ of hypertension. The present study tested the effect of naringenin on renovascular hypertensive kidney damage and explored the underlying mechanism. Methods and Results: An animal model of renovascular hypertension was established by performing 2-kidney, 1-clip (2K1C) surgery in Sprague Dawley rats. Naringenin (200 mg/kg/day) or vehicle was administered for 10 weeks. Blood pressure and urinary protein were continuously monitored. Plasma parameters, renal pathology and gene expression of nonclipped kidneys were evaluated by enzyme-linked immunosorbent assay, histology, immunohistochemistry, real-time polymerase chain reaction, and Western blot at the end of the study. Rats that underwent 2K1C surgery exhibited marked elevations of blood pressure and plasma Ang II levels and renal damage, including mesangial expansion, interstitial fibrosis, and arteriolar thickening in the nonclipped kidneys. Naringenin significantly ameliorated hypertensive nephropathy and retarded the rise of Ang II levels in peripheral blood but had no effect on blood pressure. 2K1C rats exhibited increases in the ACE/ACE2 protein ratio and AT1R/AT2R protein ratio in the nonclipped kidney compared with sham rats, and these increases were significantly suppressed by naringenin treatment. Conclusions: Naringenin attenuated renal damage in a rat model of renovascular hypertension by normalizing the imbalance of renin-angiotensin system activation. Our results suggest a potential treatment strategy for hypertensive nephropathy.

Effect of Intensive Blood Pressure Control on Carotid Morphology and Hemodynamics in Chinese Patients with Hyperhomocysteinemia-Type Hypertension and High Risk of Stroke.

BACKGROUND Different blood pressure targets should be formulated for different groups of people. This study aimed to assess the effectiveness of intensive blood control in improving the carotid morphology and hemodynamics in Chinese patients with hyperhomocysteinemia-type hypertension and high risk of stroke. MATERIAL AND METHODS Chinese hypertensive patients with high risk of stroke were randomized to intensive (n=187) and standard (n=192; controls) blood pressure management groups. Systolic blood pressure (SBP) targets were 100< SBP ≤120 and 120< SBP ≤140 mmHg, respectively. All patients received folic acid 0.8 mg/d and atorvastatin 20 mg/d. Calcium antagonist was first used. If blood pressure was still uncontrolled, angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist, ß-receptor blocker, and diuretics were added successively. Follow-up was 12 months. Carotid features, hemodynamics, and adverse events were examined. RESULTS There were no differences in sex, age, body mass index, blood lipids, baseline carotid parameters, and histories of smoking, diabetes, statin use, and stroke between the 2 groups. Carotid plaques after 12 months of treatment were 19.4±2.1 and 23.6±3.1 cm² for the intensive and control groups, respectively (P=0.038). Plaque scores were lower in the intensive group (1.75±0.52 vs. 2.45±0.47, P=0.023). Compared with controls, intensive management resulted in relatively higher Vd and significantly lower Vs/Vd, PI, and RI (all P<0.05). Major adverse events such as hypotension (n=5 (2.7%) vs. 3 (1.6%), P=0.020) and dizziness (n=20 (10.7%) vs. 16 (8.3%), P=0.041) were more frequent in the intensive group. CONCLUSIONS Intensive blood pressure management could be beneficial for Chinese patients with hyperhomocysteinemia-type hypertension and high risk of stroke.

Postnatal deficiency of ADAMTS1 ameliorates thoracic aortic aneurysm and dissection in mice.

NEW FINDINGS: What is the central question of this study? Thoracic aortic aneurysm and dissection (TAAD) is characterized by extracellular matrix remodelling and an inflammatory response. Evidence suggests that ADAMTS1 is closely associated with TAAD development, but whether it contributes to the pathophysiology of TAAD remains unknown. What is the main finding and its importance? We generated inducible postnatal ADAMTS1 knockout mice and found that ADAMTS1 deficiency attenuated ß-aminopropionitrile-dependent TAAD formation and rupture. Furthermore, ADAMTS1 deficiency suppressed neutrophil and macrophage infiltration by inhibiting inflammatory cytokine levels and macrophage migration during the early stage of ß-aminopropionitrile-induced TAAD. ADAMTS1 could be a new therapeutic target for TAAD. ABSTRACT: Thoracic aortic aneurysm and dissection (TAAD), as a life-threatening cardiovascular disease, is characterized by extracellular matrix remodelling and an inflammatory response. A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) is an inflammation-related protein that is able to degrade extracellular matrix proteins in arteries. Herein, we investigated whether ADAMTS1 contributes to the pathophysiology of TAAD in mice. Using the mouse model of ß-aminopropionitrile (BAPN)-induced TAAD, we found that ADAMTS1 expression was upregulated beginning in the early stage of TAAD development and localized predominantly in the aortic adventitia. ADAMTS1-floxed mice and whole-body tamoxifen-inducible ADAMTS1 knockout mice (ADAMTS1flox/flox Ubc-CreERT2+ , ADAMTS1 KO) were generated to investigate the direct causal role of ADAMTS1 in TAAD development. The incidence and rupture rates of BAPN-induced TAAD in ADAMTS1 KO mice were significantly lower than those in ADAMTS1flox/flox mice (45.5 versus 81.8% and 18.2 versus 42.4%, respectively). Aortas from BAPN-treated ADAMTS1flox/flox mice displayed profound destruction of the elastic lamellae, abundant neutrophil and macrophage accumulation in the adventitia, obviously increased neutrophil proportions in peripheral blood and significantly increased expression of inflammatory factors in the early stage of TAAD induction, all of which were markedly suppressed in ADAMTS1 KO mice. Furthermore, ADAMTS1-deficient macrophages exhibited abrogated migration capacity both in vivo and in vitro. In conclusion, ADAMTS1 plays a crucial role in postnatal TAAD formation and rupture by regulating inflammatory responses, suggesting that ADAMTS1 might be a new therapeutic target for TAAD.

Acute coronary syndrome secondary to allergic coronary vasospasm (Kounis Syndrome): a case series, follow-up and literature review.

BACKGROUND: Kounis syndrome (KS) is the concurrence of acute coronary syndrome associated with mast-cell and platelet activation in the setting of hypersensitivity and allergic or anaphylactic insults. Many drugs and environmental exposures had been reported as inducers, but various inducers and the mechanism of KS remained unknown till now. The widely used traditional Chinese medicine (TCM) as a potential sensitizer were scarcely reported to induce allergic vasospasm due to the ignorance of the linkage between traditional medicine allergy and vasospasm. CASE PRESENTATION: We described 5 rare cases of KS including unreported triggers of TCM and abortion, reported the treatment strategy and 1~4 years' follow-up results, and tried to probe into the etiology of KS. Case 1 and case 2 for the first time reported acute ST-segment elevation myocardial infarction (STEMI) caused by Chinese herbs related allergic coronary vasospasm. Case 3 reported recurrent angina following allergen contact and wheezing, indicating the internal linkage of coronary vasospasm and allergic asthma. Case 4 described a childbearing-age woman suffered refractory ischemic chest pain due to coronary vasospasm in a special period of post-abortion, the attacks suddenly disappeared when her menopause recovered. Case 5 described an isolated episode of allergic coronary vasospasm under exposure of smoking and stress, which was successfully prevented by avoiding the exposures. CONCLUSION: Kounis syndrome is not rare but rarely recognized and under-diagnosed. It is necessary to recognize KS and various inducers, especially for the patients suffering refractory vasospastic cardiac attacks concentrating in special periods. Blood test of eosinophil might contribute to diagnose KS and anti-allergic agents might be helpful for controlling KS attacks.

Admission homocysteine is an independent predictor of spontaneous reperfusion and early infarct-related artery patency before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction.

BACKGROUND: Spontaneous reperfusion (SR) and early infarct related artery (IRA) patency before primary percutaneous coronary intervention (PPCI) might bring extra benefit for patients with ST-segment elevation myocardial infarction (STEMI). This study premilinarily screened the independent predictors of SR, and assessed the relationship between SR and plasma homocysteine (HCY). METHODS: The medical records of 998 patients who were diagnosed as STEMI and underwent emergency coronary angiography were retrospectively studied, SR was defined as achievement of TIMI grade 3 flow in the IRA before PCI. The baseline characteristics, clinical manifestations and hematological variables were compared between SR and NSR group. Optimal cutoff point of HCY was calculated with receiving operating characteristics (ROC) analysis, multivariate logistic regression models were used to identify predictors of SR. RESULTS: 229 (22.95%) patients showed angiographic SR. For HCY, the area under the curve was 0.70 (95% CI: 0.63-0.77, P = 0.034), the optimized cut off point was 17.55 µmol/L. Preinfarct angina (95% CI: 1.61-5.65, P = 0.0005), plasma C-reactive protein (CRP) level (95% CI: 0.87-0.99, P = 0.016) and HCY < 17.55 µmol/L (95% CI: 2.43-8.72, P < 0.0001) were found to be independent predictors for SR. CONCLUSION: In patients with STEMI, HCY < 17.55 µmol/L, preinfarct angina and plasma CRP level were independent predictors of SR.

Anticoagulation after coronary stenting: a systemic review.

Introduction or background: Anticoagulant therapy is mainly used to prevent patients from suffering coronary and systemic thromboembolism after stenting. Many studies have been done to formulate an optimized regimen of a post-PCI or long-time anticoagulant therapy. Recent advances in the selection and duration of anticoagulant agents will be conducive to the management of patients who are considered to need anticoagulant therapy after stenting. Sources of data: Key recent published literature, including international guidelines and relevant reviews. Areas of agreement: Anticoagulant therapy has been acknowledged to improve the prognosis of patients after stenting by reducing the risk of coronary and systemic thromboembolism. Areas of controversy: Firstly, the benefit-risk ratio of post-PCI parenteral anticoagulation to prevent stent thrombosis locally in the coronary artery is still unclear. Secondly, the efficacy and safety of bivalirudin deserve to be discussed. Furthermore, the recommendation to use long-time oral anticoagulant therapy to prevent systemic thromboembolism after stenting should also be emphasized. Growing points: Studies of anticoagulant therapy in patients after stenting add to the understanding of an optimized anticoagulant regimen and contribute to improving clinical outcomes. Areas for developing research: The safety and efficacy of bivalirudin, a direct thrombin inhibitor, need to be further investigated by more large-scale randomized clinical trials.Based on the widespread use of ticagrelor and prasugrel for patients who need long-time oral anticoagulant therapy, further study is needed to find an optimal strategy that balances the risk of bleeding and ischemic events after coronary stenting.