Deletion of Sigmar1 leads to increased arterial stiffness and altered mitochondrial respiration resulting in vascular dysfunction.

Sigmar1 is a ubiquitously expressed, multifunctional protein known for its cardioprotective roles in cardiovascular diseases. While accumulating evidence indicate a critical role of Sigmar1 in cardiac biology, its physiological function in the vasculature remains unknown. In this study, we characterized the expression of Sigmar1 in the vascular wall and assessed its physiological function in the vascular system using global Sigmar1 knockout (Sigmar1-/-) mice. We determined the expression of Sigmar1 in the vascular tissue using immunostaining and biochemical experiments in both human and mouse blood vessels. Deletion of Sigmar1 globally in mice (Sigmar1-/-) led to blood vessel wall reorganizations characterized by nuclei disarray of vascular smooth muscle cells, altered organizations of elastic lamina, and higher collagen fibers deposition in and around the arteries compared to wildtype littermate controls (Wt). Vascular function was assessed in mice using non-invasive time-transit method of aortic stiffness measurement and flow-mediated dilation (FMD) of the left femoral artery. Sigmar1-/- mice showed a notable increase in arterial stiffness in the abdominal aorta and failed to increase the vessel diameter in response to reactive-hyperemia compared to Wt. This was consistent with reduced plasma and tissue nitric-oxide bioavailability (NOx) and decreased phosphorylation of endothelial nitric oxide synthase (eNOS) in the aorta of Sigmar1-/- mice. Ultrastructural analysis by transmission electron microscopy (TEM) of aorta sections showed accumulation of elongated shaped mitochondria in both vascular smooth muscle and endothelial cells of Sigmar1-/- mice. In accordance, decreased mitochondrial respirometry parameters were found in ex-vivo aortic rings from Sigmar1 deficient mice compared to Wt controls. These data indicate a potential role of Sigmar1 in maintaining vascular homeostasis.

Flow-Mediated Dilation, a Marker of Endothelial Cell Dysfunction, in Patients with Pulmonary Hypertension.

Background: Flow-mediated dilation (FMD) is considered a marker of endothelial cell dysfunction (ECD) and has been mostly evaluated in coronary artery disease. The role of ECD in the pathogenesis of pulmonary hypertension (PH) is not well-known. This study sought to evaluate the relationship between FMD and PH. Materials and Methods: In this cross-sectional study, the FMD of the brachial artery was measured in 40 confirmed PH patients. Meanwhile, echocardiographic findings, the 6-minute walk test (6MWT), and serum pro-brain natriuretic peptide (pro-BNP) level were evaluated. Overall, 20 patients accomplished all evaluations, and their data were analyzed using SPSS software (version 23). Results: There was an inverse relationship between pro-BNP and 6MWT (r<0, P<0.05). A significant direct relationship was observed between left ventricular ejection fraction and FMD (P=0.031). Right ventricular (RV) dilation was significantly correlated with pro-BNP (P=0.046). There was a significant direct correlation between RV function and FMD and a significant inverse relationship between pro-BNP and FMD (P=0.05). The independent t-test showed no relationship between FMD and syncope (P=0.75). Conclusion: Endothelial cell function, which can be evaluated by FMD, was involved in patients with PH. The FMD and 6MWT were helpful as objective prognostic markers in PH. Furthermore, pro-BNP was a noninvasive indicator in the diagnosis of RV systolic dysfunction.

A combined effect of Cavacurcumin, Eicosapentaenoic acid (Omega-3s), Astaxanthin and Gamma -linoleic acid (Omega-6) (CEAG) in healthy volunteers- a randomized, double-blind, placebo-controlled study.

BACKGROUND: Inflammation plays a key role and is one of the early steps in the pathogenesis of endothelial function, thereby increasing the risk of hypertension (HTN), coronary artery disease (CAD), stroke and several other risk factors of cardiovascular disease (CVD). We assessed the efficacy for improving cardiovascular health (blood pressure, inflammation and endothelial reactivity) over a 4-week intervention period in healthy individuals. METHODS: We performed a randomized, double-blinded, placebo-controlled, randomized clinical trial to investigate Curcumin, Eicosapentaenoic acid (EPA), Astaxanthin and Gamma -linoleic acid (GLA) (CEAG) supplements with 80 individuals (30 men and 50 women). The mean age of participants was 48.8 ± 16.0 years. Participants were enrolled and randomized to active or placebo and followed for 4 weeks. Paired and Independent T-tests were used to analyze the mean differences between and within groups. RESULTS: The primary endpoints of the study were the effect on inflammatory markers (IL-6, CRP), endothelial function and blood pressure at 4 weeks. There was a significant reduction in mean SBP at 4 weeks in the CEAG group compared to placebo [mean ± SD 4.7 ± 6.8 (p = 0.002)]. Relative to placebo, active group showed a significant decrease in High sensitivity C Reactive Protein (hsCRP) (-0.49 ± 1.9 vs + 0.51 ± 2.5, p = 0.059) and blunted increase in IL-6 (+0.2 vs + 0.4 in placebo, p = 0.60). CONCLUSION: Inflammatory markers were reduced or blunted by CEAG, with a robust increase in both EPA levels and the fatty acid index. Furthermore, systolic BP was reduced over 4 weeks with concurrent improvement in endothelial function. CLINICALTRIALS. GOV ID: NCT03906825.

Recent updates on echocardiography and ultrasound for Kawasaki disease: beyond the coronary artery.

Kawasaki disease (KD) is a systemic vasculitis with a predilection for damage to the coronary arteries. In the acute phase, clinical decision making for KD relies on the measurements of the coronary z-score obtained by 2-dimensional echocardiography (2DE). In the convalescent phase, KD patients with coronary artery abnormalities (CAAs) eventually show arteriosclerotic vascular remodeling characterized by marked intimal proliferation and neoangiogenesis after KD vasculitis, which often induces myocardial ischemia. To date, several well-established surrogate markers including dobutamine stress echocardiography (DSE), the carotid intima-media thickness (CIMT) and flow-mediated dilatation (FMD), have been made available for risk assessment and the prediction of cardiovascular disease (CVD) in KD patients. Additionally, the use of carotid contrast-enhanced ultrasonography (CEUS), has enabled the visualization and quantification of the adventitial vasa vasorum (VV) network, assessing active vascular remodeling at remote arterial sites in KD patients with CAAs. However, there was no evidence of major vascular structural changes in KD patients in whom CAAs had never been detected. Thus, assessment of multiple modalities using 2DE may provide direct information not only on the vascular health but also on the stratification of the risk of CVD in KD patients with CAAs.

Endothelial Dysfunction Markers in Low Cardiovascular Risk Individuals: Comparison of Males and Females.

BACKGROUND: Cardiovascular diseases (CVD) account for approximately 50% of the total deaths in Turkey. Most of them are related with atherosclerotic coronary heart disease. Predictive value of endothelial dysfunction markers related with the earliest stage of atherosclerosis has been getting more attention. We hypothesized that differences in endothelial dysfunction biochemical markers among genders would aid to capture proatherogenic activity that was not diagnosed by conventional risk assessment scoring systems. METHODS: We assessed the endothelial dysfuntion markers in 92 Turkish adults who were in the ¼low CV risk group« according to ESC (European Society of Cardiology)-Score Risk Charts. We compared the males and females. RESULTS: We observed higher endothelial dysfunction rates in males, with higher median and mean levels of e-NOS, ox-LDL before and after adjustment for HDL lowness and obesity (P=0.018, P=0.036 for NOS; P=0.000, P=0.004 for ox-LDL, respectively). Men had higher hs-CRP levels than females before adjustment (P=0.021). Decreased e-NOS levels were related with FMD for females before adjustment for confounders (P=0.028). We also found significant correlation between e-NOS and ox-LDL levels both before (r=0.360, P<0.001) and after adjustment (r=0.366, P<0.01) for confounders which pointed out the nitrosative stress. In multivariate regression analyses, after adjusting for other endothelial dysfunction markers which were not included in the ESC-risk scoring system, decreased e-NOS levels were independently asssociated with impaired flow mediated dilatation for females (odds ratio 0.3; P=0.038). CONCLUSIONS: Our results underline the importance of gender in evaluating endothelial dysfunction biochemical markers to assess cardiovascular risk for low CV risk indivuals.

Visfatin versus Flow-Mediated Dilatation as a Marker of Endothelial Dysfunction in Pediatric Renal Transplant Recipients.

BACKGROUND: Renal transplantation (RTx) is the treatment of choice for paediatric end-stage renal disease (ESRD). A major cause of morbidity and mortality after RTx is cardiovascular disease. Independent predictors of cardiovascular events were shown to constitute an endothelial dysfunction (ED). This study aims to evaluate Visfatin serum level in comparison to brachial artery flow-mediated dilatation (FMD) as a marker of endothelial dysfunction in paediatric RTx recipients. METHODS: Visfatin serum level has been evaluated in 30 patients on regular hemodialysis (HD), 36 patients post-RTx and 30 controls as a measure for ED, and has been compared to brachial artery FMD. RESULTS: Visfatin level in transplant recipients was significantly lower than the hemodialysis group as well as FMD was better in transplant recipients. In spite of marked improvement of FMD and marked reduction of visfatin in post-RTx no direct statistical correlation was found between serum Visfatin level and flow-mediated dilatation. CONCLUSION: Pediatric RTx recipients show lower serum Visfatin level and better FMD than those on regular hemodialysis, reflecting less endothelial dysfunction (ED) and less cardiovascular risk. FMD in kidney transplant recipients tends to be less than normal subjects while visfatin level of the same group is similar to controls. Pediatric RTx appears to have a positive impact on the growth development of children with ESRD.

Mediation of coffee-induced improvements in human vascular function by chlorogenic acids and its metabolites: Two randomized, controlled, crossover intervention trials.

BACKGROUND & AIMS: Polyphenol intake has been linked to improvements in human vascular function, although data on hydroxycinnamates, such as chlorogenic acid (CGA) have not yet been studied. We aimed to investigate the impact of coffee intake rich in chlorogenic acid on human vascular function and whether CGAs are involved in potential effects. METHODS: Two acute randomized, controlled, cross-over human intervention trials were conducted. The impact of coffee intake, matched for caffeine but differing in CGA content (89, and 310 mg) on flow-mediated dilatation (FMD) was assessed in 15 healthy male subjects. In a second intervention trial conducted with 24 healthy male subjects, the impact of pure 5-caffeoylquinic acid (5-CQA), the main CGA in coffee (5-CQA; 450 mg and 900 mg) on FMD was also investigated. RESULTS: We observed a bi-phasic FMD response after low and high polyphenol, (89 mg and 310 mg CGA) intake, with increases at 1 (1.10 ± 0.43% and 1.34 ± 0.62%, respectively) and 5 (0.79% ± 0.32 and 1.52% ± 0.40, respectively) hours post coffee consumption. FMD responses to coffee intake was closely paralleled by the appearance of CGA metabolites in plasma, notably 3-, 4- and 5-feruloylquinic acid and ferulic-4'-O-sulfate at 1 h and isoferulic-3'-O-glucuronide and ferulic-4'-O-sulfate at 5 h. Intervention with purified 5-CQA (450 mg) also led to an improvement in FMD response relative to control (0.75 ± 1.31% at 1 h post intervention, p = 0.06) and concomitant appearance of plasma metabolites. CONCLUSIONS: Coffee intake acutely improves human vascular function, an effect, in part, mediated by 5-CQA and its physiological metabolites. STUDY REGISTRATION: The National Institutes of Health (NIH) on ClinicalTrials.govNCT01813981 and NCT01772784.

Correlations between brachial endothelial function and cardiovascular risk factors: a survey of 2,511 Chinese subjects.

OBJECTIVE: We examined the relationship of several cardiovascular risk factors (CVRF) to brachial artery flow-mediated dilatation (FMD) in Chinese subjects. METHODS: This was a cross-sectional study. In 2,511 Chinese adults (age 46.86±9.52 years, 1,891 men and 620 women) recruited from people who underwent health screening at The Third Xiangya Hospital, patients' CVRF [age, body mass index (BMI), waist circumference (WC), blood pressure (BP), cholesterol parameters, creatinine (Cr), uric acid (UA), glucose level and smoking] and prevalence of present disease (hypertension, diabetes mellitus, coronary heart disease and hyperlipidemia) were investigated. RESULTS: Multivariate analysis revealed that FMD negative correlated with age (ß=-0.29, P<0.001), gender (ß=-0.12, P<0.001), BMI (ß=-0.12, P=0.001), WC (ß=-0.10, P=0.011), systolic BP (SBP) (ß=-0.12, P<0.001), fasting glucose (ß=-0.04, P=0.009), total cholesterol (TC) (ß=-0.04, P=0.014), smoking (ß=-0.05, P=0.003), and baseline brachial artery diameter (ß=-0.35, P<0.001). FMD decreased with increasing age in both genders. In women, FMD was higher than men and age-related decline in FMD was steepest after age 40; FMD was similar in men above 55 years old. CONCLUSIONS: In Chinese subjects, FMD may be a usefully marker of CVRF. Age, gender, BMI, WC, SBP, fasting glucose, TC, smoking, and baseline brachial artery diameter were independent variables related to the impairment of FMD. The influence of CVRF on endothelial function is more in women than men.