Impaired Flow-mediated Vasodilation Research Articles

The Impact of Flow-Mediated Vasodilatation on Mechanism and Prognosis in Patients with Acute Coronary Syndrome: A FMD and OCT Study.

Endothelial dysfunction, characterized by impaired flow-mediated vasodilation (FMD), is associated with atherosclerosis. However, the relationship between FMD, plaque morphology, and clinical outcomes in patients with acute coronary syndrome (ACS) remains underexplored. This study aims to investigate the influence of FMD on the morphology of culprit plaques and subsequent clinical outcomes in patients with ACS. This study enrolled 426 of 2482 patients who presented with ACS and subsequently underwent both preintervention FMD and optical coherence tomography (OCT) between May 2020 and July 2022. Impaired FMD was defined as an FMD% less than 7.0%. Major adverse cardiac events (MACEs) included cardiac death, nonfatal myocardial infarction, revascularization, or rehospitalization for angina. Within a one-year follow-up, 34 (8.0%) patients experienced MACEs. The median FMD% was 4.0 (interquartile range 2.6-7.0). Among the patients, 225 (52.8%) were diagnosed with plaque rupture (PR), 161 (37.8%) with plaque erosion (PE), and 25 (5.9%) with calcified nodules (CN). Impaired FMD was found to be associated with plaque rupture (odds ratio [OR] = 4.22, 95% confidence interval [CI]: 2.07-6.72, p = 0.012) after adjusting for potential confounding factors. Furthermore, impaired FMD was linked to an increased incidence of MACEs (hazard ratio [HR] = 3.12, 95% CI: 1.27-6.58, p = 0.039). Impaired FMD was observed in three quarters of ACS patients and can serve as a noninvasive predictor of plaque rupture and risk for future adverse cardiac outcomes.

RF34 | PMON276 The Effect of Gender Affirming Hormone Therapy (GAHT) on Non-Conventional Cardiovascular Risk Markers in Transgender Men: A Systematic Review

Abstract The process of gender transitioning includes the employment of gender-affirming hormone therapy (GAHT) to attenuate gender dysphoria. Although considered relatively safe, there is still debate whether GAHT may increase the risk of cardiovascular disease (CVD) in transgender men (TM). Non-conventional subclinical cardiovascular (CV) risk markers, such as inflammation or coagulation markers, endothelial activity-related substances, and the use of ultrasound-assisted vascular function evaluation, may improve CV risk prediction in specific populations. Therefore, we conducted a systematic review to summarize the available findings regarding GAHT and its effects on these non-conventional cardiovascular risk markers in TM. Medline, LILACS, SCOPUS, and Embase databases were searched for cross-sectional, case-control, cohort, or randomized clinical trial studies published until July 2020. The selection criteria for the studies were as follows: ≥ 18 years old transgender male, no established CVD, using GAHT (androgens) for at least 2 months and compared with cis women or untreated transmen or before and during/after treatment for cohort studies. From 152 studies initially identified, 7 studies (3 cohorts and 4 case-control) were included in the systematic review. Some of these studies assessed different CV risk markers in the same group of participants. No changes were found in t-PA PAI-1, ICAMs, and PCR-us after 4 and 12 months of GAHT. Fibrinogen did not differ either in TM with or with no GAHT. Three studies evaluated flow-mediated-vasodilation (FMD) of the brachial artery. The only cohort study found no changes in FMD after 12 months of GAHT. One case-control study observed significant impaired FMD, and another one showed impaired FMD- after-nitroglycerin in transmen compared with cis women. One study reported increased homocysteine and higher carotid intima-media thickness (C-MIT) after 12 months of hormone use. Further, one study observed testosterone did not affect distensibility (DC) or compliance (CC) coefficient after 12 months, but the changes in fasting insulin levels were negatively associated with changes in the CC and DC. One study assessed the vascular function using brachial-ankle pulse wave velocity (baPWV) and observed a higher risk in TM with GAHT versus the untreated group. The results of the present systematic review suggest that GAHT may be associated with worse subclinical cardiovascular markers in TM. Further studies assessing long-term clinical follow-up of transgender men using GAHT could positively impact the prevention of CVD and management strategies for this population. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:00 p.m. - 1:05 p.m.

Study of Endothelial Dysfunction in Patients With Non-alcoholic Fatty Liver Disease.

BackgroundMetabolic syndrome (syndrome X) is the name for a group of risk factors that raises your risk for heart disease and other health problems, such as diabetes and stroke. Dilatation of blood vessels following stress is a function of vasodilators produced by the endothelium. Flow-mediated vasodilation assesses endothelial function. In the case of endothelial dysfunction, flow-mediated vasodilation is impaired, resulting in decreased or even absence of vasodilation following stress. The easy availability of ultrasound machines nowadays and the non-invasive nature of the test make this a practical test for assessing endothelial dysfunction and the risk of cardiovascular diseases. Various studies have confirmed the presence of impaired flow-mediated vasodilation in patients with coronary artery disease. However, the presence of impaired flow-mediated vasodilation in individuals with risk factors but no cardiovascular diseases can prove that this can be used to predict individuals at risk. This study tries to confirm the presence of endothelial dysfunction in patients with non-alcoholic fatty liver disease (NAFLD) attending a tertiary center hospital in Kochi.ObjectivesThe study's main aim is to compare flow-mediated dilatation in patients with NAFLD and normal individuals.Materials and methodsThe comparative study was conducted among 50 patients attending various outpatient departments in Amrita Institute of Medical Sciences, Kochi. History and examination of cases and controls and relevant investigations were done after obtaining consent. In addition, both groups underwent measurement of flow-mediated vasodilation in the radiology department. Data were entered in Microsoft Excel and were analyzed using SPSS.ResultsFlow-mediated vasodilation was found to be less in patients with fatty liver (7.37 ± 2.75) when compared to individuals with normal liver (12.41 ± 3.71). In addition, flow-mediated vasodilatation was inversely proportional to BMI and age.ConclusionThis study has proved that there will be endothelial dysfunction in NAFLD, as shown by the decrease in flow-mediated vasodilation when compared with normal liver.

Abstract P029: Non-high Density Lipoprotein Is A Residual Risk For The Progression Of Endothelial Dysfunction In Patients With Well Controlled Low-density Lipoprotein Cholesterol: Multicenter Prospective Study FMDJ Study

Introduction: Recently, several guidelines suggest the usefulness of non-high density lipoprotein cholesterol (non-HDLC) as a secondary treatment target for CVD prevention, next to low-density lipoprotein cholesterol (LDLC). However, its effect on endothelial dysfunction have not been fully clarified. The objective of this multicenter-prospective-observational study, FMD-J Study, is to evaluate whether non-HDLC is a residual risk for the progression of endothelial dysfunction in patients with hypertension. Hypothesis: Non-HDLC is a residual risk for the progression of endothelial dysfunction in patients with hypertension. Methods: 633 treated hypertensive patients (mean age 62±9 years) in the FMD-J study were followed for 3 years. Endothelial function was evaluated by the change of flow mediated vasodilation (FMD). Multivariate regression analysis adjusted for established coronary heart disease (CHD) risk factors (sex, age, BMI, systolic blood pressure, heart rate, fasting blood glucose, high density lipoprotein cholesterol, baseline FMD, current smoking, treatment of diabetes, and treatment of dyslipidemia) was performed to evaluate whether LDLC and non-HDLC were associated with the change of FMD. We also performed secondary analysis to evaluate whether non-HDLC is associated with progression of endothelial dysfunction in patients with well controlled LDLC level according to their CHD risk. CHD risk was evaluated by Suita score, which is established risk score to assess the 10-year risk of CHD for the Japanese population. (High-risk: 56≦Suita score, Mid-risk: 41≦Suita score≦55, Low-risk: Suita score≦40) Target controlled LDLC levels according to CHD risk were defined as follows; High-risk: LDLC<70 mg/dl, Mid-risk: LDLC<100 mg/dl, Low-risk: LDLC<70 mg/dl. Results: Mean change of FMD after 3 years was 0.07±2.97% and mean Suita score was 46.4±8.9. Overall, both higher LDLC and non-HDLC was significantly associated with impairment of FMD. (Adjusted 1SD increase of LDLC; β: -0.26±0.11, P=0.02, Adjusted 1SD increase of non-HDLC; β: -0.25±0.11, P=0.03 ). In secondary analysis, 97 patients’ LDLC reached target LDLC level according to CHD risk. Among LDLC controlled group, higher non-HDLC was significantly associated with impairment of FMD. (Adjusted 1SD increase of non-HDLC; β: -0.75±0.13, P=0.02). However, among 536 patients whose LDLC did not reach target LDLC value, non-HDLC was not associated with the change pf FMD. (Adjusted 1SD increase of non-HDLC; β: -0.15±0.12, P=0.20). Conclusions: Non-HDLC may be a residual risk for the progression of endothelial dysfunction in patients with hypertension, especially in hypertensive patients with well controlled LDLC.

Omega-3 fatty acids improve flow-induced vasodilation by enhancing TRPV4 in arteries from diet-induced obese mice.

Previous studies have shown the intake of omega-3 polyunsaturated fatty acids is associated with low rates of obesity and ischaemic pathologies. Omega-3 also have anti-inflammatory and plaque-stabilization effects and regulate vasodilation and constriction. However, there are few studies of the role of omega-3 in flow-induced vasodilation involving Ca2+-permeable ion channel TRPV4 in high-fat diet-induced obese (DIO) mouse. Here, we determined whether omega-3 protect against vascular dysfunction induced by a high-fat diet by enhancing TRPV4 activity and subsequently improving flow-mediated vasodilation. Flow-mediated vasodilation in second-order mesenteric arteries from mice was measured using a pressure myograph. The intracellular Ca2+ concentration in response to flow and GSK1016790A (a TRPV4 agonist) was measured by Fluo-4 fluorescence. Whole-cell current was measured by patch clamp. Cell membrane tether force was measured by atomic force microscopy. Impairment of flow-mediated vasodilation in arteries and Ca2+ influx in endothelial cells from DIO mice was restored by omega-3 treatment. The improved flow-induced vasodilation was inhibited by the TRPV4 antagonist HC067047 and in TRPV4-/- mice. Omega-3 treatment enhanced endothelial TRPV4 activity and altered cell membrane mechanic property, as indicated by enhanced GSK1016790A-induced Ca2+ influx and whole-cell current and altered membrane mean tether force in endothelial cells from DIO mice. Omega-3 improve vascular function by improving flow-induced vasodilation via enhancing TRPV4 activity in the endothelium of obese mice which may be related to improved cell membrane physical property. Activation of TRPV4 in endothelium plays an important role in the protective mechanisms of omega-3 against vascular dysfunction in obesity by improving flow-mediated vasodilation.

Age‐associated Arterial Dysfunction is Rejuvenated by Targeted Reactivation of Protein Kinase Cδ

Genetic repression of endothelial cell (EC) autophagy impairs EC glycolysis and EC ATP production (Bharath et al., ATVB, 2017). This limits purinergic 2Y1 receptor mediated activating phosphorylation of EC nitric oxide (NO) synthase (p‐eNOSS1177) via protein kinase C δ (PKCδT505). A consequence of this impaired signaling pathway is compromised shear‐stress ‐ induced NO generation. We sought to determine whether reactivating PKCδT505 in the context of repressed EC autophagy restores EC function. First, we hypothesized that bryostatin‐1 (Bry‐1) rescues shear‐induced p‐eNOSS1177 and NO generation in human arterial ECs (HAECs) with genetic autophagy compromise. Bry‐1 binds to the regulatory C1 domain of the PKC isoforms. As anticipated, laminar shear stress x 45‐min elevated (p<0.05) p‐PKCδT505, p‐eNOSS1177, and NO generation in HAECs with intact autophagy but not in HAECs after Atg3 knockout (+Atg3KO; n=6). All responses were restored in HAECs + Atg3KO by incubation with Bry‐1, without affecting autophagy, cell death, or apoptosis. Next, we hypothesized that reactivating PKCδ restores vasodilatory function in arteries from aged mice with physiological repression of vascular autophagy. Lower (p<0.05) mRNA and protein expression of autophagy indexes was confirmed in primary arterial ECs and vascular homogenates from ~24 month (old; O) vs. ~7 month (adult, A) old male mice (n=5). Further, basal, glucose‐stimulated, and oligomycin‐stimulated extracellular acidification rate was suppressed (p<0.05) in primary arterial ECs from O vs. A mice, indicating impaired EC glycolysis. Femoral arteries from the same mice were examined ex vivo. Vasodilatory responses to intraluminal flow evoked by pressure gradients of 6, 12, 18, 24, and 30 mmHg (x 3‐min each @ 60 mmHg) was blunted (p<0.05) in O vs. A mice (n=5). As hypothesized, Bry‐1 restored intraluminal flow‐mediated vasodilation (FMD) in arteries from O mice to values observed in A mice (n=5). Vascular smooth muscle function, evaluated by vasodilatory responses to sodium nitroprusside, was not different between groups. In a separate cohort of vessels, nitric oxide synthase inhibition attenuated intraluminal FMD to a greater extent (p<0.05) in arteries from A vs. O mice (n=4). Finally, we hypothesized that Bry‐1 improves PKCδT505 and p‐eNOSS1177 in primary arterial ECs from aged humans. As background, earlier we reported p‐PKCδT505 and p‐eNOSS1177 was lower (p<0.05) in primary ECs obtained from the radial artery of older (~ 68 y) vs. adult (~ 23 y) males that also displayed impaired brachial artery FMD peak (Park et al, FASEB J, 2019). To test this, radial artery ECs were obtained from older males (n=4) via sterile j‐wire. Treatment of non‐fixed ECs with Bry‐1 elevated (p<0.05) PKCδT505 and p‐eNOSS1177 vs. non‐fixed ECs treated with vehicle. Here, we provide proof of concept that activating p‐PKCδT505 using Bry‐1 in the context of impaired vascular autophagy has potential to rejuvenate EC function.Support or Funding InformationJMC (UU Graduate Research Fellowship); SKP (17POST33670663); JDS (NIH RO1HL141540)

Effects of Gene‐Environment Interactions on Endothelial Function in Adolescents: GSTM1 and GSTT1 Polymorphisms and Tobacco Smoke Exposure

IntroductionSecond‐hand smoke (SHS) exposure is a significant risk factor for cardiovascular disease (CVD) and related CV complications. SHS exposure increases arterial endothelial damage and has been associated with impaired flow‐mediated vasodilation (FMD), an ultrasonic assessment of endothelial function. There are established ethnic and sex‐related CVD health disparities attributable to SHS exposure among African Americans (AAs). In disease‐free adolescents and adults, AAs also have earlier manifestations of vascular damage including impaired FMD. Furthermore, polymorphisms in glutathione S‐transferase genes GSTM1 and GSTT1 result in the absence of enzyme activity necessary to detoxify several toxins in tobacco smoke. There is a lack of research on the impact of these GST null genotypes on endothelial function, especially within the context of smoke exposure (exposure alone or actual smoker) among normotensive disease‐free adolescents. Also, we are unaware of other studies that have examined these gene‐environment interactions with adolescents who all have an established biological family history of CVD disease (i.e., hypertension and or early myocardial infarction < 55 yrs. of age in at least one parent or grandparent).PurposeTo investigate the potential gene‐environment interactions (GSTM1, GSTT1) and SHS exposure and the moderating effects of ethnicity/race on the pre‐clinical CVD risk factor (i.e. FMD) in an adolescent at‐risk cohort based on family history.MethodsSubjects were 262 normotensive adolescents aged 16–22 yrs., with nearly equal distribution of Caucasians and AAs. SHS exposure was measured by plasma cotinine using liquid chromatography with mass‐spectrometric detection and FMD of the left superficial femoral artery was determined using established procedures. To examine the effect of race, SHS and genotype (i.e., GSTT1 or GSTM1) on FMD, analysis of covariance was used.ResultsCaucasians had higher mean plasma cotinine concentrations compared with AAs (42.2 and 24.6 ng/ml, respectively), and males had higher concentrations than females (73.78 and 31.88 ng/ml, respectively). A significant three‐factor interaction was found between SHS exposure and presence of GSTM1 and GSTT1 (p = 0.016 and 0.0304, respectively) after adjusting for pre‐occlusion arterial diameter. Among all participants, AAs with the GSTM1‐1 genotype and who were also smokers exhibited the poorest %FMD compared to all other subgroups (Adjusted Mean = 0.30; SE 2.28).ConclusionHigher SHS exposure may be particularly harmful based on gene‐environment interactions in African American youth and especially in those who are already at high‐risk of developing CVD based on a positive family history. Although further research is needed, the association between GSTM1‐1 and lower %FMD in AAs may be related to early endothelial dysfunction, which is an independent predictor of CVD risk and events.Support or Funding InformationNIH/National Institute of Nursing Research 03/01/06‐2/28/08R15NR008871; PI: MSTingenThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impaired flow-mediated vasodilatation in mutated estrogen receptor alpha (ERα) mouse reveals a role of unliganted membrane, but not nuclear, ERα in shear stress-dependent mechanotransduction

Flow-mediated dilation (FMD) of resistance arteries (RAs) plays a key role in tissue perfusion. A reduced FMD is the hallmark of the endothelium dysfunction occurring early in cardiovascular and metabolic disorders. Estrogen therapy improves FMD in diseased conditions without major effect in healthy subjects. Nevertheless, estrogen receptor alpha (ERα) mutation in a man was associated with severe and selective FMD reduction. Thus, we evaluated the role of ERα in FMD in healthy young male mice. FMD was determined in vitro in mesenteric RAs isolated from mice lacking ERα (ERα−/−), the ERα nuclear activation function AF2 (AF2-ERα−/−) or the ERα palmitoylation site (C451A-ERα−/−, inactivation of the membrane effects or ERα), compared to littermate wild-type (WT or+/+) mice. We found that FMD was significantly reduced in ERα−/− compared to ERα+/+ male and female (ovariectomized or not) mice. Exogenous ERα stimulation or blockade did not affect FMD. FMD was not affected in AF2-ERα−/− mice whereas it was significantly decreased in C451A-ERα−/− mice. NO-synthesis blockade with L-NNA strongly reduced FMD in WT and AF2-ERα−/− mice without major effect in ERα-/- and C451A-ERα−/− mice. Acetylcholine-mediated relaxation, not affected by the absence of ERα was similarly reduced by L-NNA in all groups. After ROS reduction in vivo, NO-dependent FMD was equivalent in C451A-ERα−/− and C451A-ERα+/+ mice. Thus, membrane ERα is important for FMD through activation of eNOS activity and reduction of ROS production, possibly in a ligand-independent manner.

Abstract 374: Gpr68 Senses Blood Flow and is Essential for Vascular Physiology

Mechanotransduction plays a crucial role in vascular biology. One example of this is local regulation of vascular resistance via flow-mediated vasodilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction, and a precursor to a wide array of vascular diseases such as hypertension and atherosclerosis. And yet, the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium, and is a critical signaling component in cardiovascular pathophysiology.

Non-Alcoholic Fatty Liver Disease in Asian Indians:Relationship With Insulin Resistance, Diabetes and Cardiovascular Risk

Prevalence of non-alcoholic fatty liver disease (NAFLD) varies in India; up to one-third of the urban population is affected by the disease. In Asian Indians, presence of NAFLD is driven by multiple factors – presence of excess abdominal fat (abdominal subcutaneous and intra-abdominal fat) and lifestyle factors (imbalanced diets and physical inactivity), and it is correlated closely with insulin resistance, the metabolic syndrome and dysglycaemia in the background of genetic predisposition (investigated genes in Asian Indians: APOC3, PNPLA-3, PPARγ, SREBP-2, adiponectin, SAMM50, PARVB and PZP). Recent studies also show that presence of NAFLD independently correlates with subclinical inflammation and surrogate markers of atherosclerosis (carotid intima-media thickness, impaired flow-mediated vasodilatation) in Asian Indians. A prediction equation (Indian Fatty Liver Index) which includes simple measures has been developed for Asian Indians. On the other hand, increased (more than 15.6 cm) liver span (surrogate marker of fatty liver), in a preliminary study, predicted diabetes in non-obese Asian Indians. Dietary factors are important for the development of NAFLD, and some evidence indicates that regular use of high monounsaturated fatty acid rich oils, and low amount of saturated fat intake are beneficial.

Peripheral Vascular Endothelial Dysfunction in Central Serous Chorioretinopathy.

To explore the pathophysiology of central serous chorioretinopathy (CSC) by comparing peripheral vascular endothelium function in patients with CSC and control subjects. This study included 34 patients with CSC who attended the Department of Ophthalmology and 34 healthy age- and sex-matched healthy control subjects from a routine physical check-up population. Endothelium-dependent flow-mediated vasodilation (FMD) and endothelium-independent nitroglycerine-mediated vasodilation (NMD) were measured using high-resolution, two-dimensional ultrasonographic imaging of the brachial artery. Blood samples were taken to test serum glucose, cholesterol, triglyceride, alanine aminotransferase, uric acid, and high-sensitivity C-reactive protein (hs-CRP) levels. The mean age of patients with CSC was 44.0 years (SD ±8.1) and that of controls 46.1 years (±9.9) (P = 0.352). There were no significant differences between groups in serum biochemical data, including serum glucose, alanine aminotransferase, uric acid, cholesterol, triglyceride, and hs-CRP. FMD was significantly impaired in patients with CSC compared with control subjects (CSC: 4.62 ± 1.96, control: 7.52 ± 2.63, P < 0.001), whereas NMD did not differ significantly between the two groups (CSC: 16.31 ± 5.60, control: 16.22 ± 5.56, P = 0.950). This study demonstrated impaired FMD in patients with CSC and the results have provided evidence of peripheral endothelium dysfunction associated with CSC in patients.

Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk.

Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.

Association of Nonalcoholic Fatty Liver Disease with Subclinical Cardiovascular Changes: A Systematic Review and Meta-Analysis.

In the last 20 years, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide, primarily as a result of the epidemic of obesity. NAFLD is strongly associated with insulin resistance, glucose intolerance, and dyslipidemia and is currently regarded as the liver manifestation of the metabolic syndrome, a highly atherogenic condition even at a very early age. Patients with NAFLD including pediatric subjects have a higher prevalence of subclinical atherosclerosis, as shown by impaired flow-mediated vasodilation, increased carotid artery intima-media thickness, and arterial stiffness, which are independent of obesity and other established risk factors. More recent work has identified NAFLD as a risk factor not only for premature coronary heart disease and cardiovascular events, but also for early subclinical abnormalities in myocardial structure and function. Thus, we conducted a systematic review and meta-analysis to test the hypothesis that NAFLD is associated with evidence of subclinical cardiac structural and functional abnormalities.

Erectile dysfunction is associated with low total serum testosterone levels and impaired flow-mediated vasodilation in intermediate risk men according to the framingham risk score

Background: The role erectile dysfunction (ED) coupled with low testosterone levels as early markers of atherosclerosis is not well understood. Objectives: To analyze the relationship between serum testosterone levels with both ED and brachial artery flow-mediated vasodilation (FMD), in a primary prevention sample of men. Methods: We enrolled 802 asymptomatic, intermediate CV risk patients, according to the Framingham Risk Score, aged 40–80 years, who underwent the ultrasound examination of FMD, the evaluation of ED and the assessment of total serum testosterone levels. Results: Testosterone levels correlated both with FMD (r = 0.85; p < 0.0001) and IIEF-5 score (rs = 0.65; p < 0.0001). Multivariable logistic regression analyses revealed that lower serum testosterone levels were strongly associated (p < 0.001) with severe (OR 0.78; 95% CI: 0.62–0.86), and moderate ED (OR 0.85; 95% CI: 0.72–0.97), while impaired FMD percentages were strongly associated (p < 0.001) with severe (OR 0.68; 95% CI: 0.59–0.79), moderate (OR 0.76; 95% CI: 0.63–0.83) and mild to moderate ED (OR 0.8; 95% CI: 0.69–0.94). Mild ED resulted statistically associated with lower FMD (OR 0.94; 95% CI: 0.82 – 1.07; p = 0.03) but not with serum testosterone levels. These relations were not substantially affected by adjustments for further potential confounders including smoking status, hypertension, diabetes mellitus and body mass index. Conclusions: lower total serum testosterone levels are associated with impaired FMD and ED in this sample of intermediate CV risk men according to the Framingham Risk Score.

Nonalcoholic fatty liver disease and the heart in children and adolescents.

Over the last two decades, the rise in the prevalence rates of overweight and obesity explains the emergence of nonalcoholic fatty liver disease (NAFLD) as the leading cause of chronic liver disease worldwide. As described in adults, children and adolescents with fatty liver display insulin resistance, glucose intolerance, and dyslipidemia. Thus NAFLD has emerged as the hepatic component of the metabolic syndrome (MetS) and a strong cardiovascular risk factor even at a very early age. Several studies, including pediatric populations, have reported independent associations between NAFLD and markers of subclinical atherosclerosis including impaired flow-mediated vasodilation, increased carotid artery intima-media thickness, and arterial stiffness, after adjusting for cardiovascular risk factors and MetS. Also, it has been shown that NAFLD is associated with cardiac alterations, including abnormal left ventricular structure and impaired diastolic function. The duration of these subclinical abnormalities may be important, because treatment to reverse the process is most likely to be effective earlier in the disease. In the present review, we examine the current evidence on the association between NAFLD and atherosclerosis as well as between NAFLD and cardiac dysfunction in the pediatric population, and discuss briefly the possible biological mechanisms linking NAFLD and cardiovascular changes. We also address the approach to treatment for this increasingly prevalent disease, which is likely to have an important future global impact on the burden of ill health, to prevent not only end-stage liver disease but also cardiovascular disease.

Endothelial dysfunction: the link between homocysteine and hydrogen sulfide.

High level of homocysteine (hyperhomocysteinemia, HHcy) is associated with increased risk for vascular disease. Evidence for this emerges from epidemiological studies which show that HHcy is associated with premature peripheral, coronary artery and cerebrovascular disease independent of other risk factors. Possible mechanisms by which homocysteine causes vascular injury include endothelial injury, DNA dysfunction, proliferation of smooth muscle cells, increased oxidative stress, reduced activity of glutathione peroxidase and promoting inflammation. HHcy has been shown to cause direct damage to endothelial cells both in vitro and in vivo. Clinically, this manifests as impaired flow-mediated vasodilation and is mainly due to a reduction in nitric oxide synthesis and bioavailability. The effect of impaired nitric oxide release can in turn trigger and potentiate atherothrombogenesis and oxidative stress. Endothelial damage is a crucial aspect of atherosclerosis and precedes overt manifestation of disease. In addition, endothelial dysfunction is also associated with hypertension, diabetes, ischemia reperfusion injury and neurodegenerative diseases. Homocysteine is a precursor of hydrogen sulfide (H2S) which is formed by transulfuration process catalyzed by the enzymes, cystathionine β-synthase and cystathionine γ-lyase. H2S is a gasotransmitter that has emerged recently as a novel mediator in cardiovascular homeostasis. As a potent vasodilator, it plays several roles which include regulation of vessel diameter, protection of endothelium from redox stress, ischemia reperfusion injury and chronic inflammation. However, the precise mechanism by which it mediates these beneficial effects is complex and still remains unclear. Current evidence indicates H2S modulates cellular functions by a variety of intracellular signaling processes. In this review, we summarize the mechanisms of HHcy-induced endothelial dysfunction and the metabolism and physiological functions of H2S as a protective agent.

Masked Hypertension as an Unrecognized Destructive Condition

We have read the article “Masked Hypertension Defined by Home Blood Pressure Monitoring Is Associated With Impaired Flow-Mediated Vasodilatation in Patients With Cardiovascular Risk Factors” written by Kabutoya and colleagues1 with great interest. They speculated that home blood pressure (BP) and masked hypertension defined by home BP would be associated with integrated flow-mediated dilatation (FMD) response in patients with a cardiovascular risk factor. The study concluded that home systolic BP was associated with a decrease in FMD. This finding may likely contribute to an increased incidence of cardiovascular events in this group. The subject is important in terms of daily practice and the study justifies emphasis with its successful design and documentation. Ambulatory and home BP measurement have been shown to be superior to conventional measurement of BP in terms of reproducibility, relationship to the impact of high BP on target organs, and the prediction of cardiovascular events.2 Masked hypertension is defined as a clinical condition in which a patient's office BP is <140/90 mm Hg and home BP is ≥135 mm Hg and/or 85 mm Hg.3 Reactivity to daily life stressors and behavioral factors such as smoking, alcohol use, contraceptive use in women, and sedentary habits can influence masked hypertension. Masked hypertension should also be investigated in individuals who are at increased risk for cardiovascular complications, including patients with kidney disease.4 Masked hypertension defined by 24-hour ambulatory BP is associated with an increased serum glucose level and urinary albumin-creatinine ratio.5 For this reason, if the authors gave information about kidney function tests and lifestyle of patients, the results of the present study may be useful and different. Patients with masked hypertension have been demonstrated to have a greater-than-normal prevalence of organ damage, particularly with higher prevalence of metabolic risk factors, left ventricular mass index, carotid intima-media thickness, and impaired large artery distensibility compared with patients with a truly normal BP level. Masked hypertension is a predictor of cardiovascular disease, and FMD may measure the endothelial dysfunction and accelerated atherogenesis associated with masked hypertension. FMD measurement is a gold standard method for endothelial function; however, it may be associated with many conditions that are related to inflammation or endothelial impairment. Therefore, researchers who use this method should pay attention to inflammatory diseases or related conditions. Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are common in clinical practice. Cardiovascular complications, which are also common in patients with OSAS, have been linked to morbidity and mortality in these patients based on endothelial dysfunction. In addition, the presence and degree of NAFLD are associated with higher inflammatory parameters. Additionally, common pathways involved in the pathogenesis of NAFLD include hepatic insulin resistance, subclinical inflammation, and atherosclerosis.6 Because NAFLD and OSAS are associated with inflammatory status and insulin resistance, if the authors had mentioned these factors, it would be stronger. Inflammatory status can also be affected by many conditions including inflammatory disease such as psoriasis,7 cardiac syndrome X, and infection.8 In the present study, the authors did not mention some of these possible contributing factors. It would have been better if the authors gave information about these factors. In conclusion, FMD itself without other inflammatory indicators may not provide information to clinicians about masked hypertension. For this reason, we think that it should be evaluated together with other serum inflammatory markers in routine clinical practice.9 We believe that these findings will act as a guide for further studies that will assess inflammatory status as a surrogate marker of endothelial dysfunction and its relationship with masked hypertension. There are no conflict of interests.

Assessment of early atherosclerotic findings in patients with nasal polyposis

To investigate early markers of atherosclerosis in patients with nasal polyposis (NP) through measurements of carotid artery intima-media thickness (CIMT), flow-mediated vasodilatation (FMD) of the brachial artery and serum paraoxonase-1 (PON-1) activity. Forty-five patients with NP were included in the study group and 45 healthy individuals in the control group. The diagnosis of patients with NP was predicated on anterior rhinoscopy, endoscopic nasal examination and coronal paranasal sinus computed tomography (CT). Measurements of CIMT and FMD of the brachial artery were performed by high-resolution ultrasonography. Serum PON-1 activity was evaluated by measuring the rate of paraoxon hydrolysis. Mean CIMT values were found to be increased in the NP group compared to the control group. However, mean FMD % values and serum PON-1 activity were significantly lower in the NP group compared to the control group. Moreover; the endoscopic polyps' scores and paranasal sinus CT scores were positively correlated with CIMT and negatively correlated with FMD % values and PON-1 activity. Disease duration also was positively correlated with CIMT and negatively correlated with FMD % values. Impaired FMD, increased CIMT and decreased serum PON-1 activity may be considered to be risk factors for accelerated atherosclerosis in patients with NP who may have subclinical atherosclerosis and be at risk for cardiovascular events in the future.

Predictors of Endothelial Dysfunction in Patients With Rheumatoid Arthritis

We investigated the predictors of endothelial dysfunction in patients with rheumatoid arthritis (RA) by brachial artery flow-mediated vasodilatation (FMD). The study population included 50 patients with RA and 30 controls. Disease activity score (DAS28) was calculated for patients with RA. An FMD response <7% was accepted as impaired FMD. Brachial artery Doppler study revealed that in patients with RA, FMD% was significantly lower as compared with controls (6.6% ± 3.5% vs 9.7% ± 41%, P = .002). After multivariate logistic regression analysis, erythrocyte sedimentation rate (ESR; OR: 1.086, 95% confidence interval [CI]: 1.012-1.167, P = .023), duration of RA (OR: 1.392, 95% CI: 1.044-1.856, P = .024), and DAS28 (OR: 3.335, 95% CI: 1.067-10.42, P = .038) were independent predictors of impaired FMD in patients with RA. Endothelial function is impaired in patients with RA. Disease duration, DAS28, and ESR indicating active inflammation are independent predictors of impaired FMD in patients with RA.

Endothelial Dysfunction is a Marker of Systemic Response to the Cardiac Resynchronization Therapy in Heart Failure

BackgroundCardiac resynchronization therapy (CRT) induces a significant improvement in patients with heart failure (HF), who are often characterized by the presence of endothelial dysfunction (ED) with impaired flow-mediated vasodilation (FMD). We aimed to study the ED in patients with HF candidates to CRT with defibrillator (CRT-D). Methods and ResultsWe studied 57 consecutive patients affected by HF and undergoing CRT-D. At the baseline we recorded a high prevalence of ED (64.9%) with impaired FMD (4.1 ± 3.8%). After 12 months of CRT, we reported a marked increase of the mean FMD (8.8 ± 4.8% vs 4.1 ± 3.8%; P < .05) along with significant improvement of left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), New York Heart Association (NYHA) functional class, and 6-minute walk test (6MWT); 42 patients (73.7%) were classified as responders according to standard criteria. FMD was related to LVEF (r = 0.169; P < .05), LVESV (r = −0.169; P < .05), NYHA functional class (r = −0.27; P < .051), and 6MWT (r = 0.360; P < .01). ConclusionsED is not an independent predictor of CRT response, but it is able to intercept the systemic effects of CRT and is an affordable marker of response to CRT, especially in patients unable to perform the 6MWT.