Brachial Artery Flow-mediated Vasodilation Research Articles

Influence of heart failure (HF) comorbidity in chronic obstructive pulmonary disease (COPD) and isolated forms of HF and COPD on cardiovascular function during hospitalization

IntroductionCoexistence of chronic obstructive pulmonary disease(COPD) and heart failure(HF) is associated with systemic inflammation, myocardial injury, and arterial stiffening, impacting cardiovascular risk and prognosis in patients. Arterial stiffness, reduced nitric oxide synthesis, and altered cardiac autonomic control further link COPD and HF pathophysiology, emphasizing the need for comprehensive cardiovascular assessment. ObjectiveTo investigate a cardiovascular profile in patients hospitalized with exacerbation COPD(ECOPD) in coexistence with HF compared with isolated diseases. MethodsA cross-sectional study including patients diagnosed with ECOPD and decompensated HF, approached between 24 and 48 h after hospital admission. Assessments included: endothelial function by brachial artery flow-mediated vasodilation(FMD); hemodynamic through analysis of pulse wave and arterial stiffness by carotid-femoral pulse wave velocity(cfPWV) and cardiac autonomic modulation(CAM) by heart rate variability(HRV). ResultsThe mean FMD was 4.45 %, indicating endothelial dysfunction in all patients. Date is present in mean(confidence interval) sequency COPD(n = 12), COPD-HF(n = 21) and HF(n = 21). FMD: 5.47(3.96–6.91); 2.66(0.09–3.48); 4.60(2.30–6.43) p < 0.01. However, COPD-HF had worse FMD. Arterial stiffens (AIx: 29.0(19.0–42.6); 34.6(24.3–43.2); 14.5(8.0–24.0)p < 0.01; cfPWV: (6.5(5.4–7.2); 7.7(7.0–8.5); 6.0(5.0–6.5)); COPD-HF also showed greater activation of the sympathetic nervous system compared to patients with isolated diseases (PNS: 1.32(-2.53 to −0.62); −2.33(-2.60 to −2.12); −1.32(-1.42 to −1.01) p < 0.01; SNS: 3.50(1.40–8.55); 7.11(5.70–8.29); 2.32(1.78–5.01) p < 0.01). In addition, rMSSD, NN50, pNN50, and TINN also indicate worse CAM in the COPD-HF group compared to isolated diseases. ConclusionDuring hospitalization, the worst impairment in vascular function and cardiac autonomic modulation were found in patients with COPD and HF comorbidity compared to the isolated diseases(HF or COPD).

Natural Autoantibodies in Biologic-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients: Associations with Vascular Pathophysiology.

Cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Natural autoantibodies (nAAb) are involved in innate immunity, as well as autoimmunity, inflammation, and atherosclerosis. There have not been any studies assessing the effects of biologics on nAAbs in RA and AS, also in relation to vascular pathophysiology. Fifty-three anti-TNF-treated RA and AS patients were included in a 12-month follow-up study. Anti-citrate synthase (CS) and anti-topoisomerase I fragment 4 (TOPO-F4) IgM and IgG levels were determined by ELISA. Ultrasonography was performed to assess brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV). Other variables were also evaluated at baseline and 6 and 12 months after treatment initiation. Anti-TNF therapy improved FMD in RA and PWV in AS and stabilized ccIMT. TNF inhibition increased anti-CS IgM and IgG, and possibly also anti-TOPO-F4 IgG levels. Various correlation analyses revealed that nAAbs might be independently involved in autoimmunity as well as changes in inflammation and vascular pathology over time in biologic-treated patients (p < 0.05). We also found associations between anti-TOPO-F4 IgG and anti-Hsp60 IgG (p < 0.05). Baseline nAAb levels or nAAb level changes might determine changes in CRP, disease activity, FMD, PWV, and ccIMT over time (p < 0.05). The interplay between arthritis and inflammatory atherosclerosis, as well as the effects of anti-TNF biologics on these pathologies, might independently involve nAAbs.

(134) Early Impact of Androgen Deprivation Therapy on Endothelial Function and Metabolic Parameters in Prostate Cancer Patients: A Prospective Study

Abstract Introduction Androgen deprivation therapy (ADT) is considered one of the mainstays in the treatment of prostate cancer. ADT slows cancer progression, alleviates cancer-related symptoms, and is associated with survival gains. Despite these proven benefits, this treatment is related to several side effects, such as increased cardiovascular risk, changes in body composition and various metabolic changes. Although the well-established association between circulating testosterone level and endothelial integrity, the direct effects of ADT on endothelial function remain controversial. Objective This study aimed to investigate the impact of ADT on endothelial function, through the analysis of vascular parameters of the brachial artery and measurement of serum inflammatory markers. It was also our aim to evaluate the early impact of ADT on body composition and metabolic parameters. Methods We prospectively evaluated men with moderate to high-risk prostate cancer treated with ADT from January to December 2022 at our institution. Smokers and those who quit smoking less than five years ago, decompensated diabetics (glycated hemoglobin &amp;gt; 9%) and those who had already had a cardiovascular event were excluded. High-resolution B-mode ultrasound was used to assess vascular diameter and endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery. Our metabolic and inflammatory profile included measurement of serum total cholesterol and fractions, triglycerides, fasting glucose, glycated hemoglobin, basal insulin, C-reactive protein and assessment of body fat distribution through bioelectrical impedance. Subjects were evaluated at baseline and 3 months after starting ADT with goserelin acetate 10.80 mg. Results A total of 32 men were included. The mean age was 69 years and the prevalence of diabetes was 31.25%. FMD demonstrated a worsening trend after ADT, which did not reach statistical significance after 3 months (mean 3.39 ± 6.83 vs 1.16 ± 7.65; p = 0.14) (figure 1). Baseline brachial artery diameter also showed a tendency to worsen with ADT compared to baseline (0.44 ± 0.06 vs 0.42 ± 0.06; p = 0.06). With regard to the metabolic profile, ADT significantly increased insulin resistance: fasting glucose (mean 104.10 ± 18.96 vs 110.60 ± 25.29; p = 0.01), fasting insulin levels (mean 13.05 ± 8.76 vs 16.82 ± 11.36; p = 0.003), glycated hemoglobin (mean 5.89% ± 0.46 vs 6.15% ± 0.67; p = 0.008) and homeostatic model assessment insulin resistance (mean 3.47 ± 2.55 vs 5.05 ± 4.50; p = 0.005) increased significantly after 3 months. Triglycerides concentrations (mean 142.30 ± 69.66 vs 165.50 ± 93.04; p = 0.03) were higher after 3 months of ADT. Abdominal circumference (mean 98.66 ± 10.16 vs 99.76 ± 9.39; p = 0.02) and body mass index (mean 27.46 ± 4.06 vs 27.76 ± 3.89; p = 0.02) also increased after ADT. Conclusions Although not statistically significant, the present study demonstrated a trend towards a decrease in brachial artery FMD. We also observed an important and surprisingly early worsening of the metabolic profile with ADT, especially increased insulin resistance and dyslipidemia, which represent well-established risk factors for cardiovascular events. Disclosure No.

A Cross-Sectional Study Evaluating the Association of Brachial Artery Flow Mediated Vasodilation with Physical Activity Measured by Accelerometry in Patients with the Overlap of Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Overlap Syndrome (OS), the co-occurrence of Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease. Clustering of patients in subgroups with similar pre-clinical manifestations (ie, endothelial dysfunction) may identify relevant therapeutic phenotype categories for patients with OS who are at high risk of CVD. We therefore conducted a cross-sectional pilot study of endothelial function in 7 patients with OS (Forced Expiratory Volume in 1 second/Forced Vital Capacity < 0.7) on continuous positive airway pressure therapy (n = 7) to assess the relationship between FMD and physical activity. We found a strong association between FMD and step counts (rho = 0.77, p = 0.04); and FMD and moderate physical activity (rho = 0.9, p = 0.005). Further, larger studies are needed to confirm that FMD may identify patients with OS at high risk of CVD who benefit from increased physical activity.

Subclinical atherosclerosis in young adults predicting cardiovascular disease: The Cardiovascular Risk in Young Finns Study

Background and aimsAtherosclerosis is accompanied by pre-clinical vascular changes that can be detected using ultrasound imaging. We examined the value of such pre-clinical features in identifying young adults who are at risk of developing atherosclerotic cardiovascular disease (ASCVD). MethodsA total of 2641 individuals free of ASCVD were examined at the mean age of 32 years (range 24–45 years) for carotid artery intima-media thickness (IMT) and carotid plaques, carotid artery elasticity, and brachial artery flow-mediated endothelium-dependent vasodilation (FMD). The average follow-up time to event/censoring was 16 years (range 1–17 years). ResultsSixty-seven individuals developed ASCVD (incidence 2.5%). The lowest incidence (1.1%) was observed among those who were estimated of having low risk according to the SCORE2 risk algorithm (<2.5% 10-year risk) and who did not have plaque or high IMT (upper decile). The highest incidence (11.0%) was among those who were estimated of having a high risk (≥2.5% 10-year risk) and had positive ultrasound scan for carotid plaque and/or high IMT (upper decile). Carotid plaque and high IMT remained independently associated with higher risk in multivariate models. The distributions of carotid elasticity indices and brachial FMD did not differ between cases and non-cases. ConclusionsScreening for carotid plaque and high IMT in young adults may help identify individuals at high risk for future ASCVD.

(228) Cell-Based Therapy Can Restore Erectile Function in Men with Type 2 Diabetes and Metabolic Syndrome by Promoting Angiogenesis and Endothelial Repair

Abstract Introduction Although there has been a growing interest in restorative therapies for erectile dysfunction (ED) in recent years, there is still limited mechanistic evidence to support their effectiveness in the clinical setting. Objective The goal of this research was to investigate the mechanistic impact of cell-based therapy in men with ED secondary to Type 2 Diabetes Mellitus (DM2) and Metabolic Syndrome (MetS) through analysis of plasma biomarkers. Methods International Index of Erectile Function (IIEF) was completed by all men in the ACESO (NCT02886884) and CERES (NCT03059355) clinical trials. ACESO and CERES were both randomized, blinded, pilot phase clinical trials in which all participants received cellular therapy at varying doses and sources to treat endothelial dysfunction secondary to either DM2 or MetS, respectively. The intervention in both trials was peripheral intravenous infusion of allogeneic Mesenchymal Stem Cells (MSCs) of either 20 or 100 million cells derived from either bone marrow (BM) or umbilical cord tissue (UC). Follow-up was for 1 year. Endothelial function was measured via Brachial Artery Flow Mediated Vasodilation (FMD) and Endothelial Progenitor Cell-Colony Forming Units (EPC-CFU) assay. Plasma aliquots were isolated from blood samples and subjected to multiplex ELISA assay for analysis of angiogenic biomarkers. Results Data was pooled from all 20 men in the ACESO and CERES clinical trials. Overall, 7 received 20 million BM-MSCs, 9 received 100 million BM-MSCs, 2 received 20 million UC-MSCs, and 2 received 100 million UC-MSCs. There were no treatment emergent serious adverse effects (TE-SAEs) within 30 days following infusion in any of the participants. Among men with ED (IIEF-EF&amp;lt;25), 31.25% achieved MCID in erectile function. Participants with mild or moderate ED at baseline showed greater improvements in erectile function and endothelial function compared to those with severe ED. Participants who achieved MCID following cell therapy also experienced statistically significant improvements in FMD (P=0.05), whereas those who did not achieve MCID or had normal erectile function at baseline did not experience an improvement in FMD. Furthermore, men with Metabolic Syndrome who met MCID criteria were found to have increased Angiopoietin 1 and decreased Angiopoietin 2 following cell therapy. Conclusions The findings of this study demonstrate the potential of cell-based therapies in improving erectile function, angiogenic, and endothelial function. Future studies should aim to identify the causative mechanisms underlying these restorative effects in humans, paving the way for enhanced understanding and optimization of such therapies. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Longeveron LLC.

Effect of tofacitinib therapy on angiotensin converting enzyme activity in rheumatoid arthritis.

The Renin-Angiotensin-Aldosterone system (RAAS) has been implicated in the regulation of the cardiovascular system and linked to rheumatoid arthritis (RA). Little information has become available on the effects of Janus kinase (JAK) inhibition on RAAS. Here we studied the effects of 12-month tofacitinib treatment on angiotensin converting enzyme (ACE), ACE2 production and ACE/ACE2 ratios in RA along with numerous other biomarkers. Thirty RA patients were treated with tofacitinib in this prospective study. Serum ACE concentrations were assessed by ELISA. ACE2 activity was determined by a specific quenched fluorescent substrate. ACE/ACE2 ratios were calculated. We also determined common carotid intima-media thickness (ccIMT), brachial artery flow-mediated vasodilation (FMD) and carotid-femoral pulse-wave velocity (cfPWV) by ultrasound. C-reactive protein (CRP), rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) were also determined. All measurements were performed at baseline, as well as after 6 and 12 months of tofacitinib treatment. After the dropout of 4 patients, 26 completed the study. Tofacitinib treatment increased ACE levels after 6 and 12 months, while ACE2 activity only transiently increased at 6 months. The ACE/ACE2 ratio increased after 1 year of therapy (p < 0.05). Logistic regression analyses identified correlations between ACE, ACE2 or ACE/ACE2 ratios and RF at various time points. Baseline disease duration also correlated with erythrocyte sedimentation rate (ESR) (p < 0.05). One-year changes of ACE or ACE2 were determined by tofacitinib treatment plus ACPA or RF, respectively (p < 0.05). JAK inhibition increases serum ACE and ACE/ACE2 ratio in RA. Baseline inflammation (ESR), disease duration and ACPA, as well as RF levels at various time points can be coupled to the regulation of ACE/ACE2 ratio. The effect of tofacitinib on RAAS provides a plausible explanation for the cardiovascular effects of JAK inhibition in RA.

Development and validation of a clinical prediction model for detecting coronary heart disease in middle-aged and elderly people: a diagnostic study

ObjectiveTo develop and validate a multivariate prediction model to estimate the risk of coronary heart disease (CHD) in middle-aged and elderly people and to provide a feasible method for early screening and diagnosis in middle-aged and elderly CHD patients.MethodsThis study was a single-center, retrospective, case–control study. Admission data of 932 consecutive patients with suspected CHD were retrospectively assessed from September 1, 2020 to December 31, 2021 in the Department of Integrative Cardiology at China-Japan Friendship Hospital. A total of 839 eligible patients were included in this study, and 588 patients were assigned to the derivation set and 251 as the validation set at a 7:3 ratio. Clinical characteristics of included patients were compared between derivation set and validation set by univariate analysis. The least absolute shrinkage and selection operator (Lasso) regression analysis method was performed to avoid collinearity and identify key potential predictors. Multivariate logistic regression analysis was used to construct a clinical prediction model with identified predictors for clinical practice. Bootstrap validation was used to test performance and eventually we obtained the actual model. And the Hosmer–Lemeshow test was carried out to evaluate the goodness-fit of the constructed model. The area under curve (AUC) of receiver operating characteristic (ROC), calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were plotted and utilized with validation set to comprehensively evaluate the predictive accuracy and clinical value of the model.ResultsA total of eight indicators were identified as risk factors for the development of CHD in middle-aged and elderly people by univariate analysis. Of these candidate predictors, four key parameters were defined to be significantly related to CHD by Lasso regression analysis, including age (OR 1.034, 95% CI 1.002 ~ 1.067, P = 0.040), hemoglobin A1c (OR 1.380, 95% CI 1.078 ~ 1.768, P = 0.011), ankle-brachial index (OR 0.078, 95% CI 0.012 ~ 0.522, P = 0.009), and brachial artery flow-mediated vasodilatation (OR 0.848, 95% CI 0.726 ~ 0.990, P = 0.037). The Hosmer–Lemeshow test showed a good calibration performance of the clinical prediction model (derivation set, χ2 = 7.865, P = 0.447; validation set, χ2 = 11.132, P = 0.194). The ROCs of the nomogram in the derivation set and validation set were 0.722 and 0.783, respectively, suggesting excellent predictive power and suitable performance. The clinical prediction model presented a greater net benefit and clinical impact based on DCA and CIC analysis.ConclusionOverall, the development and validation of the multivariate model combined the laboratory and clinical parameters of patients with CHD, which could be beneficial to the individualized prediction of middle-aged and elderly people, and helped to facilitate clinical assessments and decisions during treatment and management of CHD.

Early Effects of Ticagrelor Versus Clopidogrel on Peripheral Endothelial Function After Non-ST-Elevation Acute Coronary Syndrome and Assessment of Its Relationship With Coronary Microvascular Function

Peripheral endothelial dysfunction is an independent predictor of adverse long-term prognosis after acute coronary syndrome. Data are lacking on the effects of oral P2Y12-inhibitors on peripheral endothelial function in non-ST-elevation acute coronary syndrome (NSTEACS). Furthermore, the relation between peripheral endothelial function and invasive indexes of coronary microvascular function in NSTEACS is unclear. Between March 2018 and July 2020, hospitalized patients with NSTEACS were randomized (1:1) to ticagrelor or clopidogrel. Peripheral endothelial function was assessed with brachial artery flow-mediated vasodilation (FMD). Invasive indexes of coronary microvascular function were obtained using an intracoronary pressure-temperature sensor-tipped wire. In 70 patients included, mean age was 58.6years, 78.6% (n=55) were male and 20% (n=14) had diabetes mellitus. Compared with clopidogrel, ticagrelor significantly improved FMD (14.2±5.4% vs 8.9±5.3%, p<0.001) after a median treatment time of 41.2hours. The FMD was significantly correlated with the index of microcirculatory resistance (IMR) measured in the infarct-related artery (r=-0.38, p=0.001), with a stronger correlation found in those who did not have percutaneous coronary intervention (r=-0.52, p=0.03). Using receiver operating characteristic curve analysis, an FMD of 8.2% identified an IMR of >34 as the threshold, with 77.6% sensitivity and 52.4% specificity. In patients who did not have a percutaneous coronary intervention, an FMD of 11.49% identified an IMR of >34 with 84.6% sensitivity and 80% specificity. In conclusion, ticagrelor significantly improved peripheral endothelial function compared with clopidogrel in patients with NSTEACS. There was a significant correlation between brachial artery FMD and IMR of the infarct-related artery.

ENDOTHELIAL FUNCTIONAL STATUS IN PATIENTS WITH HYPERTENSION AND TYPE 2 DIABETES MELLITUS AFTER COVID-19

Objective: Aim of the study was to estimate endothelial functional status in patients with hypertension and type 2 diabetes mellitus (T2DM) who underwent Covid-19. Design and method: 56 patients with hypertension and T2DM after coronavirus infection (Group I) and 56 patients with hypertension and T2DM without any history of Covid-19 (Group II) were enrolled in this study. Group I patients aged 43-75 years, mean age 62.4±12.5 years; male = 46% and Group II patients aged 42-77 years, mean age 63.6±13.7 years; male = 43%. Endothelial functional status was assessed by flow-mediated vasodilation of brachial artery (FMD). All statistical analysis were performed by SPSS 26.0 software. Results: FMD of brachial artery was significantly decreased in patients with hypertension and T2DM after Covid-19 than those patients without Covid-19 (P&lt;0.01). There were a correlation between Covid-19 and reduced FMD in Group I (r = 0.7, CI 95%, P = 0.032). When we assessed systolic function of the left ventricle, there were a positive correlation between reduced FMD and low ejection fraction (r = 0.6, CI 95%, P = 0.028), however this correlation were more pronounced in Group I (P = 0.001). Multivariate analysis revealed that reduced flow-mediated vasodilation of brachial artery was independent predictor of poor systolic function of patients with hypertension and T2DM especially in those after Covid-19 (odds ratio [OR] 1.52, P = 0.026). When we separately analyzed between men and women there were not any statistical significant changes between male and female (P&gt;0.05). Conclusions: Patients with hypertension and type 2 diabetes mellitus after Covid-19 had impaired FMD of brachial artery. Even though, there were positive correlation between flow-mediated vasodilation of brachial artery and reduced ejection fraction, patients with hypertension and T2DM after Covid-19 had strong correlation of it. In hypertensive patients with type 2 diabetes mellitus who have undergone Covid-19, FMD independently associated with poor left ventricular systolic function.

Evaluation of Circulating Platelet Extracellular Vesicles and Hypertension Mediated Organ Damage.

Elevated circulating platelet-derived extracellular vesicles (pEVs) have been associated with arterial hypertension. The role of hypertension-mediated organ damage (HMOD) to induce EV release is still unknown. We studied the micro- and macro-vascular changes (retinal vascular density and pulse wave velocity), endothelial function (flow-mediated vasodilation of brachial artery and finger plethysmography), and assessed the psychosocial status (anxiety and depression) in hypertensive patients to determine their relationship with EV release. Pulse wave velocity showed a significant positive correlation with pEVs (r = 0.33; p = 0.01). Systolic blood pressure (SBP) negatively correlated with retinal vascularity. The superficial retinal vascular plexus density in the whole image showed a significant negative correlation with 24 h SBP (r = −0.38, p < 0.01), day-SBP (r = −0.35, p = 0.01), and night-SBP (r = −0.27, p = 0.04). pEVs did not show significant associations with microvascular damage (retinal vascular density), endothelial function (flow-mediated vasodilation of brachial artery and finger plethysmography), or psychosocial status (anxiety and depression). Our results indicate that the pEV levels were associated with macrovascular damage measured by PWV, whereas no significant association between pEVs and microvascular damage, endothelial function, or emotional status could be detected. The potential utility of pEV in clinical practice in the context of HMOD may be limited to macrovascular changes.

Effects of tofacitinib therapy on arginine and methionine metabolites in association with vascular pathophysiology in rheumatoid arthritis: A metabolomic approach.

Rheumatoid arthritis (RA) has been associated with changes in lipid, arginine and NO metabolism with increased cardiovascular (CV) risk. The aim of this study is to evaluate the effect of tofacitinib, a Janus kinase (JAK) inhibitor, on arginine and methionine metabolism in correlation with inflammation, functional and pathological vascular changes during one-year treatment of patients with RA. Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) levels. We assessed brachial artery flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) by ultrasound at baseline and after 6 and 12 months. We also determined plasma L-arginine, L-citrulline, L-ornithine, inducible nitric oxide synthase (iNOS), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-N-monomethyl-arginine (L-NMMA), cysteine, homocysteine, and methionine levels at these time points. Twenty-six patients (13 on each arm) completed the study. CRP, ESR and DAS28 decreased significantly during one-year treatment with tofacitinib. Arginine and ADMA showed a negative univariate correlation with CRP but not with FMD, PWV or IMT. Tofacitinib at 10 mg bid significantly increased L-arginine, L-ornithine, iNOS and methionine levels after 12 months. ADMA and SDMA levels did not change in our study. Methionine showed negative correlation with FMD at baseline and positive correlation with PWV after 12 months. No change was observed in FMD and PWV but a significant increase was measured in IMT at 6 and 12 months. Multivariate analysis indicated variable correlations of L-arginine, L-citrulline, ADMA, L-NMMA, homocysteine and methionine with DAS28, CRP, ESR and RF but not with anti-CCP after one-year treatment. With respect to vascular pathophysiology, only PWV and methionine correlated with each other. One-year tofacitinib treatment suppressed systemic inflammation and improved functional status in RA. FMD, PWV have not been affected by one-year tofacitinib treatment., while IMT increased further despite treatment. Increased arginine and methionine might contribute to the anti-inflammatory effects of tofacitinib. Increased arginine availability with no changing ADMA may protect FMD and PWV from deterioration. The increase of IMT in the anti-inflammatory environment cannot be explained by arginine or methionine metabolism in this study.

Aerobic exercise training improves not only brachial artery flow-mediated vasodilatation but also carotid arteryreactivity: A randomized controlled, cross-over trial in older men.

It is well‐known that aerobic exercise training beneficially affects endothelial function as measured by brachial artery flow‐mediated vasodilation (FMD). This trial with older sedentary overweight and obese men, therefore, examined the effects of aerobic training on other non‐invasive markers of the vasculature, which have been studied in less detail. Seventeen men (67 ± 2 years, BMI: 30.3 ± 2.8 kg/m2) participated in this controlled cross‐over study. Study participants followed in random order a fully supervised, progressive, aerobic exercise training (three 50‐min sessions each week at 70% maximal power) and a no‐exercise control period for 8 weeks, separated by a 12‐week wash‐out period. At the end of each period, endothelial function was assessed by the carotid artery reactivity (CAR) response to a cold pressor test and FMD, and local carotid and regional aortic stiffness by the carotid‐to‐femoral pulse wave velocity (PWVc–f). The retinal microvasculature, the serum lipid profile, 24‐h ambulatory blood pressure, and 96‐h continuous glucose concentrations were also determined. Aerobic training increased CAR from 1.78% to 4.01% (Δ2.23 percentage point [pp]; 95% CI: 0.58, 3.89 pp; p = 0.012) and FMD from 3.88% to 6.87% (Δ2.99 pp; 95% CI: 0.58, 5.41 pp; p = 0.019). The stiffness index β0 increased by 1.1 (95% CI: 0.3, 1.9; p = 0.012), while PWVc–f did not change. Retinal arteriolar width increased by 4 μm (95% CI: 0, 7 μm; p = 0.041). Office blood pressure decreased, but ambulatory blood pressure, and serum lipid and continuous glucose concentrations did not change. Aerobic exercise training improved endothelial function and retinal arteriolar width in older sedentary overweight and obese men, which may reduce cardiovascular risk.

Cardiorespiratory Fitness and Endothelial Function in Aging Healthy Subjects and Patients With Cardiovascular Disease.

BackgroundIndividuals with a higher lifelong cardiorespiratory fitness show better vascular health with aging. Studies on fitness-related effects on endothelial function either analyzed samples with a narrow age-range or incompletely assessed endothelial responsiveness. This study aims to assess the impact of cardiorespiratory fitness on the association of brachial-arterial flow-mediated vasodilation (FMD) and low flow-mediated vasoconstriction (L-FMC) with age in healthy adults and patients with cardiovascular diseases.MethodsFMD, L-FMC and O2peak were prospectively measured in a population-based sample including 360 healthy adults and 99 patients with cardiovascular disease of European descend. Non-linear models were applied to assess O2peak-associated variations in age-related differences of endothelial function independent of classical cardiovascular risk factors.ResultsFMD was negatively associated with age in healthy adults (adjusted R2 = 0.27, partial R2 = 0.07, p < 0.001) and in cardiovascular patients (adjusted R2 = 0.29, partial R2 = 0.05, p = 002). L-FMC showed no association with age. In models predicting the change of FMD with higher age, O2peak accounted for 2.8% of variation in FMD (χ2(5) = 5.37, p = 0.372, s = 1.43). Thereby, O2peak-stratified changes of FMD started to fan out at around 30 years of age in women and 50 years of age in men, with 7–12% lower values at old age with O2peak ≤3rd percentile compared to O2peak ≥97th percentile) in both, the healthy sample and in cardiovascular patients.ConclusionThe statistical effect of cardiorespiratory fitness on the association of FMD with age independent of classical cardiovascular risk factors was small in both, healthy aging adults as well as patients with cardiovascular diseases. Its clinical significance should be assessed further.

Effect of Stem Cell Infusion Therapy on Sexual Function in Men and Women with Type 2 Diabetes and Metabolic Syndrome: Results from the ACESO & CERES Clinical Trials

ABSTRACT Introduction Despite growing interest in restorative therapies for sexual function, there exists a paucity of human research into potential therapeutic applications of stem cell therapy (SCT). Mesenchymal Stem Cells (MSCs) and its effects on sexual function have not yet been explored in patients with Type 2 Diabetes Mellitus (DM) and Metabolic Syndrome (MetS) Objective To determine the effect of stem cell infusion therapy on sexual function in men and women with DM or MetS. Methods We used International Index of Erectile Function (IIEF-15) collected from men and Sexual Quality of Life Questionnaire-Female (SQOL-F) collected from women enrolled in the ACESO (NCT02886884) and CERES (NCT03059355) pilot/phase I clinical trials. Participants were enrolled in the trials based on diagnosis of DM or MetS, respectively, and endothelial dysfunction - defined as Brachial Artery Flow Mediated Vasodilation (FMD) &amp;lt;7%. Intervention in both trials was peripheral intravenous infusion of allogeneic MSCs. Follow-up was for 1 year. Questionnaires were collected at baseline and at 1-, 3-, 6-, and 12-months post-infusion. Participants received 20 or 100 million MSCs from either bone marrow (n=21) or umbilical cord (n=6). We performed subgroup analyses evaluating dose, source, and study diseases. Descriptive and analytic statistics were used to analyze the data. Results Data was pooled from 20 men and 7 women from the two trials. Overall, 14 received 100 million MSCs and 13 received 20 million MSCs. Median age was 61 [IQR=55-73] years. Incidence of hypertension, coronary artery disease, smoking and alcohol use were similar among each trial. Erectile dysfunction (ED) was defined by an IIEF-Erectile Function (IIEF-EF) sub-domain score ≤24 at baseline (n=16). Among men with ED, median IIEF-EF score at baseline was 5 [IQR=2-17], 6 [IQR=3-17] at 1 month, 3 [IQR=2-8] at 3 months, 4 [IQR=3-13] at 6 months, and 5.5 [IQR=2-16] at the end of 12 months (p=0.8127). Subgroup analyses revealed no changes in erectile function in either treatment dose. Similar patterns were found in other IIEF sub-domains, except median sexual desire score which increased among all men from 1-3 months post-infusion, then subsided from 6-12 months (p=0.4723). SQOL-f is a validated self-assessment questionnaire rated on a six-point scale in which higher scores reflect better female sexual quality of life. Median SQOL score among all women at baseline was 30 [IQR=19-50], 25 [IQR=23-36] at 1 month, 34 [IQR=19-46] at 3 months, 29 [IQR=21-32] at 6 months, and 34 [IQR=26-49] at the end of 12 months (p=0.8866). Main limitations of this study include the small sample size, sexual function was not a primary endpoint, and the absence of a placebo comparison arm. Conclusions Neither ED or SQOL appears to have improved following peripheral infusion of MSCs in patients with DM and MetS, but nevertheless appears to be safe with no decline in sexual function over 1 year. The optimal route, source, and dose of SCT to enact a meaningful change in sexual function in different patient populations has yet to be determined and deserves further research in future larger randomized clinical trials. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Longeveron LLC

Longer-term soy nut consumption improves vascular function and cardiometabolic risk markers in older adults: Results of a randomized, controlled cross-over trial

Soy foods may contribute to the beneficial health effects of healthy plant-based diets on the risk to develop cardiovascular disease (CVD). However, their effects on vascular function have hardly been studied. To investigate longer-term effects of soy nut consumption on vascular function and cardiometabolic risk markers in healthy older men and women. Twenty-three healthy participants (age: 60-70 years; BMI: 20-30kg/m2) participated in a randomized, controlled, single-blinded cross-over trial with an intervention (67g/day of soy nuts providing 25.5g protein and 174mg isoflavones) and control period (no nuts) of 16 weeks, separated by eight weeks wash-out. Adults followed the Dutch food-based dietary guidelines. No serious adverse events were reported and the soy nut regime was well tolerated. Body weights remained stable during the whole study. A higher protein (3.1 energy percent [En%]) and a lower carbohydrate intake (2.0 En%) was observed during the intervention period. Total fat intake was comparable, but that of saturated (-1.3 En%), cis-monounsaturated (-1.5 En%) and cis-polyunsaturated fatty acids (+1.9 En%) differed. Serum isoflavone concentrations were higher after the intervention as compared with the control period (daidzein: 127.8ng/mL; 95% CI: 74.3-181.3ng/mL; p<0.001 and genistein: 454.2ng/mL; 95% CI: 266.6-641.8ng/mL; p<0.001). Brachial artery flow-mediated vasodilation was 1.48 percent points (pp; 95% CI: 0.08-2.89 pp; p=0.040) higher following soy nut intake. The carotid artery reactivity response and arterial stiffness did not differ. Serum LDL-cholesterol was lower (0.17mmol/L; 95% CI: 0.02-0.32mmol/L; p=0.027), while HDL-cholesterol and triacylglycerol concentrations were comparable. Mean arterial pressure (MAP) was lower (3mmHg; 95% CI: 0-6mmHg; p=0.035). Longer-term soy nut intake as part of a healthy diet improved endothelial function, LDL-cholesterol concentrations and MAP levels, suggesting mechanisms by which an increased soy food intake beneficially affects CVD risk in older adults. Registered under ClinicalTrials.gov Identifier no. NCT03627637.

Abstract P184: Racial Differences In Mental Stress-induced Transient Endothelial Dysfunction And Its Association With Cardiovascular Outcomes

Background: An established link exists between acute mental stress and the development of transient endothelial dysfunction (TED) as assessed by brachial artery flow-mediated vasodilation (FMD). Black individuals have a high burden of cardiovascular (CV) risk factors and social disadvantages, which may result in adverse vascular responses to stress. We investigated differences in TED with mental stress in Black and non-Black individuals with coronary artery disease (CAD), and whether TED is associated with CV outcomes in both groups. Methods: We enrolled 812 patients with stable CAD between June 2011 and March 2016 and followed them through February 2020. Study participants were subjected to a public-speaking mental stress task and FMD (derived from % vasodilation with brachial artery hyperemia testing) was assessed by ultrasound before and 30 minutes after mental stress. TED was defined as a lower post-stress FMD than pre-stress FMD. We compared pre-stress FMD, post-stress FMD, and TED between Black and non-Black participants. In both groups, we examined the association of TED with an adjudicated composite end point of CV death and myocardial infarction (MI) after adjusting for demographic, clinical, and socioeconomic factors. Both first and recurring events were counted and multivariable models for repeated events were used for analysis. Results: The mean (SD) age was 59 (10) years, and 328 (40%) were Black. Pre-stress FMD was lower in Black than non-Black participants [3.7 (2.8) vs. 4.9 (3.8) p&lt;0.001], and significantly declined with mental stress in both groups. TED occurred more often in Black (76%) than non-Black patients (67%), age- and sex-adjusted OR, 1.6, 95% CI, 1.4-1.7). Race related differences in TED persisted after adjustment for demographic factors, CAD risk factors and medications (Black vs. non-Black OR, 1.6, 95% CI, 1.5-1.7). After further adjusting for socioeconomic indicators (education, income, and employment status), TED remained elevated in Black patients (OR, 1.4 (95% CI, 1.3-1.6). Over a median (interquartile range) follow-up period of 75 (65-82) months, 142 (18%) patients had at least one event. Development of TED with mental stress was associated with an increased risk for the study outcome both in Black (age- and sex-adjusted HR, 3.0; 95% CI, 1.3-6.8) and non-Black participants (HR, 1.7, 95% CI, 0.96-3.0), p=0.26 for interaction. Adjustment for demographic, clinical and socioeconomic factors did not diminish these associations. Conclusions: Among CAD patients, Black individuals are more likely than non-Black individuals to develop endothelial dysfunction with mental stress, which in turn is associated with an increased risk of adverse cardiovascular events. Endothelial dysfunction in response to psychological stress may represent an important mechanism for the disproportionate risk of adverse CV outcomes in Black patients.

Effects of L-citrulline supplementation and watermelon consumption on longer-term and postprandial vascular function and cardiometabolic risk markers: A meta-analysis of randomized controlled trials in adults.

L-citrulline may improve non-invasive vascular function and cardiometabolic risk markers through increases in L-arginine bioavailability and nitric oxide synthesis. A meta-analysis of randomized controlled trials (RCTs) was performed to examine longer-term and postprandial effects of L-citrulline supplementation and watermelon consumption on these markers for cardiovascular disease in adults. Summary estimates of weighted mean differences (WMDs) in vascular function and cardiometabolic risk markers with accompanying 95% confidence intervals (CIs) were calculated using random or fixed-effect meta-analyses. Seventeen RCTs were included involving an L-citrulline intervention, of which six studied postprandial and twelve longer-term effects. Five studies investigated longer-term effects of watermelon consumption and five assessed effects during the postprandial phase. Longer-term L-citrulline supplementation improved brachial artery flow-mediated vasodilation (FMD) by 0.9 %-point (95 % CI: 0.7 to 1.1, P < 0.001). Longer-term watermelon consumption improved pulse wave velocity by 0.9 m/s (95% CI: 0.1 to 1.5, P < 0.001), while effects on FMD were not studied. No postprandial effects on vascular function markers were found. Postprandial glucose concentrations decreased by 0.6 mmol/L (95% CI: 0.4 to 0.7, P < 0.001) following watermelon consumption, but no other longer-term or postprandial effects were observed on cardiometabolic risk markers. To conclude, longer-term L-citrulline supplementation and watermelon consumption may improve vascular function, suggesting a potential mechanism by which increased L-citrulline intake beneficially affects cardiovascular health outcomes in adults. No effects on postprandial vascular function markers were found, while more research is needed to investigate effects of L-citrulline and watermelon on risk markers related to cardiometabolic health.

Role of endothelial cell specific molecule-1 (endocan) and cardiac imaging in early detection of cardiac involvement in psoriatic patients with or without arthritis

Aim of the workMeasuring serum endocan level to determine its potential role in detecting subclinical cardiovascular involvement in psoriatic patients with or without arthritis. Patients and methodsThis work included 14 psoriatic arthritis (PsA) patients, 14 psoriasis only (PsO) patients, and 14 age and sex matched controls. The psoriasis area severity index was evaluated. Serum endocan level was measured, subclinical atherosclerosis was assessed using brachial artery flow-mediated vasodilation (FMD), and echocardiography: standard and tissue Doppler imaging (TDI) was performed. ResultsThe mean age of PsA patients was 38.3 ± 9.9 years and for PsO was 37.9 ± 8 years. They were 3 males and 11 females in both groups with a comparable psoriasis duration (11 ± 4.9 vs 8 ± 6.3 years; p = 0.17). PsA patients had significantly increased endocan level (618 ± 227.8 ng/L) compared to those with PsO or controls (359 ± 185.7 and 130.6 ± 38.2 ng/L respectively; p < 0.001). 4 (28.6%) PsA patients, 1 (7.1%) PsO patient and none of the controls had FMD abnormality. TDI revealed early diastolic mitral annular motion velocity (E') abnormality in 5 (35.7%) PsA patients. In PsA patients, endocan level was significantly elevated in patients with FMD or E' abnormality compared to those without (p = 0.01 and p = 0.001, respectively). Serum endocan significantly negatively correlated with FMD and E' in psoriatic patients. Serum endocan significantly detected FMD and E' abnormalities in psoriatic patients (p = 0.002 and p = 0.001, respectively). ConclusionSubclinical cardiovascular involvement was evident among psoriatic patients, particularly those with arthritis. Serum endocan is a promising endothelial biomarker for detecting subclinical atherosclerosis and preclinical cardiac dysfunction in psoriatic patients.

Association of enhanced circulating trimethylamine N-oxide with vascular endothelial dysfunction in periodontitis patients.

Accumulating evidences indicate that periodontitis is closely associated with endothelial dysfunction. Trimethylamine-N-oxide (TMAO), a harmful microbiota generated metabolite, has been implicated as a nontraditional risk factor for impaired endothelial function. However, whether increased circulating levels of TMAO in periodontitis patients induces endothelial dysfunction remains unknown. Patients with periodontitis and periodontally healthy controls were enrolled. Periodontal inflamed surface area (PISA) was calculated to assess the inflammatory burden posed by periodontitis. The circulating TMAO was measured by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Vascular endothelial function including peripheral endothelial progenitor cells (EPCs), brachial arterial flow-mediated vasodilation (FMD), and brachial-ankle pulse wave velocity (baPWV) were assessed. We also isolated and cultured EPCs from participants' peripheral blood to investigate the effect of TMAO on EPC functions in vitro. One hundred and twenty two patients with Stage III-IV periodontitis and 81 healthy controls were included. Patients with periodontitis presented elevated TMAO (P=0.002), lower EPCs (P=0.025), and declined FMD levels (P=0.005). The TMAO concentrations were correlated with reduced circulating EPCs and FMD levels. Moreover, TMAO can injury EPCs function in vitro, and may induce cell pyroptosis via Bax/caspase-3/GSDME pathway. The present study demonstrates for the first time that circulating TMAO levels are increased in patients with Stage III-IV periodontitis, and correlated with vascular endothelial dysfunction. These findings may provide a novel insight into the mechanism of vascular endothelial dysfunction in patient with periodontitis via TMAO-downregulated EPC functions.