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Item Arterial Elasticity in Ehlers-Danlos Syndromes(MDPI, 2020-01-04) Miller, Amanda J.; Schubart, Jane R.; Sheehan, Timothy; Bascom, Rebecca; Francomano, Clair A.; Medical and Molecular Genetics, School of MedicineEhlers-Danlos Syndromes (EDS) are a group of heritable disorders of connective tissue (HDCT) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Orthostatic intolerance (OI) is highly prevalent in EDS however mechanisms linking OI to EDS remain poorly understood. We hypothesize that impaired blood pressure (BP) and heart rate control is associated with lower arterial stiffness in people with EDS. Orthostatic vital signs and arterial stiffness were assessed in a cohort of 60 people with EDS (49 female, 36 ± 16 years). Arterial elasticity was assessed by central and peripheral pulse wave velocity (PWV). Central PWV was lower in people with EDS compared to reference values in healthy subjects. In participants with EDS, central PWV was correlated to supine systolic BP (r = 0.387, p = 0.002), supine diastolic BP (r = 0.400, p = 0.002), and seated systolic BP (r = 0.399, p = 0.002). There were no significant correlations between PWV and changes in BP or heart rate with standing (p > 0.05). Between EDS types, there were no differences in supine hemodynamics or PWV measures (p > 0.05). These data demonstrate that increased arterial elasticity is associated with lower BP in people with EDS which may contribute to orthostatic symptoms and potentially provides a quantitative clinical measure for future genotype-phenotype investigations.Item Arterial stiffness is not acutely modified by consumption of a caffeinated soft drink sweetened with high‐fructose corn syrup in young healthy adults(Wiley, 2021) Freemas, Jessica A.; Greenshields, Joel T.; Baker, Tyler; Carter, Stephen J.; Johnson, Blair D.; Schlader, Zachary J.; Medicine, School of MedicineWe tested the hypothesis that ingestion of a caffeinated soft drink sweetened with high-fructose corn syrup acutely increases arterial stiffness. In a randomized counterbalanced, crossover design, fourteen healthy adults (25 ± 3 years, 6 women) reported to the laboratory for two experimental visits where 500 ml of tap water (H2 O) or 500 ml of Mountain Dew® (a caffeinated soft drink sweetened with high-fructose corn syrup (HFCS)) were consumed. Arterial stiffness (carotid-to-femoral pulse wave velocity (cfPWV)), peripheral and central blood pressures were measured pre-consumption, 30 min post-consumption, and 120 min post-consumption. Prior to each measurement period, beat-to-beat hemodynamic measures were collected. Changes in heart rate, blood pressure, and cardiac output from pre-consumption did not differ between trials at any timepoint (p ≥ 0.06). Moreover, changes in peripheral or central blood pressures from pre-consumption did not differ between trials (p ≥ 0.84). Likewise, changes in cfPWV from pre-consumption to 30 min post-consumption (HFCS: 0.2 ± 0.3 m/s, H2 O: 0.0 ± 0.3 m/s, p = 0.34) and 120 min post-consumption (HFCS: 0.3 ± 0.4 m/s, H2 O: 0.2 ± 0.3 m/s, p = 0.77) did not differ. Changes in aortic augmentation pressure, augmentation index, augmentation index corrected to a heart rate of 75 bpm, and reflection magnitude did not differ between conditions at 30 min post- (p ≥ 0.55) or 120 min post- (p ≥ 0.18) consumption. In healthy young adults, ingesting 500 ml of a commercially available caffeinated soft drink sweetened with high-fructose corn syrup does not acutely change indices of arterial stiffness and wave reflection.Item Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD(Wolters Kluwer, 2022) Nowak, Kristen L.; Farmer-Bailey, Heather; Wang, Wei; You, Zhiying; Steele, Cortney; Cadnapaphornchai, Melissa A.; Klawitter, Jelena; Patel, Nayana; George, Diana; Jovanovich, Anna; Soranno, Danielle E.; Gitomer, Berenice; Chonchol, Michel; Pediatrics, School of MedicineBackground and objectives: Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD. Design, setting, participants, & measurements: In a randomized, placebo-controlled, double-blind trial, 68 children/young adults 6-25 years of age with ADPKD and eGFR>80 ml/min per 1.73 m2 were randomized to either curcumin supplementation (25 mg/kg body weight per day) or placebo administered in powder form for 12 months. The coprimary outcomes were brachial artery flow-mediated dilation and aortic pulse-wave velocity. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume) by magnetic resonance imaging. In a subgroup of participants ≥18 years, vascular oxidative stress was measured as the change in brachial artery flow-mediated dilation following an acute infusion of ascorbic acid. Results: Enrolled participants were 18±5 (mean ± SD) years, 54% were girls, baseline brachial artery flow-mediated dilation was 9.3±4.1% change, and baseline aortic pulse-wave velocity was 512±94 cm/s. Fifty-seven participants completed the trial. Neither coprimary end point changed with curcumin (estimated change [95% confidence interval] for brachial artery flow-mediated dilation [percentage change]: curcumin: 1.14; 95% confidence interval, -0.84 to 3.13; placebo: 0.33; 95% confidence interval, -1.34 to 2.00; estimated difference for change: 0.81; 95% confidence interval, -1.21 to 2.84; P=0.48; aortic pulse-wave velocity [centimeters per second]: curcumin: 0.6; 95% confidence interval, -25.7 to 26.9; placebo: 6.5; 95% confidence interval, -20.4 to 33.5; estimated difference for change: -5.9; 95% confidence interval, -35.8 to 24.0; P=0.67; intent to treat). There was no curcumin-specific reduction in vascular oxidative stress or changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared with placebo. Conclusions: Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD.Item Diastolic dysfunction in women with ischemia and no obstructive coronary artery disease: Mechanistic insight from magnetic resonance imaging(Elsevier, 2021) Samuel, T. Jake; Wei, Janet; Sharif, Behzad; Tamarappoo, Balaji K.; Pattisapu, Varun; Maughan, Jenna; Cipher, Daisha J.; Suppogu, Nissi; Aldiwani, Haider; Thomson, Louise E. J.; Shufelt, Chrisandra; Berman, Daniel S.; Li, Debiao; Bairey Merz, C. Noel; Nelson, Michael D.; Medicine, School of MedicineBackground: Ischemia with no obstructive coronary artery disease (INOCA) is prevalent in women and is associated with increased risk of developing heart failure with preserved ejection fraction (HFpEF); however, the mechanism(s) contributing to this progression remains unclear. Given that diastolic dysfunction is common in women with INOCA, defining mechanisms related to diastolic dysfunction in INOCA could identify therapeutic targets to prevent HFpEF. Methods: Cardiac MRI was performed in 65 women with INOCA and 12 reference controls. Diastolic function was defined by left ventricular early diastolic circumferential strain rate (eCSRd). Contributors to diastolic dysfunction were chosen a priori as coronary vascular dysfunction (myocardial perfusion reserve index [MPRI]), diffuse myocardial fibrosis (extracellular volume [ECV]), and aortic stiffness (aortic pulse wave velocity [aPWV]). Results: Compared to controls, eCSRd was lower in INOCA (1.61 ± 0.33/s vs. 1.36 ± 0.31/s, P = 0.016); however, this difference was not exaggerated when the INOCA group was sub-divided by low and high MPRI (P > 0.05) nor was ECV elevated in INOCA (29.0 ± 1.9% vs. 28.0 ± 3.2%, control vs. INOCA; P = 0.38). However, aPWV was higher in INOCA vs. controls (8.1 ± 3.2 m/s vs. 6.1 ± 1.5 m/s; P = 0.045), and was associated with eCSRd (r = -0.50, P < 0.001). By multivariable linear regression analysis, aPWV was an independent predictor of decreased eCSRd (standardized β = -0.39, P = 0.003), as was having an elevated left ventricular mass index (standardized β = -0.25, P = 0.024) and lower ECV (standardized β = 0.30, P = 0.003). Conclusions: These data provide mechanistic insight into diastolic dysfunction in women with INOCA, identifying aortic stiffness and ventricular remodeling as putative therapeutic targets.