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Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD: A Randomized Controlled Trial.
Nowak, KL, Farmer-Bailey, H, Wang, W, You, Z, Steele, C, Cadnapaphornchai, MA, Klawitter, J, Patel, N, George, D, Jovanovich, A, et al
Clinical journal of the American Society of Nephrology : CJASN. 2022;(2):240-250
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Abstract
BACKGROUND 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. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD, NCT02494141. PODCAST This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_07_CJN08950621.mp3.
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A Low-Calorie Diet with or without Exercise Reduces Postprandial Aortic Waveform in Females with Obesity.
Heiston, EM, Gilbertson, NM, Eichner, NZM, Malin, SK
Medicine and science in sports and exercise. 2021;(4):796-803
Abstract
PURPOSE Arterial stiffness is considered a predictor of cardiovascular disease. Females have higher values of arterial stiffness than males, suggesting a greater risk of heart-related complications. Although a low-calorie diet (LCD) reduces fasting arterial stiffness, in part through weight loss, it is unknown if interval exercise (INT) adds to the benefit of LCD on fasting and postprandial arterial stiffness in females with obesity. METHODS Twenty-five females (47 ± 2.6 yr, 37.6 ± 1.3 kg·m-2) were randomized to 13 d of LCD (n = 12; mixed meals of ~1200 kcal·d-1) or LCD + INT (n = 13; 60 min·d-1 of supervised 3-min intervals at 90% HRpeak and 50% HRpeak). Arterial stiffness (augmentation index [AIx] and carotid-femoral pulse wave velocity [cfPWV]) and blood biochemistries were measured during a 75-g oral glucose tolerance test before and after the intervention to determine fasting and postprandial arterial stiffness as well as insulin sensitivity (simple index of insulin sensitivity [SIIS]) and inflammation (C-reactive protein, interleukin 8, and tumor necrosis factor alpha). RESULTS Although LCD + INT increased V˙O2peak and HDL compared with LCD (P = 0.04 and P < 0.01, respectively), both interventions decreased body fat, LDL, total cholesterol, and triglycerides (all P < 0.01) and increased SIIS (P = 0.03). Despite no effect on fasting AIx (P = 0.27), LCD and LCD + INT decreased AIx60min (-7.4% ± 4.3% vs -7.0% ± 5.0%, P = 0.04) and tAUC120min (-663 ± 263 vs -457 ± 406, P = 0.03). There were no changes in fasting cfPWV (P = 0.91) or cfPWV120min (P = 0.62). Increased SIIS and decreased interleukin 8 were associated with reduced fasting AIx (r = -0.44, P = 0.03, and r = 0.40, P = 0.055), whereas decreased C-reactive protein correlated with reduced postprandial AIx60min (r = 0.43, P = 0.04). CONCLUSION Independent of exercise, 13 d of LCD reduces postprandial AIx in females with obesity. Insulin sensitivity and inflammation correlated with improved arterial stiffness, suggesting unique mechanisms regulate fasted versus postprandial arterial stiffness.
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Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial.
Katakami, N, Mita, T, Yoshii, H, Shiraiwa, T, Yasuda, T, Okada, Y, Torimoto, K, Umayahara, Y, Kaneto, H, Osonoi, T, et al
Cardiovascular diabetology. 2021;(1):4
Abstract
BACKGROUND Tofogliflozin, an SGLT2 inhibitor, is associated with favorable metabolic effects, including improved glycemic control and serum lipid profile and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the effects of tofogliflozin on the brachial-ankle pulse wave velocity (baPWV) in patients with type 2 diabetes (T2DM) without a history of apparent cardiovascular disease. METHODS The using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. As one of the prespecified secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofogliflozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline. RESULTS In a mixed-effects model, the progression in the right, left, and mean baPWV over 104 weeks was significantly attenuated with tofogliflozin compared to that with conventional treatment (- 109.3 [- 184.3, - 34.3] (mean change [95% CI] cm/s, p = 0.005; - 98.3 [- 172.6, - 24.1] cm/s, p = 0.010; - 104.7 [- 177.0, - 32.4] cm/s, p = 0.005, respectively). Similar findings were obtained even after adjusting the mixed-effects models for traditional cardiovascular risk factors, including body mass index (BMI), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, systolic blood pressure (SBP), hypertension, smoking, and/or administration of drugs, including hypoglycemic agents, antihypertensive agents, statins, and anti-platelets, at baseline. The findings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardiovascular risk factors, resembled those generated by the mixed-effects models. CONCLUSIONS Tofogliflozin significantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofogliflozin suppressed the progression of arterial stiffness. Trial Registration UMIN000017607. Registered 18 May 2015. ( https://www.umin.ac.jp/icdr/index.html ).
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The Effect of Aerobic Exercise Training Frequency on Arterial Stiffness in a Hyperglycemic State in Middle-Aged and Elderly Females.
Kobayashi, R, Asaki, K, Hashiguchi, T, Negoro, H
Nutrients. 2021;(10)
Abstract
The frequency of aerobic exercise training in reducing the increase in arterial stiffness during acute hyperglycemia, a risk factor for cardiovascular disease, is unknown. The aim of the study was to determine the aerobic exercise training frequency on arterial stiffness in a hyperglycemic state in middle-aged and elderly females. Twenty healthy elderly people were randomly assigned to a two-times-a-week (T2, n = 10) and four-times-a-week (T4, n = 10) exercise group. All participants exercised for 35 min per session, which consisted of jogging exercises with a heart rate intensity of 65%. Brachial-ankle (ba), and heart-brachial (hb) pulse wave velocity (PWV) were measured before, 4 and 8 weeks after intervention; before the oral ingestion of 75-g of glucose; and 30, 60, and 90 min after ingestion. The baPWV before and 4 weeks after the intervention increased in both groups (p < 0.05), but only increased 8 weeks after intervention in the T2 group. hbPWV was unchanged before, 4 and 8 weeks after intervention in both groups. These findings show that frequent aerobic exercise suppresses the increase in arterial stiffness following glucose intake. The results of this study can be used to support the implementation of exercise programs for middle-aged and elderly patients.
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Efficacy of dulaglutide on vascular health indexes in subjects with type 2 diabetes: a randomized trial.
Tuttolomondo, A, Cirrincione, A, Casuccio, A, Del Cuore, A, Daidone, M, Di Chiara, T, Di Raimondo, D, Corte, VD, Maida, C, Simonetta, I, et al
Cardiovascular diabetology. 2021;(1):1
Abstract
BACKGROUND Recent cardiovascular outcome trials have shown significant reductions in major cardiovascular (CV) events with glucagon-like peptide (GLP)-1 receptor agonists. Additionally, adjunctive surrogates for cardiovascular risk validated by some studies include arterial stiffness and endothelial function indexes. To date, no randomized trial has addressed the possible effects of antidiabetic interventional drugs such as GLP1 agonists on endothelial and arterial stiffness indexes as surrogate markers of vascular damage. AIMS We aimed to evaluate metabolic efficacy and surrogate vascular efficacy endpoints of once-weekly dulaglutide (1.5 mg) plus traditional antidiabetic treatment compared with traditional antidiabetic treatment alone in subjects with type 2 diabetes. METHODS Men and women (aged ≥ 50 years) with established or newly detected type 2 diabetes whose HbA1c level was 9.5% or less on stable doses of up to two oral glucose- lowering drugs with or without basal insulin therapy were eligible for randomization. Subcutaneous dulaglutide was initiated at the full dose (1.5 mg/day weekly). Arterial stiffness (PWV: pulse wave velocity and augmentation index) and endothelial function (RHI: reactive hyperaemia index) were evaluated at baseline and at three-month and nine-month examination visits. At each visit (at 3 and 9 months), the subjects were also evaluated for glycaemic variables such as fasting plasma glucose (FPG) and HbA1c and lipid variables such as total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels. RESULTS At the three-month follow-up, the subjects treated with dulaglutide showed significantly lower serum levels of FPG and HbA1c than control subjects treated with conventional therapy. At the 9-month follow-up, subjects treated with dulaglutide showed significant lower values of the mean diastolic blood pressure, BMI, total serum cholesterol, LDL cholesterol, FPG, HbA1c and PWV and higher mean RHI values than control subjects treated with conventional therapy. CONCLUSIONS Our randomized trial showed that subjects with type 2 diabetes treated with conventional therapy plus 1.5 mg/day of subcutaneous dulaglutide compared with subjects treated with conventional therapy alone showed favourable metabolic effects associated with positive effects on vascular health markers such as arterial stiffness and endothelial function markers. These findings are consistent with previous study findings indicating the strict relationship between cardiovascular risk factors such as systolic blood pressure, total serum cholesterol and LDL levels and cardiovascular events and vascular health surrogate markers.
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Daily 100% watermelon juice consumption and vascular function among postmenopausal women: A randomized controlled trial.
Ellis, AC, Mehta, T, Nagabooshanam, VA, Dudenbostel, T, Locher, JL, Crowe-White, KM
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2021;(10):2959-2968
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BACKGROUND AND AIMS Watermelon juice is a rich food source of cardioprotective compounds such as arginine, citrulline, and lycopene. Preventative interventions are warranted as risk of cardiovascular disease increases among women after menopause, and age alone is an independent risk factor for vascular dysfunction. Thus, this study evaluated the effects of 100% watermelon juice on measures of vascular function. METHODS AND RESULTS In this randomized, double-blind, placebo-controlled, crossover trial, 21 healthy postmenopausal women were randomized to consume two 360 mL servings of 100% watermelon juice per day or an isocaloric placebo for four weeks. Following a two-week washout period, they consumed the other beverage for an additional four weeks. Before and after each treatment arm, a fasting blood sample was taken for measurement of serum arginine, citrulline, lycopene, glucose, and insulin. Assessments of vascular function included pulse pressure, pulse wave velocity, 24-h ambulatory blood pressure, and flow-mediated dilation. General linear mixed models with intent-to-treat analyses were used to examine the effects of the intervention. Despite a significant treatment effect for circulating lycopene (p = 0.002), no changes in arginine, citrulline, or any vascular measures were observed. Although the juice intervention resulted in a slight but significant increase in fasting serum glucose (p = 0.001), changes in glucose homeostasis were not clinically significant. CONCLUSION In contrast to findings from previous studies in younger adults and those with pre-existing hypertension, measures of vascular function in this cohort of healthy postmenopausal women were not impacted by supplemental watermelon juice. CLINICALTRIALS. GOV IDENTIFIER NCT03626168.
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Long Chain Omega-3 Polyunsaturated Fatty Acids Improve Vascular Stiffness in Abdominal Aortic Aneurysm: A Randomized Controlled Trial.
Meital, LT, Schulze, K, Magee, R, O'Donnell, J, Jha, P, Meital, CY, Donkin, R, Bailey, TG, Askew, CD, Russell, FD
Nutrients. 2020;(1)
Abstract
Abdominal aortic aneurysm (AAA) is a vascular disease involving permanent focal dilation of the abdominal aorta (≥30 mm) that can lead to catastrophic rupture. Destructive remodeling of aortic connective tissue in AAA contributes to wall stiffening, a mechanical parameter of the arterial system linked to a heightened risk of cardiovascular morbidity and mortality. Since aortic stiffening is associated with AAA progression, treatment options that target vascular inflammation would appear prudent. Given this, and growing evidence indicating robust anti-inflammatory and vasoprotective properties for long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs), this study evaluated the impact of these nutrients (1.8 g/day for 12 weeks) on indices of vascular stiffness in patients with AAA. At baseline, pulse wave velocity (PWV) and augmentation index normalized to a heart rate of 75 bpm (AIx75) were significantly higher in patients with AAA compared to control participants (PWV: 14.2 ± 0.4 m.s-1 vs. 12.6 ± 0.4 m.s-1, p = 0.014; AIx75: 26.4 ± 1.7% vs. 17.3 ± 2.7%, p = 0.005). Twelve-week LC n-3 PUFA supplementation significantly decreased PWV (baseline: 14.2 ± 0.6 m.s-1, week 12: 12.8 ± 0.7 m.s-1, p = 0.014) and heart rate (baseline: 63 ± 3 bpm, week 12: 58 ± 3 bpm, p = 0.009) in patients with AAA. No change was observed for patients receiving placebo capsules. While this raises the possibility that LC n-3 PUFAs provide improvements in aortic stiffness in patients with AAA, the clinical implications remain to be fully elucidated.
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Effects of Cocoa-Rich Chocolate on Blood Pressure, Cardiovascular Risk Factors, and Arterial Stiffness in Postmenopausal Women: A Randomized Clinical Trial.
Garcia-Yu, IA, Garcia-Ortiz, L, Gomez-Marcos, MA, Rodriguez-Sanchez, E, Agudo-Conde, C, Gonzalez-Sanchez, J, Maderuelo-Fernandez, JA, Recio-Rodriguez, JI
Nutrients. 2020;(6)
Abstract
This study aimed to evaluate the effects of the intake of 10 g of cocoa-rich chocolate on blood pressure, other cardiovascular risk factors, and vascular structure and function in postmenopausal women. A total of 140 postmenopausal women participated in this randomized and controlled parallel clinical trial. For six months, the intervention group (IG; n = 73) consumed daily 10 g of chocolate (99% cocoa) added to their usual food intake, whereas the control group (CG; n = 67) did not receive any intervention. Blood pressure, pulse pressure (PP), cardio-ankle vascular index (CAVI), ankle-brachial index (ABI), brachial-ankle pulse wave velocity (baPWV), augmentation index, and laboratory variables were measured at baseline and six months. ANCOVA analyses adjusted for baseline values revealed no significant differences for systolic blood pressure (-1.45 mm Hg; 95% confidence interval (CI): -4.79, 1.88; p = 0.391) or baPWV (0.18 m/s; 95% CI: -0.14, 0.50; p = 0.263) between groups. A decrease in PP was observed in the IG compared to the CG (-2.05 mm Hg; 95% CI: -4.08, -0.02; p = 0.048). The rest of the vascular structure and function parameters and other measured variables remained unchanged. The daily intake of 10 g of cocoa-rich chocolate seems to provide little improvement to cardiovascular health, but neither does it cause any adverse effects on the parameters evaluated in postmenopausal women in the long term.
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The Effect of High Polyphenol Extra Virgin Olive Oil on Blood Pressure and Arterial Stiffness in Healthy Australian Adults: A Randomized, Controlled, Cross-Over Study.
Sarapis, K, Thomas, CJ, Hoskin, J, George, ES, Marx, W, Mayr, HL, Kennedy, G, Pipingas, A, Willcox, JC, Prendergast, LA, et al
Nutrients. 2020;(8)
Abstract
Extra virgin olive oil (EVOO) is suggested to be cardioprotective, partly due to its high phenolic content. We investigated the effect of extra virgin high polyphenol olive oil (HPOO) versus low polyphenol olive oil (LPOO) on blood pressure (BP) and arterial stiffness in healthy Australian adults. In a double-blind, randomized, controlled cross-over trial, 50 participants (age 38.5 ± 13.9 years, 66% female) were randomized to consume 60 mL/day of either HPOO (360 mg/kg polyphenols) or LPOO (86 mg/kg polyphenols) for three weeks. Following a two-week washout period, participants crossed over to consume the alternate oil. Anthropometric data, peripheral BP, central BP and arterial stiffness were measured at baseline and follow up. No significant differences were observed in the changes from baseline to follow up between the two treatments. However, a significant decrease in peripheral and central systolic BP (SBP) by 2.5 mmHg (95% CI: -4.7 to -0.3) and 2.7 mmHg (95% CI: -4.7 to -0.6), respectively, was observed after HPOO consumption. Neither olive oil changed diastolic BP (DBP) or measures of arterial stiffness. The reductions in SBP after HPOO consumption provide evidence for a potentially widely accessible dietary intervention to prevent cardiovascular disease in a multiethnic population. Longer intervention studies and/or higher doses of EVOO polyphenols are warranted to elucidate the potential effect on DBP and arterial stiffness.
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Exercise effects on arterial stiffness and heart health in children with excess weight: The SMART RCT.
Davis, CL, Litwin, SE, Pollock, NK, Waller, JL, Zhu, H, Dong, Y, Kapuku, G, Bhagatwala, J, Harris, RA, Looney, J, et al
International journal of obesity (2005). 2020;(5):1152-1163
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INTRODUCTION Childhood obesity and inactivity are associated with cardiovascular risk. Evidence is limited for exercise effects on arterial health in children. METHODS One hundred and seventy-five inactive children with overweight or obesity (8-11 years, ≥85th percentile BMI, 61% female, 87% Black, 73% with obesity) were randomized to an 8-month daily after-school aerobic exercise program (40 min/day, n = 90) or a sedentary control condition (n = 85). Carotid-femoral pulse wave velocity (PWV, primary outcome, arterial stiffness), fitness, adiposity, blood pressure (BP), glucose, insulin resistance, lipids, and C-reactive protein were measured at baseline and posttest (8 months). Adiposity, fitness, and BP were measured again at follow-up, 8-12 months later. Intent-to-treat analyses were conducted using mixed models. RESULTS The study had 89% retention, with attendance of 59% in exercise and 64% in the control condition, and vigorous exercise participation (average heart rate 161 ± 7 beats/min). Compared with controls, the exercise group had twice the improvement in fitness (VȮ2 peak, 2.7 (95% CI 1.8, 3.6) vs. 1.3 (0.4, 2.3) mL/kg/min) and adiposity (-1.8 (-2.4, -1.1) vs. -0.8 (-1.5, -0.1)%), each p = 0.04, and a large improvement in HDL-cholesterol (0.13 (0.075, 0.186) vs. -0.028 (-0.083, 0.023) mmol/L, p < 0.0001). There was no group × time effect on other outcomes at 8 months, or on any outcomes at follow-up. The change in PWV at 8 months correlated with changes in insulin and insulin resistance (both r = 0.32), diastolic BP (r = 0.24), BMI (r = 0.22), and adiposity (r = 0.18). CONCLUSIONS Eight months of aerobic exercise training improved fitness, adiposity, and HDL-cholesterol levels, but did not reduce arterial stiffness in children with excess weight. PWV improved as a function of insulin resistance, BP, BMI, and adiposity. Weight loss may be required to improve arterial stiffness. Exercise benefits waned after discontinuing the program.