Sex differences in microvascular function and arterial hemodynamics in nondialysis chronic kidney disease.

Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). Abnormal arterial hemodynamics contribute to CVD, a relationship that can be mediated by microvascular dysfunction. The purpose of this study was to investigate potential sex differences in arterial hemodynamics and microvascular dysfunction in patients with stages 3 to 4 CKD. Vascular function was assessed in 22 male (mean ± SD; age, 56 ± 13 yr) and 10 female (age, 63 ± 9 yr) patients. Arterial hemodynamics were acquired with combined tonometry and oscillometry. Skin blood flow was used as a model of microvascular function. Participants were instrumented with three microdialysis fibers for the delivery of 1) Ringer's solution; 2) superoxide dismutase mimetic, Tempol; and 3) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin. Blood flow was measured via laser-Doppler flowmetry during standardized local heating (42°C). Central pulse pressure (mean ± SE; 62 ± 9 vs. 46 ± 3 mmHg; P = 0.01) and augmentation index (36 ± 3 vs. 26 ± 3%; P = 0.03) were higher in females. There was a trend for higher central systolic pressures in females (146 ± 9 vs. 131 ± 3 mmHg; P = 0.06). Females reported higher forward (39 ± 4 vs. 29 ± 2 mmHg; P = 0.004) and reflected (27 ± 3 vs. 19 ± 1 mmHg; P < 0.001) wave amplitudes. Cutaneous vascular function was impaired in females compared with males (77 ± 3 vs. 89 ± 1%, P = 0.001). Microvascular function was improved following the delivery of Tempol and apocynin in females but not in males. Female patients with CKD had poorer central hemodynamics and reduced microvascular function compared with their male counterparts. Oxidative stress may contribute to lower microvascular function observed in females.NEW & NOTEWORTHY There are limited data regarding the physiological mechanisms of potential sex differences in central hemodynamics and vascular function in chronic kidney disease (CKD). We report that older female patients with nondialysis CKD have higher central pulse pressures compared with male patients with CKD. In addition, older females with CKD have lower microvascular function compared with their male counterparts, and oxidative stress contributes to the lower microvascular function in older female patients with CKD.

The effect of dietary nitrate on exercise capacity in chronic kidney disease: a randomized controlled pilot study.

BACKGROUND: Chronic Kidney Disease (CKD) patients exhibit a reduced exercise capacity that impacts quality of life. Dietary nitrate supplementation has been shown to have favorable effects on exercise capacity in disease populations by reducing the oxygen cost of exercise. This study investigated whether dietary nitrates would acutely improve exercise capacity in CKD patients. METHODS AND RESULTS: In this randomized, double-blinded crossover study, 12 Stage 3-4 CKD patients (Mean ± SEM: Age, 60 ± 5yrs; eGFR, 50.3 ± 4.6 ml/min/1.73 m2) received an acute dose of 12.6 mmol of dietary nitrate in the form of concentrated beetroot juice (BRJ) and a nitrate depleted placebo (PLA). Skeletal muscle mitochondrial oxidative function was assessed using near-infrared spectroscopy. Cardiopulmonary exercise testing was performed on a cycle ergometer, with intensity increased by 25 W every 3 min until volitional fatigue. Plasma nitric oxide (NO) metabolites (NOm; nitrate, nitrite, low molecular weight S-nitrosothiols, and metal bound NO) were determined by gas-phase chemiluminescence. Plasma NOm values were significantly increased following BRJ (BRJ vs. PLA: 1074.4 ± 120.4 µM vs. 28.4 ± 6.6 µM, p < 0.001). Total work performed (44.4 ± 10.6 vs 39.6 ± 9.9 kJ, p = 0.03) and total exercise time (674 ± 85 vs 627 ± 86s, p = 0.04) were significantly greater following BRJ. Oxygen consumption at the ventilatory threshold was also improved by BRJ (0.90 ± 0.08 vs. 0.74 ± 0.06 L/min, p = 0.04). These changes occurred in the absence of improved skeletal muscle mitochondrial oxidative capacity (p = 0.52) and VO2peak (p = 0.35). CONCLUSIONS: Our findings demonstrate that inorganic nitrate can acutely improve exercise capacity in CKD patients. The effects of chronic nitrate supplementation on CKD related exercise intolerance should be investigated in future studies.

High dietary sodium augments vascular tone and attenuates low-flow mediated constriction in salt-resistant adults.

INTRODUCTION: Low-flow mediated constriction (L-FMC) has emerged as a valuable and complementary measure of flow-mediated dilation (FMD) for assessing endothelial function non-invasively. High dietary sodium has been shown to impair FMD independent of changes in blood pressure (BP), but its effects on L-FMC are unknown. PURPOSE: To test the hypothesis that high dietary sodium would attenuate brachial artery L-FMC in salt-resistant adults. METHODS: Fifteen healthy, normotensive adults (29 ± 6 years) participated in a controlled feeding study. Following a run-in diet, participants completed a 7-day low sodium (LS; 20 mmol sodium/day) and 7-day high sodium (HS; 300 mmol sodium/day) diet in randomized order. On the last day of each diet, 24 h urine was collected and assessments of 24 h ambulatory BP and L-FMC were performed. Salt-resistance was defined as a change in 24 h ambulatory mean arterial pressure (MAP) between the LS and HS diets of ≤ 5 mmHg. Resting vascular tone and L-FMC were calculated from ultrasound-derived arterial diameters. RESULTS: High dietary sodium increased serum sodium and urinary sodium excretion (p < 0.001 for both), but 24 h MAP was unchanged (p = 0.16) by design. High dietary sodium augmented vascular tone (LS: 91 ± 23%, HS: 125 ± 56%, p = 0.01) and attenuated L-FMC (LS: - 0.58 ± 0.99%, HS: 0.17 ± 1.23%, p = 0.008). CONCLUSION: These findings in salt-resistant adults provide additional evidence that dietary sodium has adverse vascular effects independent of changes in BP.

Effects of aerobic exercise on vascular function in nondialysis chronic kidney disease: a randomized controlled trial.

Endothelial dysfunction and arterial stiffness are nontraditional risk factors of chronic kidney disease (CKD)-related cardiovascular disease (CVD) that could be targeted with exercise. This study investigated the effect of moderate to vigorous aerobic exercise on vascular function in nondialysis CKD. In this randomized, controlled trial, 36 nondialysis patients with CKD (means ± SE, age: 58 ± 2 yr, estimated glomerular filtration rate: 44 ± 2 ml·min-1·1.73 m-2) were allocated to an exercise training (EXT) or control (CON) arm. The EXT group performed 3 × 45 min of supervised exercise per week at 60-85% heart rate reserve for 12 wk, whereas the CON group received routine care. Outcomes were assessed at 0 and 12 wk. The primary outcome, microvascular function, was assessed via cutaneous vasodilation during local heating measured by laser-Doppler flowmetry coupled with microdialysis. Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution and 2) the superoxide scavenger tempol. Conduit artery function was assessed via brachial artery flow-mediated dilation. Aortic pressure waveforms and pulse wave velocity were acquired with tonometry and oscillometry. Microvascular function improved after EXT (week 0 vs.week 12, EXT: 87 ± 2% vs. 91 ± 2% and CON: 86 ± 2% vs. 84 ± 3%, P = 0.03). At baseline, pharmacological delivery of tempol improved microvascular function (Ringer solution vs. tempol: 86 ± 1% vs. 90 ± 1%, P = 0.02) but was no longer effective after EXT (91 ± 2% vs. 87 ± 1%, P = 0.2), suggesting that an improved redox balance plays a role in EXT-related improvements. Brachial artery flow-mediated dilation was maintained after EXT (EXT: 2.6 ± 0.4% vs. 3.8 ± 0.8% and CON: 3.5 ± 0.6% vs. 2.3 ± 0.4%, P = 0.02). Central arterial hemodynamics and arterial stiffness were unchanged after EXT. Aerobic exercise improved microvascular function and maintained conduit artery function and should be considered as an adjunct therapy to reduce CVD risk in CKD.

Apocynin and Tempol ameliorate dietary sodium-induced declines in cutaneous microvascular function in salt-resistant humans.

It has previously been shown that high dietary salt impairs vascular function independent of changes in blood pressure. Rodent studies suggest that NADPH-derived reactive oxygen species mediate the deleterious effect of high salt on the vasculature, and here we translate these findings to humans. Twenty-nine healthy adults (34 ± 2 yr) participated in a controlled feeding study. Participants completed 7 days of a low-sodium diet (LS; 20 mmol sodium/day) and 7 days of a high-sodium diet (HS; 300 mmol sodium/day) in random order. All participants were salt resistant, defined as a ≤5-mmHg change in 24-h mean BP determined while on the LS and HS diets. Laser Doppler flowmetry was used to assess cutaneous vasodilation in response to local heating (42°C) during local delivery of Ringer's (n = 29), 20 mM ascorbic acid (AA; n = 29), 10 µM Tempol (n = 22), and 100 µM apocynin (n = 22). Additionally, endothelial cells were obtained in a subset of participants from an antecubital vein and stained for nitrotyrosine (n = 14). Cutaneous vasodilation was attenuated by the HS diet compared with LS [LS 93.0 ± 2.2 vs. HS 86.8 ± 2.0 percentage of maximal cutaneous vascular conductance (%CVCmax); P < 0.05] and was restored by AA during the HS diet (AA 90.7 ± 1.2 %CVCmax; P < 0.05 vs. HS). Cutaneous vasodilation was also restored with the local infusion of both apocynin (P < 0.01) and Tempol (P < 0.05) on the HS diet. Nitrotyrosine expression was increased on the HS diet compared with LS (P < 0.05). These findings provide direct evidence of dietary sodium-induced endothelial cell oxidative stress and suggest that NADPH-derived reactive oxygen species contribute to sodium-induced declines in microvascular function. NEW & NOTEWORTHY High-sodium diets have deleterious effects on vascular function, likely mediating, in part, the increased cardiovascular risk associated with a high sodium intake. Local infusion of apocynin and Tempol improved microvascular function in salt-resistant adults on a high-salt diet, providing evidence that reactive oxygen species contribute to impairments in microvascular function from high salt. This study provides insight into the blood pressure-independent mechanisms by which dietary sodium impairs vascular function. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/dietary-sodium-oxidative-stress-and-microvascular-function/ .

Role of mitochondria-derived reactive oxygen species in microvascular dysfunction in chronic kidney disease.

Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Mitochondrial dysfunction secondary to CKD is a potential source of oxidative stress that may impair vascular function. This study sought to determine if mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in stage 3-5 CKD. Cutaneous vasodilation in response to local heating was assessed in 20 CKD patients [60 ± 13 yr; estimated glomerular filtration rate (eGFR) 46 ± 13 ml·kg-1·1.73 m-2] and 11 matched healthy participants (58 ± 2 yr; eGFR >90 ml·kg-1·1.73 m-2). Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution, and 2) the mitochondria- specific superoxide scavenger MitoTempo. Skin blood flow was measured via laser Doppler flowmetry during standardized local heating (42°C). Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum conductance achieved with sodium nitroprusside infusion at 43°C. Urinary isofuran/F2-isoprostane ratios were assessed by gas-chromatography mass spectroscopy. Isofuran-to-F2-isoprostane ratios were increased in CKD patients (3.08 ± 0.32 vs. 1.69 ± 0.12 arbitrary units; P < 0.01) indicative of mitochondria-derived oxidative stress. Cutaneous vasodilation was impaired in CKD compared with healthy controls (87 ± 1 vs. 92 ± 1%CVCmax; P < 0.01). Infusion of MitoTempo significantly increased the plateau phase CVC in CKD patients (CKD Ringer vs. CKD MitoTempo: 87 ± 1 vs. 93 ± 1%CVCmax; P < 0.01) to similar levels observed in healthy controls ( P = 0.9). These data provide in vivo evidence that mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in CKD and suggest that mitochondrial dysfunction may be a potential therapeutic target to improve CKD-related vascular dysfunction.

NADPH oxidase-derived reactive oxygen species contribute to impaired cutaneous microvascular function in chronic kidney disease.

Oxidative stress promotes vascular dysfunction in chronic kidney disease (CKD). We utilized the cutaneous circulation to test the hypothesis that reactive oxygen species derived from NADPH oxidase and xanthine oxidase impair nitric oxide (NO)-dependent cutaneous vasodilation in CKD. Twenty subjects, 10 stage 3 and 4 patients with CKD (61 ± 4 yr; 5 men/5 women; eGFR: 39 ± 4 ml·min(-1)·1.73 m(-2)) and 10 healthy controls (55 ± 2 yr; 4 men/6 women; eGFR: >60 ml·min(-1)·1.73 m(-2)) were instrumented with 4 intradermal microdialysis fibers for the delivery of 1) Ringer solution (Control), 2) 10 µM tempol (scavenge superoxide), 3) 100 µM apocynin (NAD(P)H oxidase inhibition), and 4) 10 µM allopurinol (xanthine oxidase inhibition). Skin blood flow was measured via laser-Doppler flowmetry during standardized local heating (42°C). N(g)-nitro-l-arginine methyl ester (L-NAME; 10 mM) was infused to quantify the NO-dependent portion of the response. Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum CVC achieved during sodium nitroprusside infusion at 43°C. Cutaneous vasodilation was attenuated in patients with CKD (77 ± 3 vs. 88 ± 3%, P = 0.01), but augmented with tempol and apocynin (tempol: 88 ± 2 (P = 0.03), apocynin: 91 ± 2% (P = 0.001). The NO-dependent portion of the response was reduced in patients with CKD (41 ± 4 vs. 58 ± 2%, P = 0.04), but improved with tempol and apocynin (tempol: 58 ± 3 (P = 0.03), apocynin: 58 ± 4% (P = 0.03). Inhibition of xanthine oxidase did not alter cutaneous vasodilation in either group (P > 0.05). These data suggest that NAD(P)H oxidase is a source of reactive oxygen species and contributes to microvascular dysfunction in patients with CKD.

Inverse Association between Exercising Blood Pressure Response and Left Ventricular Chamber Size and Mass in Women Who Habitually Resistance Train.

Exercise is a major modifiable lifestyle factor that leads to temporarily increased systolic blood pressure (SBP), which is thought to influence left ventricular mass normalized to body surface area (LVM/BSA). This relationship has never been studied in women who habitually perform resistance exercise. PURPOSE: To determine if a direct correlation exists between the SBP response to resistance exercise (change from rest; eSBP) and LVM/BSA in young healthy women who habitually resistance train. METHODS: Leg extension resistance exercise was performed while continuously monitoring blood pressure using finger plethysmography. LVM was estimated using echocardiography. Data are shown as mean ± SD. RESULTS: Thirty-one women participated (age 23 ± 3 years, height 164 ± 7 cm, body mass 63.7 ± 10.3 kg). Resting SBP (110 ± 8 mmHg, r = 0.355, p = 0.049) was shown to be directly correlated to LVM/BSA (72.0 ± 28.4 g/m2). Conversely, eSBP (30.8 ± 14.6 ∆mmHg, r = -0.437, p = 0.014) was inversely related to LVM/BSA. eSBP was not correlated to interventricular septum width (0.88 ± 0.12 cm, r = -0.137, p = 0.463) or posterior wall thickness (0.91 ± 0.15 cm, r = -0.084, p = 0.654). eSBP was inversely related to left ventricle internal diameter during diastole (LVIDd) (4.25 ± 0.33 cm, r = -0.411, p = 0.021). CONCLUSION: Counter to the hypothesis, these data suggest an inverse association between eSBP during resistance exercise and LVM/BSA in healthy young women who resistance train. This relationship is due to a smaller LVIDd with greater eSBP.

A randomized trial of aerobic exercise in chronic kidney disease: Evidence for blunted cardiopulmonary adaptations.

BACKGROUND: Patients with chronic kidney disease have reduced cardiorespiratory fitness levels that contribute to mortality. OBJECTIVES: The purpose of this study was to investigate the effects of aerobic exercise on cardiopulmonary function in patients with chronic kidney disease. METHODS: A total of 36 patients (mean [SD] estimated glomerular filtration rate 44 [12] ml/min/1.73m2) were randomly allocated to an exercise training or a control arm over 12 weeks. The exercise training group performed aerobic exercise for 45min 3 times/week at 65% to 80% heart rate reserve. The control group received routine care. Outcome measures were assessed at baseline and 12 weeks. Cardiopulmonary exercise testing was performed on a cycle ergometer with workload increased by 15W/min. A battery of physical function tests were administered. Habitual physical activity levels were recorded via accelerometry. Data are mean [SD]. RESULTS: Exercise training improved VO2peak as compared with the control group (exercise: 17.89 [4.18] vs 19.98 [5.49]; control: 18.29 [6.49] vs 17.36 [5.99] ml/kg/min; P<0.01). Relative O2 pulse improved following exercise, suggestive of improved left ventricular function (exercise: 0.12 [0.02] vs 0.14 [0.04]; control: 0.14 [0.05] vs 0.14 [0.04] ml/beat/kg; P=0.03). Ventilation perfusion mismatching (VE/VCO2) remained evident after exercise (exercise: 32 [5] vs 33 [5]; control: 32 [7] vs 34 [5] AU; P=0.1). Exercise did not affect the ventilatory cost of oxygen uptake (VE/VO2; exercise: 40 [7] vs 42 [8]; control: 3 [7] vs 41 [8] AU; P=0.5) and had no effect on autonomic function assessed by maximal and recovery heart rates. We found no changes in physical function or habitual physical activity levels. CONCLUSIONS: Cardiopulmonary adaptations appeared to be attenuated in patients with chronic kidney disease and were not fully restored to levels observed in healthy individuals. Improvements in exercise capacity did not confer benefits to physical function. Interventions coupled with exercise may be required to enhance adaptations in chronic kidney disease. Performed according to CONSORT guidelines; ClinicalTrials.gov: NCT02050035.

High dietary sodium reduces brachial artery flow-mediated dilation in humans with salt-sensitive and salt-resistant blood pressure.

Recent studies demonstrate that high dietary sodium (HS) impairs endothelial function in those with salt-resistant (SR) blood pressure (BP). The effect of HS on endothelial function in those with salt-sensitive (SS) BP is not currently known. We hypothesized that HS would impair brachial artery flow-mediated dilation (FMD) to a greater extent in SS compared with SR adults. Ten SR (age 42 ± 5 yr, 5 men, 5 women) and 10 SS (age 39 ± 5 yr, 5 men, 5 women) healthy, normotensive participants were enrolled in a controlled feeding study consisting of a run-in diet followed by a 7-day low dietary sodium (LS) (20 mmol/day) and a 7-day HS (300 mmol/day) diet in random order. Brachial artery FMD and 24-h BP were assessed on the last day of each diet. SS BP was individually assessed and defined as a change in 24-h mean arterial pressure (MAP) of >5 mmHg between the LS and HS diets (ΔMAP: SR -0.6 ± 1.2, SS 7.7 ± 0.4 mmHg). Brachial artery FMD was lower in both SS and SR individuals during the HS diet (P < 0.001), and did not differ between groups (P > 0.05) (FMD: SR LS 10.6 ± 1.3%, SR HS 7.2 ± 1.5%, SS LS 12.5 ± 1.7%, SS HS 7.8 ± 1.4%). These data indicate that an HS diet impairs brachial artery FMD to a similar extent in adults with SS BP and SR BP.