RESUMEN
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.
Asunto(s)
Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Humanos , Femenino , Masculino , Anciano , Adulto , Persona de Mediana Edad , Vasodilatación/fisiología , Caracteres Sexuales , Hemodinámica , Insuficiencia Renal Crónica/diagnóstico , NADPH OxidasasRESUMEN
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.
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Tolerancia al Ejercicio/efectos de los fármacos , Nitratos/uso terapéutico , Insuficiencia Renal Crónica/dietoterapia , Adulto , Anciano , Beta vulgaris/química , Estudios Cruzados , Suplementos Dietéticos , Método Doble Ciego , Prueba de Esfuerzo/efectos de los fármacos , Femenino , Jugos de Frutas y Vegetales , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/efectos de los fármacos , Proyectos PilotoRESUMEN
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.
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Arteria Braquial/fisiopatología , Terapia por Ejercicio , Microcirculación , Microvasos/fisiopatología , Insuficiencia Renal Crónica/terapia , Piel/irrigación sanguínea , Rigidez Vascular , Vasodilatación , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuperación de la Función , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Factores de Tiempo , Resultado del TratamientoRESUMEN
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.
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Microcirculación , Microvasos/metabolismo , Microvasos/fisiopatología , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Piel/irrigación sanguínea , Vasodilatación , Anciano , Velocidad del Flujo Sanguíneo , Estudios de Casos y Controles , F2-Isoprostanos/orina , Femenino , Depuradores de Radicales Libres/administración & dosificación , Furanos/orina , Humanos , Masculino , Microcirculación/efectos de los fármacos , Microdiálisis , Microvasos/efectos de los fármacos , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Nitroprusiato/administración & dosificación , Compuestos Organofosforados/administración & dosificación , Piperidinas/administración & dosificación , Flujo Sanguíneo Regional , Vasodilatación/efectos de los fármacos , Vasodilatadores/administración & dosificaciónRESUMEN
Endogenous opioid release has been linked to exercise. We investigated if opioid blockade following forced swimming, a common model of rodent exercise, influenced cerebral glucose metabolism in mice. PET scan was used to assess the uptake of Fludeoxyglucose (FDG-18), a marker of cerebral glucose metabolism in 19 regions of the interest in the brain following: forced swimming, an acute dose of the opioid receptor blocker naltrexone or a combination of both. Forced swimming increased glucose uptake in the cerebellum, while naltrexone + forced swimming increased glucose uptake in the hypothalamus, forebrain, septum and amygdala. This suggests that opioid blockade alters the typical pattern of cerebral glucose uptake following forced swimming in mice in certain areas of the brain.
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Naltrexona , Natación , Animales , Glucosa , Ratones , Naltrexona/farmacología , Péptidos Opioides , Receptores OpioidesRESUMEN
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.
Asunto(s)
Capacidad Cardiovascular , Insuficiencia Renal Crónica , Ejercicio Físico , Estado de Salud , Humanos , Insuficiencia Renal Crónica/terapiaRESUMEN
Background Reductions in exercise capacity associated with exercise intolerance augment cardiovascular disease risk and predict mortality in chronic kidney disease. This study utilized cardiopulmonary exercise testing to (a) investigate mechanisms of exercise intolerance; (b) unmask subclinical abnormalities that may precede cardiovascular disease in chronic kidney disease. Design The design of this study was cross-sectional. Methods Cardiopulmonary exercise testing was carried out in 31 Stage 3-4 chronic kidney disease patients (60 ± 11 years; estimated glomerular filtration rate 43 ± 13 ml/min/1.73 m2) and 21 matched healthy individuals (healthy controls; 56 ± 5 years; estimated glomerular filtration rate>90 ml/min/1.73 m2) on a cycle ergometer with workload increased by 15 W every minute until volitional fatigue. Breath-by-breath respiratory gas analysis was performed with an automated gas analyzer and averaged over 10 s intervals. Results Peak oxygen uptake was reduced in chronic kidney disease compared to healthy controls (17.43 ± 1.03 vs 28 ± 2.05 ml/kg/min; p < 0.01), as was oxygen uptake at the ventilatory threshold (9.44 ± 0.53 vs15.55 ± 1.34 ml/kg/min; p < 0.01). A steeper minute ventilation rate/carbon dioxide production slope (32 ± 0.8 vs 28 ± 1; p < 0.01) and a lower expired carbon dioxide pressure in chronic kidney disease (27 ± 0.6 vs 31 ± 0.9 vs 0.9; p < 0.01) indicated ventilation perfusion mismatching in these patients. The ventilatory cost of oxygen uptake was higher in chronic kidney disease (37 ± 0.8 vs 33 ± 1; p < 0.01). Maximum heart rate (134 ± 5 vs 159 ± 3 bpm) and one-minute heart rate recovery (15 ± 1 vs 20 ± 2 bpm) were reduced in chronic kidney disease ( p < 0.01). Conclusion This study suggests that both central and peripheral limitations likely contribute to reduced exercise capacity in non-dialysis chronic kidney disease. Additionally, cardiopulmonary exercise testing revealed subclinical cardiopulmonary abnormalities in these patients in the absence of overt cardiovascular disease. Cardiopulmonary exercise testing could potentially be a tool for unmasking cardiopulmonary abnormalities preceding cardiovascular disease in chronic kidney disease.
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Capacidad Cardiovascular , Enfermedades Cardiovasculares/fisiopatología , Prueba de Esfuerzo , Tolerancia al Ejercicio , Tasa de Filtración Glomerular , Riñón/fisiopatología , Insuficiencia Renal Crónica/fisiopatología , Anciano , Enfermedades Asintomáticas , Pruebas Respiratorias , Enfermedades Cardiovasculares/diagnóstico , Estudios de Casos y Controles , Estudios Transversales , Femenino , Estado de Salud , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Insuficiencia Renal Crónica/diagnóstico , Factores de RiesgoRESUMEN
High dietary sodium intake can lead to hypertension and increased incidence of cardiovascular disease. We sought to determine the effect of short-term dietary sodium loading on central blood pressure and arterial stiffness in young (YG; 22-40 years) and middle-aged (MA; 41-60 years) normotensive adults. YG (n = 49; age: 27 ± 1 years) and MA (n = 36; age: 52 ± 1 years) subjects were randomized, in a cross-over design, to 7 days of low-sodium (LS; 20 mmol/d) or high-sodium (HS; 300 mmol/d) diet. On the last day of each diet, central pressures, forward and reflected wave amplitudes (via radial artery applanation tonometry), and carotid-femoral pulse wave velocity were assessed. Central systolic blood pressure (cSBP) was greater after HS in both YG (LS: 96 ± 1 vs. HS: 99 ± 1 mm Hg; P = .012) and MA (LS: 106 ± 2 vs. HS: 115 ± 3 mm Hg; P < .001). However, the increase in cSBP was greater in MA (YG: 4 ± 1 vs. MA: 9 ± 2; P = .02). In MA subjects, HS elicited greater forward (LS: 25 ± 1 vs. HS: 29 ± 1 mm Hg; P < .001) and reflected (LS: 19 ± 1 vs. HS: 23 ± 1 mm Hg; P < .001) wave amplitudes. Carotid-femoral pulse wave velocity was also greater in MA on HS but after adjustment for mean arterial pressure, the difference was no longer significant. Our data indicate that HS intake leads to a greater increase in cSBP in MA adults, which may be the result of increased forward and reflected wave amplitudes.