Acute hypernatremia increases functional connectivity of NaCl sensing regions in the human brain: An fMRI pilot study.

Rodent studies demonstrated specialized sodium chloride (NaCl) sensing neurons in the circumventricular organs, which mediate changes in sympathetic nerve activity, arginine vasopressin, thirst, and blood pressure. However, the neural pathways involved in NaCl sensing in the human brain are incompletely understood. The purpose of this pilot study was to determine if acute hypernatremia alters the functional connectivity of NaCl-sensing regions of the brain in healthy young adults. Resting-state fMRI scans were acquired in 13 participants at baseline and during a 30 min hypertonic saline infusion (HSI). We used a seed-based approach to analyze the data, focusing on the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) as regions of interest (ROIs). Blood chemistry and perceived thirst were assessed pre- and post-infusion. As expected, serum sodium increased from pre- to post-infusion in the HSI group. The primary finding of this pilot study was that the functional connectivity between the SFO and a cluster within the OVLT increased from baseline to the late-phase of the HSI. Bidirectional connectivity changes were found with cortical regions, with some regions showing increased connectivity with sodium-sensing regions while others showed decreased connectivity. Furthermore, the functional connectivity between the SFO and the posterior cingulate cortex (a control ROI) did not change from baseline to the late-phase of the HSI. This finding indicates a distinct response within the NaCl sensing network in the human brain specifically related to acute hypernatremia that will need to be replicated in large-scale studies.

Effects of a mitochondrial-targeted ubiquinol on vascular function and exercise capacity in chronic kidney disease: a randomized controlled pilot study.

Mitochondria-derived oxidative stress has been implicated in vascular and skeletal muscle abnormalities in chronic kidney disease (CKD). The purpose of this study was to investigate the effects of a mitochondria-targeted ubiquinol (MitoQ) on vascular function and exercise capacity in CKD. In this randomized controlled trial, 18 patients with CKD (means ± SE, age: 62 ± 3 yr and estimated glomerular filtration rate: 45 ± 3 mL/min/1.73 m2) received 4 wk of 20 mg/day MitoQ (MTQ group) or placebo (PLB). Outcomes assessed at baseline and follow-up included macrovascular function measured by flow-mediated dilation, microvascular function assessed by laser-Doppler flowmetry combined with intradermal microdialysis, aortic hemodynamics assessed by oscillometry, and exercise capacity assessed by cardiopulmonary exercise testing. Compared with PLB, MitoQ improved flow-mediated dilation (baseline vs. follow-up: MTQ, 2.4 ± 0.3% vs. 4.0 ± 0.9%, and PLB, 4.2 ± 1.0% vs. 2.5 ± 1.0%, P = 0.04). MitoQ improved microvascular function (change in cutaneous vascular conductance: MTQ 4.50 ± 2.57% vs. PLB -2.22 ± 2.67%, P = 0.053). Central aortic systolic and pulse pressures were unchanged; however, MitoQ prevented increases in augmentation pressures that were observed in the PLB group (P = 0.026). MitoQ did not affect exercise capacity. In conclusion, this study demonstrates the potential for a MitoQ to improve vascular function in CKD. The findings hold promise for future investigations of mitochondria-targeted therapies in CKD.NEW & NOTEWORTHY In this randomized controlled pilot study, we investigated the effects of a mitochondria-targeted ubiquinol (MitoQ) on vascular function and exercise capacity in chronic kidney disease. Our novel findings showed that 4-wk supplementation of MitoQ was well tolerated and improved macrovascular endothelial function, arterial hemodynamics, and microvascular function in patients with stage 3-4 chronic kidney disease. Our mechanistic findings also suggest that MitoQ improved microvascular function in part by reducing the NADPH oxidase contribution to vascular dysfunction.

Effect of acute handgrip and aerobic exercise on wasted pressure effort and arterial wave reflections in healthy aging.

Aging increases arterial stiffness and wave reflections that augment left ventricular wasted pressure effort (WPE). A single bout of exercise may be effective at acutely reducing WPE via reductions in arterial wave reflections. In young adults (YA) acute aerobic exercise decreases, whereas handgrip increases, wave reflections. Whether acute exercise mitigates or exacerbates WPE and arterial wave reflection in healthy aging warrants further examination. The purpose of this study was to determine if there are age-related differences in WPE and wave reflection during acute handgrip and aerobic exercise. When compared with baseline, WPE increased substantially in older adults (OA) during handgrip (5,219 ± 2,396 vs. 7,019 ± 2,888 mmHg·ms, P < 0.001). When compared with baseline, there was a robust reduction in WPE in OA during moderate-intensity aerobic exercise (5,428 ± 2,084 vs. 3,290 ± 1,537 mmHg·ms, P < 0.001), despite absolute WPE remaining higher in OA compared with YA during moderate-intensity aerobic exercise (OA 3,290 ± 1,537 vs. YA 1,188 ± 962 mmHg·ms, P < 0.001). There was no change in wave reflection timing indexed to ejection duration in OA during handgrip (40 ± 6 vs. 38 ± 4%, P = 0.41) or moderate-intensity aerobic exercise (40 ± 5 vs. 42 ± 8%, P = 0.99). Conversely, there was an earlier return of wave reflection in YA during handgrip (60 ± 11 vs. 52 ± 6%, P < 0.001) and moderate-intensity aerobic exercise (59 ± 7 vs. 51 ± 9%, P < 0.001). Changes in stroke volume were not different between groups during handgrip (P = 0.08) or aerobic exercise (P = 0.47). The greater increase in WPE during handgrip and decrease in WPE during aerobic exercise suggest that aortic hemodynamic responses to acute exercise are exaggerated with healthy aging without affecting stroke volume.NEW & NOTEWORTHY We demonstrated that acute aerobic exercise attenuated, whereas handgrip augmented, left ventricular hemodynamic load from wave reflections more in healthy older (OA) compared with young adults (YA) without altering stroke volume. These findings suggest an exaggerated aortic hemodynamic response to acute exercise perturbations with aging. They also highlight the importance of considering exercise modality when examining aortic hemodynamic responses to acute exercise in older adults.

Inverse salt sensitivity in normotensive adults: role of demographic factors.

BACKGROUND: Salt sensitivity and inverse salt sensitivity [ISS; a reduction in blood pressure (BP) on a high sodium diet] are each associated with increased incidence of hypertension. The purpose of this analysis was to determine the prevalence of ISS in normotensive adults and whether ISS is associated with any demographic characteristic(s). METHODS: Healthy normotensive, nonobese adults [ n  = 84; 43 women; age = 37 ±â€Š13 years; baseline mean arterial pressure (MAP) = 89 ±â€Š8 mmHg] participated in a controlled feeding study, consuming 7-day low-sodium (20 mmol sodium/day) and high-sodium (300 mmol sodium/day) diets. Twenty-four-hour ambulatory BP was assessed on the last day of each diet. ISS was defined as a reduction in 24-h MAP more than 5 mmHg, salt sensitivity as an increase in MAP more than 5 mmHg and salt resistance as a change in MAP between -5 and 5 mmHg from low sodium to high sodium. RESULTS: Using this cutoff, 10.7% were ISS, 76.2% salt resistant, and 13.1% salt sensitive. Prevalence of ISS was similar between sexes and age groups ( P  > 0.05). However, ISS was more prevalent in those with normal BMI (15.8% ISS) compared with those with overweight BMI (0% ISS; P  < 0.01). Interestingly, classification of participants using a salt sensitivity index (ΔMAP/Δ urinary sodium excretion) categorized 21.4% as ISS, 48.8% salt resistant, and 29.8% salt sensitive. CONCLUSION: Overall, we found that the prevalence of ISS was 10.7% (5 mmHg cutoff) or 21.4% (salt sensitivity index), and that ISS was associated with lower BMI. These results highlight the importance of future work to understand the mechanisms of ISS and to standardize salt sensitivity assessment.

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.

Dietary sodium and health: How much is too much for those with orthostatic disorders?

High dietary salt (NaCl) increases blood pressure (BP) and can adversely impact multiple target organs including the vasculature, heart, kidneys, brain, autonomic nervous system, skin, eyes, and bone. However, patients with orthostatic disorders are told to increase their NaCl intake to help alleviate symptoms. While there is evidence to support the short-term benefits of increasing NaCl intake in these patients, there are few studies assessing the benefits and side effects of long-term high dietary NaCl. The evidence reviewed suggests that high NaCl can adversely impact multiple target organs, often independent of BP. However, few of these studies have been performed in patients with orthostatic disorders. We conclude that the recommendation to increase dietary NaCl in patients with orthostatic disorders should be done with care, keeping in mind the adverse impact on dietary NaCl in people without orthostatic disorders. Modest, rather than robust, increases in NaCl intake may be sufficient to alleviate symptoms but also minimize any long-term negative effects.

Lower-body dynamic exercise reduces wave reflection in healthy young adults.

NEW FINDINGS: What is the central question of this study? There is a paradoxical reduction in augmentation index during lower-body dynamic (LBD) exercise in the face of an increase in central pressure. To determine causality, the amplitudes of forward and backward pressure waves were assessed separately using wave separation analysis. What is the main finding and its importance? Reflection magnitude decreased during LBD exercise in healthy young adults and was attributable to an increased forward pressure wave amplitude and decreased backward pressure wave amplitude. This vasoactive response might limit the adverse effects of wave reflection during LBD exercise, optimizing ventricular-arterial interactions. ABSTRACT: Acute lower-body dynamic (LBD) exercise decreases surrogate measures of wave reflection, such as the augmentation index. However, the augmentation index is influenced by the combined effects of wave reflection timing, magnitude and other confounding factors external to wave reflection, which make it difficult to discern the origin of changes in surrogate measures. The relative contributions of forward (Pf) and backward (Pb) pressure wave amplitudes to central pressure can be determined by wave separation analysis. Reflection magnitude (RM = Pb/Pf) and the timing of apparent wave reflection return can also be determined. We tested the hypothesis that acute LBD exercise decreases RM and reflected wave transit time (RWTT). Applanation tonometry was used to record radial artery pressure waveforms in 25 adults (24 ± 4 years of age) at baseline and during light-, moderate- and vigorous-intensity exercise. Wave separation analysis was conducted offline using a personalized physiological flow wave to determine Pf, Pb, RM and RWTT. The RM decreased during all intensities of exercise compared with baseline (all P < 0.001; baseline, 43 ± 5%; light, 33 ± 6%; moderate, 23 ± 7%; vigorous, 17 ± 5%). The reduction in RM was attributable to the combined effect of increased Pf and decreased Pb during exercise. The RWTT decreased during all intensities of exercise compared with baseline (all P < 0.04; baseline, 156 ± 17 ms; light, 144 ± 15 ms; moderate, 129 ± 16 ms; vigorous, 121 ± 17 ms). Lastly, in a stepwise multilinear regression, Pf, but not Pb and RWTT, contributed to increased central pulse pressure during LBD exercise. These data show that wave reflection decreased and that central pulse pressure is most influenced by Pf during LBD exercise.

Pulsatile load and wasted pressure effort are reduced following an acute bout of aerobic exercise.

Following aerobic exercise, sustained vasodilation and concomitant reductions in total peripheral resistance (TPR) result in a reduction in blood pressure that is maintained for two or more hours. However, the time course for postexercise changes in reflected wave amplitude and other indices of pulsatile load on the left ventricle have not been thoroughly described. Therefore, we tested the hypothesis that reflected wave amplitude is reduced beyond an hour after cycling at 60% V̇o2peak for 60 min. Aortic pressure waveforms were derived in 14 healthy adults (7 men, 7 women; 26 ± 3 yr) from radial pulse waves acquired via high-fidelity applanation tonometry at baseline and every 20 min for 120 min postexercise. Concurrently, left ventricle outflow velocities were acquired via Doppler echocardiography and pressure-flow analyses were performed. Aortic characteristic impedance (Zc), forward (Pf) and backward (Pb) pulse wave amplitude, reflected wave travel time (RWTT), and wasted pressure effort (WPE) were derived. Reductions in aortic blood pressure, Zc, Pf, and Pb were all sustained postexercise whereas increases in RWTT emerged from 60 to 100 min post exercise (all P < 0.05). WPE was reduced by ∼40% from 40 to 100 min post exercise (all P < 0.02). Stepwise multiple regression analysis revealed that the peak ΔWPE was associated with ΔRWTT (ß = -0.57, P = 0.003) and ΔPb (ß = 0.52, P = 0.006), but not Δcardiac output, ΔTPR, ΔZc, or ΔPf. These results suggest that changes in pulsatile hemodynamics are sustained for ≥100 min following moderate intensity aerobic exercise. Moreover, decreased and delayed reflected pressure waves are associated with decreased left ventricular wasted effort after exercise.NEW & NOTEWORTHY We demonstrate that pulsatile load on the left ventricle is diminished following 60 min of moderate intensity aerobic exercise. During recovery from exercise, the amplitude of the forward and backward traveling pressure waves are attenuated and the arrival of reflected waves is delayed. Thus, the work imposed upon the left ventricle by reflected pressure waves, wasted pressure effort, is decreased after exercise.

Personalized physiologic flow waveforms improve wave reflection estimates compared to triangular flow waveforms in adults.

Central aortic pressure waveforms contain valuable prognostic information in addition to central systolic pressure. Using pressure-flow relations, wave separation analysis can be used to decompose aortic pressure waveforms into forward- (Pf) and backward-traveling (Pb) components. Reflection magnitude, the ratio of pressure amplitudes (RM = Pb/Pf), is a predictor of heart failure and all-cause mortality. Aortic flow can be measured via Doppler echocardiography or estimated using a triangular flow waveform; however, the latter may underestimate the flow waveform convexity and overestimate Pb and RM. We sought to determine the accuracy of a personalized synthetic physiologic flow waveform, compared with triangular and measured flow waveforms, for estimating wave reflection indices in 49 healthy young (27 ± 6 yr) and 29 older adults [66 ± 6 yr; 20 healthy, 9 chronic kidney disease (CKD)]. Aortic pressure and measured flow waveforms were acquired via radial tonometry and echocardiography, respectively. Triangular and physiologic flow waveforms were constructed from aortic pressure waveforms. Compared with the measured flow waveform, the triangular waveform underestimated Pf in older, but not young, adults and overestimated Pb and RM in both groups. The physiologic waveform was equivalent to measured flow in deriving all wave reflection indices and yielded smaller mean absolute biases than the triangular waveform in all instances (P < 0.05). Lastly, central pulse pressure was associated with triangular, but not physiologic, mean biases for Pb and RM independent of age or central arterial stiffness (P < 0.05). These findings support the use of personalized physiologic flow waveforms as a more robust alternative to triangular flow waveforms when true flow cannot be measured.NEW & NOTEWORTHY We demonstrate that triangular flow waveforms overestimate wave reflection indices, particularly at higher central pulse pressures independent of age or carotid-femoral pulse wave velocity. In contrast, personalized physiologic flow waveforms provide equivalent wave reflection estimates as measured flow waveforms, thereby offering a more robust alternative to triangulation when aortic flow cannot be measured.

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.

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.

Dynamic and isometric handgrip exercise increases wave reflection in healthy young adults.

Early return and increased magnitude of wave reflection augments pulsatile load, wastes left ventricular effort, and is associated with cardiovascular events. Acute handgrip (HG) exercise increases surrogate measures of wave reflection such as augmentation index. However, augmentation index does not allow distinguishing between timing versus magnitude of wave reflection and is affected by factors other than wave reflection per se. Wave separation analysis decomposes central pressure into relative contributions of forward (Pf) and backward (Pb) pressure wave amplitudes to calculate reflection magnitude (RM = Pb/Pf) and determine the timing of apparent wave reflection return. We tested the hypothesis that acute dynamic and isometric HG exercise increases RM and decreases reflected wave transit time (RWTT). Applanation tonometry was used to record radial artery pressure waveforms in 30 adults (25 ± 4 yr) at baseline and during dynamic and isometric HG exercise. Wave separation analysis was performed offline using a physiological flow wave to derive Pf, Pb, RM, and RWTT. We found that RM increased during dynamic and isometric HG exercise compared with baseline (P = 0.04 and P < 0.01, respectively; baseline 40 ± 5, dynamic 43 ± 6, isometric 43 ± 7%). Meanwhile, RWTT decreased during dynamic and isometric HG exercise compared with baseline (P = 0.03 and P < 0.001, respectively; baseline 164 ± 23, dynamic 155 ± 23, isometric 148 ± 20 ms). Moreover, the changes in RM and RWTT were not different between dynamic and isometric HG exercise. The present data suggest that wave reflection timing (RWTT) and magnitude (RM) are important factors that contribute to increased central blood pressure during HG exercise.NEW & NOTEWORTHY This study demonstrated that wave reflection magnitude is increased while reflected wave transit time is decreased during handgrip exercise in healthy young adults. The larger backward pressure waves and earlier return of these pressure waves were not different between dynamic and isometric handgrip exercise. These acute changes in wave reflection during handgrip exercise transiently augment pulsatile load.

Quantitation of Gait and Stance Alterations Due to Monosodium Iodoacetate-induced Knee Osteoarthritis in Yucatan Swine.

Knee osteoarthritis is one of the most common causes of chronic pain worldwide, and several animal models have been developed to investigate disease mechanisms and treatments to combat associated morbidities. Here we describe a novel method for assessment of locomotor pain behavior in Yucatan swine. We used monosodium iodoacetate (MIA) to induce osteoarthritis in the hindlimb knee, and then conducted live observation, quantitative gait analysis, and quantitative weight-bearing stance analysis. We used these methods to test the hypothesis that locomotor pain behaviors after osteoarthritis induction would be detected by multiparameter quantitation for at least 12 wk in a novel large animal model of osteoarthritis. MIA-induced knee osteoarthritis produced lameness quantifiable by all measurement techniques, with onset at 2 to 4 wk and persistence until the conclusion of the study at 12 wk. Both live observation and gait analysis of kinetic parameters identified mild and moderate osteoarthritis phenotypes corresponding to a binary dose relationship. Quantitative stance analysis demonstrated the greatest sensitivity, discriminating between mild osteoarthritis states induced by 1.2 and 4.0 mg MIA, with stability of expression for as long as 12 wk. The multiparameter quantitation used in our study allowed rejection of the null hypothesis. This large animal model of quantitative locomotor pain resulting from MIA-induced osteoarthritis may support the assessment of new analgesic strategies for human knee osteoarthritis.

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.

Objective evaluation of female feet and leg joint conformation at time of selection and post first parity in swine1.

Feet and legs of replacement females were objectively evaluated at selection, i.e., approximately 150 d of age (n = 319) and post first parity, i.e., any time after weaning of first litter and before second parturition (n = 277) to 1) compare feet and leg joint angle ranges between selection and post first parity; 2) identify feet and leg joint angle differences between selection and first 3 wk of second gestation; 3) identify feet and leg joint angle differences between farms and gestation days during second gestation; and 4) obtain genetic variance components for conformation angles for the two time points measured. Angles for carpal joint (knee), metacarpophalangeal joint (front pastern), metatarsophalangeal joint (rear pastern), tarsal joint (hock), and rear stance were measured using image analysis software. Between selection and post first parity, significant differences were observed for all joints measured (P < 0.05). Knee, front and rear pastern angles were less (more flexion), and hock angles were greater (less flexion) as age progressed (P < 0.05), while the rear stance pattern was less (feet further under center) at selection than post first parity (only including measures during first 3 wk of second gestation). Only using post first parity leg conformation information, farm was a significant source of variation for front and rear pasterns and rear stance angle measurements (P < 0.05). Knee angle was less (more flexion; P < 0.05) as gestation age progressed. Heritability estimates were low to moderate (0.04-0.35) for all traits measured across time points. Genetic correlations between the same joints at different time points were high (>0.8) between the front leg joints and low (<0.2) between the rear leg joints. High genetic correlations between time points indicate that the trait can be considered the same at either time point, and low genetic correlations indicate that the trait at different time points should be considered as two separate traits. Minimal change in the front leg suggests conformation traits that remain between selection and post first parity, while larger changes in rear leg indicate that rear leg conformation traits should be evaluated at multiple time periods.

Cardiopulmonary exercise testing reveals subclinical abnormalities in chronic kidney disease.

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.

Optimization of Tubulysin Antibody-Drug Conjugates: A Case Study in Addressing ADC Metabolism.

As part of our efforts to develop new classes of tubulin inhibitor payloads for antibody-drug conjugate (ADC) programs, we developed a tubulysin ADC that demonstrated excellent in vitro activity but suffered from rapid metabolism of a critical acetate ester. A two-pronged strategy was employed to address this metabolism. First, the hydrolytically labile ester was replaced by a carbamate functional group resulting in a more stable ADC that retained potency in cellular assays. Second, site-specific conjugation was employed in order to design ADCs with reduced metabolic liabilities. Using the later approach, we were able to identify a conjugate at the 334C position of the heavy chain that resulted in an ADC with considerably reduced metabolism and improved efficacy. The examples discussed herein provide one of the clearest demonstrations to-date that site of conjugation can play a critical role in addressing metabolic and PK liabilities of an ADC. Moreover, a clear correlation was identified between the hydrophobicity of an ADC and its susceptibility to metabolic enzymes. Importantly, this study demonstrates that traditional medicinal chemistry strategies can be effectively applied to ADC programs.

Design, Synthesis, and Cytotoxic Evaluation of Novel Tubulysin Analogues as ADC Payloads.

The tubulysin class of natural products has attracted much attention from the medicinal chemistry community due to its potent cytotoxicity against a wide range of human cancer cell lines, including significant activity in multidrug-resistant carcinoma models. As a result of their potency, the tubulysins have become an important tool for use in targeted therapy, being widely pursued as payloads in the development of novel small molecule drug conjugates (SMDCs) and antibody-drug conjugates (ADCs). A structure-based and parallel medicinal chemistry approach was applied to the synthesis of novel tubulysin analogues. These efforts led to the discovery of a number of novel and potent cytotoxic tubulysin analogues, providing a framework for our simultaneous report, which highlights the discovery of tubulysin-based ADCs, including use of site-specific conjugation to address in vivo stability of the C-11 acetate functionality.