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.

Interleukin-6 is higher in naturally menstruating women compared with oral contraceptive pill users during the low-hormone phase.

Endogenous sex hormone concentrations vary between healthy naturally menstruating (non-OCP) and oral contraceptive pill-using (OCP) women, as well as across cycles. The aim of this study was to investigate potential differences in concentrations of inflammatory cytokine interleukin-6 (IL-6) and vasoconstrictive substance endothelin-1 (ET-1) and measures of vascular function among relatively lower- and higher-hormone phases of non-OCP and OCP women. Concentrations of estrogen, progesterone, IL-6, and ET-1 and measures of vascular function were collected in 22 women (22 ± 1 yr, OCP: n = 12) during the early follicular (EF, ≤5 days of menstruation onset) and early luteal (EL, 4 ± 2 days postovulation) phases of non-OCP subjects and were compared to the placebo pill (PP, ≤5 days of PP onset) and active pill (AP, ≤5 days of highest-dose AP) phases of OCP subjects. Vascular function was assessed via brachial artery flow-mediated dilation (%FMD). Concentrations of endogenous estrogen and progesterone were higher in the EL phase compared with the EF phase of non-OCP (P = 0.01) but were similar between phases of OCP (P > 0.05). IL-6 was higher in non-OCP during the EF phase compared with the EL phase (P = 0.03) as well as compared with OCP during the PP phase (P = 0.002) but was similar between groups during the EL and AP phases, respectively (P > 0.05). Concentrations of ET-1 and measures of %FMD were similar between groups and unaffected by phase (P > 0.05). Thus, there exists variation in inflammation between young, healthy non-OCP and OCP women during the lower-hormone phase, despite similarities in vascular function and concentrations of ET-1 between groups and phases.NEW & NOTEWORTHY We demonstrate that despite having similar macrovascular function and concentrations of the vasoconstrictive substance endothelin-1 (ET-1) healthy naturally menstruating women display higher concentrations of circulating IL-6 during the lower-hormone phase of their menstrual cycle compared with 1) the higher-hormone phase of their menstrual cycle and 2) the lower-hormone phase of healthy women using oral contraceptive pills.

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.

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.

Carotid Artery Longitudinal Wall Motion Is Unaffected by 12 Weeks of Endurance, Sprint Interval or Resistance Exercise Training.

Carotid artery longitudinal wall motion (CALM) exhibits reduced magnitude in older adults and in individuals with chronic diseases, although longitudinal data are lacking to indicate how changes in CALM might develop over time. Therefore, the aim of this study was to investigate the effect of exercise training in healthy men on CALM using a retrospective design. Carotid ultrasound data were analysed from two previous studies in which men performed 12 wk of moderate-intensity continuous exercise training (n = 9), sprint-interval training (n = 7), higher-repetition resistance exercise training (n = 15) or lower-repetition resistance exercise training (n = 15). The CALM pattern was unaltered after 12 wk of exercise training, regardless of exercise mode, with no differences in systolic or diastolic CALM magnitudes (p > 0.05), similar to carotid intima-media thickness (p > 0.05). Our findings suggest that CALM is resistant to transient changes in lifestyle factors, similar to wall thickness in otherwise healthy populations.

Brachial artery endothelial function is stable across a menstrual and oral contraceptive pill cycle but lower in premenopausal women than in age-matched men.

Sex hormone concentrations differ between men, premenopausal women with natural menstrual cycles (NAT), and premenopausal women using oral contraceptive pills (OCP), as well as across menstrual or OCP phases. This study sought to investigate how differences in sex hormones, particularly estradiol, between men and women and across cycle phases might influence brachial artery endothelial function. Fifty-three healthy adults (22 ± 3 yr, 20 men, 15 NAT women, and 18 second-, third-, or fourth-generation OCP women) underwent assessments of sex hormones and endothelial [flow-mediated dilation (FMD) test] and smooth muscle [nitroglycerin (NTG) test] function. Men were tested three times at 1-wk intervals, and women were tested three times throughout a single menstrual or OCP cycle (NAT: menstrual, midfollicular, and luteal phases and OCP: placebo/no pill, "early", and "late" active pill phases). Endogenous estradiol concentration was comparable between men and women in their NAT menstrual or OCP placebo phase ( P = 0.36) but increased throughout a NAT cycle ( P < 0.001). Allometrically scaled FMD did not change across a NAT or OCP cycle but was lower in both groups of women than in men ( P = 0.005), whereas scaled NTG was lower only in NAT women ( P = 0.001). Changes in estradiol across a NAT cycle were not associated with changes in relative FMD ( r2 = 0.01, P = 0.62) or NTG ( r2 = 0.09, P = 0.13). Duration of OCP use was negatively associated with the average relative FMD for second-generation OCP users only ( r = -0.65, P = 0.04). Our findings suggest that brachial endothelial function is unaffected by cyclic hormonal changes in premenopausal women but may be negatively impacted by longer-term use of second-generation OCPs. NEW & NOTEWORTHY We demonstrate that brachial artery flow-mediated dilation does not change across a menstrual or oral contraceptive pill cycle in premenopausal women but is lower in women than in men. Although unaffected by within-cycle changes in estradiol, brachial flow-mediated dilation is negatively correlated with duration of oral contraceptive pill use for second-generation pills.

Brachial artery endothelial function is unchanged after acute sprint interval exercise in sedentary men and women.

NEW FINDINGS: What is the central question of this study? What is the acute brachial artery endothelial function response to sprint interval exercise and are there sex-based differences? What is the main finding and its importance? Brachial artery endothelial function did not change in either men or women following an acute session of SIT consisting of 3 × 20 s 'all-out' cycling sprints. Our findings suggest this low-volume protocol may not be sufficient to induce functional changes in the brachial artery of sedentary, but otherwise healthy adults. ABSTRACT: Sprint interval training (SIT) is a potent metabolic stimulus, but studies examining its acute effects on brachial artery endothelial function are limited. The influence of oestradiol on the acute arterial response to this type of exercise is also unknown. We investigated the brachial artery endothelial function response to a single session of SIT in sedentary healthy men (n = 8; 22 ± 4 years) and premenopausal women tested in the mid-follicular phase of the menstrual cycle (n = 8; 21 ± 3 years). Participants performed 3 × 20 s 'all-out' cycling sprints interspersed with 2 min of active recovery. Brachial artery flow-mediated dilatation (FMD) and haemodynamic parameters were measured before and 1 and 24 h post-exercise. Despite attenuations in some haemodynamic parameters at 1 h post-exercise, there were no changes in absolute (P = 0.23), relative (P = 0.23) or allometrically scaled FMD (P = 0.38) following a single session of SIT. Resting and peak dilatory diameters did not change in men or women (P > 0.05 for all) and there were no interactions between time and sex for any measure (P > 0.05). Oestradiol was not correlated with relative FMD at baseline (r = -0.22, P = 0.42) or with the change in relative FMD from baseline to 1 h post-exercise (r = 0.24, P = 0.40). Overall, brachial artery FMD appears to be unchanged in men and women following an acute session of SIT, and the higher oestradiol concentrations in women do not augment the baseline or post-exercise FMD response. The 3 × 20 s model of low-volume sprint interval exercise may not be sufficient to alter brachial artery endothelial function in healthy men and women.

Effect of sex, menstrual cycle phase, and monophasic oral contraceptive pill use on local and central arterial stiffness in young adults.

Arterial stiffness is associated with increased cardiovascular disease risk. Previous sex-based investigations of local and central stiffness report inconsistent findings and have not controlled for menstrual cycle phase in women. There is also evidence that sex hormones influence the vasculature, but their impact on arterial stiffness across a natural menstrual (NAT) or oral contraceptive pill (OCP) cycle has been understudied. This study sought to 1) examine potential sex differences in local and central stiffness, 2) compare stiffness profiles between NAT and OCP cycles, and 3) investigate the relationship between duration of OCP use and arterial stiffness. Sex hormone concentrations, ß-stiffness index (local stiffness), and carotid-femoral pulse wave velocity [cfPWV (central stiffness)] were assessed in 53 healthy adults (22 ± 3 yr old, 20 men, 15 NAT women, and 18 OCP women). All participants were tested three times: men on the same day and time 1 wk apart, NAT women in menstrual, midfollicular and luteal phases of the menstrual cycle, and OCP women in placebo, early active and late active pill phases. ß-Stiffness was higher in men than NAT and OCP women ( P < 0.001), whereas cfPWV was similar between groups ( P = 0.09). ß-Stiffness and cfPWV did not differ across or between NAT and OCP cycles ( P > 0.05 for both) and were not associated with duration of OCP use (ß-stiffness: r = 0.003, P = 0.99; cfPWV: r = -0.26, P = 0.30). The apparent sex differences in local, but not central, stiffness highlight the importance of assessing both indexes in comparisons between men and women. Furthermore, fluctuating sex hormone levels do not appear to influence ß-stiffness or cfPWV. Therefore, these stiffness indexes may need to be assessed during only one cycle phase in women in future investigations. NEW & NOTEWORTHY We observed higher local, but not central, arterial stiffness in men than women. We also demonstrated that there are no differences in arterial stiffness between naturally cycling women and women who use monophasic oral contraceptive pills, and that the duration of oral contraceptive pill use does not influence arterial stiffness.

Automated ultrasound edge-tracking software comparable to established semi-automated reference software for carotid intima-media thickness analysis.

Many commercial ultrasound systems are now including automated analysis packages for the determination of carotid intima-media thickness (cIMT); however, details regarding their algorithms and methodology are not published. Few studies have compared their accuracy and reliability with previously established automated software, and those that have were in asymptomatic adults. Therefore, this study compared cIMT measures from a fully automated ultrasound edge-tracking software (EchoPAC PC, Version 110.0.2; GE Medical Systems, Horten, Norway) to an established semi-automated reference software (Artery Measurement System (AMS) II, Version 1.141; Gothenburg, Sweden) in 30 healthy preschool children (ages 3-5 years) and 27 adults with coronary artery disease (CAD; ages 48-81 years). For both groups, Bland-Altman plots revealed good agreement with a negligible mean cIMT difference of -0·03 mm. Software differences were statistically, but not clinically, significant for preschool images (P = 0·001) and were not significant for CAD images (P = 0·09). Intra- and interoperator repeatability was high and comparable between software for preschool images (ICC, 0·90-0·96; CV, 1·3-2·5%), but slightly higher with the automated ultrasound than the semi-automated reference software for CAD images (ICC, 0·98-0·99; CV, 1·4-2·0% versus ICC, 0·84-0·89; CV, 5·6-6·8%). These findings suggest that the automated ultrasound software produces valid cIMT values in healthy preschool children and adults with CAD. Automated ultrasound software may be useful for ensuring consistency among multisite research initiatives or large cohort studies involving repeated cIMT measures, particularly in adults with documented CAD.

Changes in brachial artery endothelial function and resting diameter with moderate-intensity continuous but not sprint interval training in sedentary men.

Moderate-intensity continuous training (MICT) improves peripheral artery function in healthy adults, a phenomenon that reverses as continued training induces structural remodeling. Sprint interval training (SIT) elicits physiological adaptations similar to MICT, despite a lower exercise volume and time commitment; however, its effect on peripheral artery function and structure is largely unexplored. We compared peripheral artery responses to 12 wk of MICT and SIT in sedentary, healthy men (age = 27 ± 8 yr). Participants performed MICT (45 min of cycling at 70% peak heart rate; n = 10) or SIT (3 × 20-s "all out" cycling sprints with 2 min of recovery; n = 9), and responses were compared with a nontraining control group (CTL, n = 6). Allometrically scaled brachial flow-mediated dilation (FMD) increased 2.2% after 6 wk of MICT and returned to baseline levels by 12 wk, but did not change in SIT or CTL (group × time interaction, P = 0.04). Brachial artery diameter increased after 6 and 12 wk (main effect, P = 0.03), with the largest increases observed in MICT. Neither training protocol affected popliteal relative FMD and diameter, or central and lower limb arterial stiffness (carotid distensibility, central and leg pulse wave velocity) (P > 0.05 for all). Whereas earlier and more frequent measurements are needed to establish the potential presence and time course of arterial responses to low-volume SIT, our findings suggest that MICT was superior to the intense, but brief and intermittent SIT stimulus at inducing brachial artery responses in healthy men.NEW & NOTEWORTHY We compared the effects of 12 wk of moderate-intensity continuous training (MICT) and sprint interval training (SIT) on peripheral artery endothelial function and diameter, and central and lower limb stiffness in sedentary, healthy men. Whereas neither training program affected the popliteal artery or stiffness indexes, we observed changes in brachial artery function and diameter with MICT but not SIT. Brachial artery responses to SIT may follow a different time course or may not occur at all.