Browsing by Author "Edwards, David G."
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Item Antecubital venous endothelial ETB receptor protein expression is preserved with aging in men(American Journal of Physiology - Heart and Circulatory Physiology, 2024-01-01) Tummala, Saumya; Kuczmarski, Andrew V.; Del Vecchio, Angelica R.; Schwab, Allyson I.; Edwards, David G.; Wenner, Megan M.Changes in endothelial function precede the development of cardiovascular disease (CVD). We have previously shown that age-related declines in endothelial function in women are due in part to a reduction in endothelial cell endothelin-B receptor (ETBR) protein expression. However, it is not known if ETBR protein expression changes with aging in men. The purpose of this study was to test the hypothesis that ETBR protein expression is attenuated in older men (OM) compared with younger men (YM). Primary endothelial cells were harvested from the antecubital vein of 14 OM (60 ± 6 yr; 26 ± 3 kg/m2) and 17 YM (24 ± 5 yr; 24 ± 2 kg/m2). Cells were stained with 4′,6-diamidino-2-phenylindole, vascular endothelial cadherin, and ETBR. Images were quantified using immunocytochemistry. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD). Systolic BP was similar (OM, 123 ± 11 vs. YM, 122 ± 10 mmHg) whereas diastolic BP was higher in OM (OM, 77 ± 7 vs. YM, 70 ± 6 mmHg; P < 0.01). Total testosterone was lower in OM (OM, 6.28 ± 4.21 vs. YM, 9.10 ± 2.68 ng/mL; P = 0.03). As expected, FMD was lower in OM (OM, 3.85 ± 1.51 vs. YM, 6.40 ± 2.68%; P < 0.01). However, ETBR protein expression was similar between OM and YM (OM, 0.39 ± 0.17 vs. YM, 0.42 ± 0.17 AU; P = 0.66). These data suggest that ETBR protein expression is not altered with age in men. These findings contrast with our previous data in women and further support sex differences in the endothelin system. NEW & NOTEWORTHY Our laboratory has previously shown that age-related declines in endothelial function are associated with a reduction in endothelial cell ETBR protein expression in women. However, it is unclear if endothelial cell ETBR protein expression is reduced with aging in men. This study demonstrates that endothelial cell ETBR protein expression is preserved with aging in men, and provides additional evidence for sex differences in the endothelin system.Item Characterizing vascular and hormonal changes in women across the life span: a cross-sectional analysis(American Journal of Physiology - Heart and Circulatory Physiology, 2024-11-01) Wenner, Megan M.; Shenouda, Ninette; Shoemaker, Leena; Kuczmarski, Andrew; Haigh, Katherine; Del Vecchio, Angelica; Schwab, Allyson; McGinty, Shane J.; Edwards, David G.; Pohlig, Ryan T.; Nuckols, Virginia R.; DuBose, Lyndsey; Moreau, Kerrie L.Vascular dysfunction, marked by lower endothelial function and increased aortic stiffness, is a nontraditional risk factor that precedes the development of cardiovascular disease (CVD). However, the age at which these changes in vascular function occur in women and the degree to which reproductive hormones mediate these changes has not been characterized. Women free from major disease were enrolled across the adult life span (aged 18–70 yr, n = 140). Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery during reactive hyperemia using duplex ultrasound and expressed as percent dilation. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). Blood samples were obtained to quantify reproductive hormone concentration. Regression models determined age-related breakpoints and mediating factors between age and vascular outcomes. FMD declined with age with a breakpoint and steeper decline occurring at 47 yr of age. Thereafter, age was independently associated with lower FMD (B = −0.13, P < 0.001). cfPWV was relatively stable until a breakpoint at age 48, and age was independently associated with higher cfPWV thereafter (B = 0.10, P < 0.001). Path analysis revealed that the association between age and FMD was partially mediated by follicle-stimulating hormone (abind = 0.051, P = 0.01) and progesterone (abind = 0.513, P < 0.001) but not estradiol (abind = −0.004, P = 0.08). No mediation was present for cfPWV. Age was associated with endothelial dysfunction and aortic stiffness in women beginning at 47 and 48 yr old, respectively, 3 to 4 yr before the average age of menopause. The association between age and endothelial dysfunction was explained in part by elevations in follicle-stimulating hormone and progesterone, but not declining estradiol. NEW & NOTEWORTHY We demonstrate that the age at which endothelial function declines and aortic stiffness increases in healthy women is 47 and 48, respectively. The inflection point in flow-mediated dilation (FMD) is 6 yr earlier than previously reported, and the association between age and FMD was mediated by follicle-stimulating hormone (FSH) and progesterone (P4) but not estradiol (E2). Graphical abstract available at: https://doi.org/10.1152/ajpheart.00373.2024Item Effect of acute handgrip and aerobic exercise on wasted pressure effort and arterial wave reflections in healthy aging(American Journal of Physiology - Heart and Circulatory Physiology, 2023-10-01) Stock, Joseph M.; Shenouda, Ninette; Chouramanis, Nicholas; Patik, Jordan C.; Martens, Christopher R.; Farquhar, William B.; Chirinos, Julio A.; Edwards, David G.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.Item Effects of a mitochondrial-targeted ubiquinol on vascular function and exercise capacity in chronic kidney disease: a randomized controlled pilot study(American Journal of Physiology - Renal Physiology, 2023-10-01) Kirkman, Danielle L.; Stock, ,Joseph M.; Shenouda, Ninette; Bohmke, Natalie J.; Kim, Youngdeok; Kidd, Jason; Townsend, Raymond R.; Edwards, David G.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.Item Impact of angiotensin receptor–neprilysin inhibition on vascular function in heart failure with reduced ejection fraction: A pilot study(Physiological Reports, 2022-03-05) Nathaniel, Sangeetha; McGinty, Shane; Witman, Melissa A. H.; Edwards, David G.; Farquhar, William B.; Hosmane, Vinay; Wenner, Megan M.The mechanisms for the benefits of Angiotensin Receptor Neprilysin Inhibition (ARNi) in heart failure patients with reduced ejection fraction (HFrEF) are likely beyond blood pressure reduction. Measures of vascular function such as arterial stiffness and endothelial function are strong prognostic markers of cardiovascular outcomes in HFrEF, yet the impact of ARNi on vascular health remains to be explored. We hypothesized that arterial stiffness and endothelial function would improve after 12 weeks of ARNi in HFrEF. We tested 10 stable HFrEF patients at baseline and following 12 weeks of ARNi [64 ± 9 years, Men/Women: 9/1, left ventricular ejection fraction (EF): 28 ± 6%] as well as 10 stable HFrEF patients that remained on conventional treatment (CON: 60 ± 7 years, Men/Women: 6/4, EF: 31 ± 5%; all p = NS). Arterial stiffness was assessed via carotid-femoral pulse wave velocity (PWV) and endothelial function was assessed via brachial artery flow-mediated dilation (FMD). PWV decreased after 12 weeks of ARNi (9.0 ± 2.1 vs. 7.1 ± 1.2 m/s; p < 0.01) but not in CON (7.0 ± 2.4 vs. 7.5 ± 2.3 m/s; p = 0.35), an effect that remained when controlling for reductions in mean arterial pressure (p < 0.01). FMD increased after 12 weeks of ARNi (2.2 ± 1.9 vs. 5.5 ± 2.1%; p < 0.001) but not in CON (4.8 ± 3.8 vs. 5.4 ± 3.4%; p = 0.34). Baseline PWV (p = 0.06) and FMD (p = 0.07) were not different between groups. These preliminary data suggest that 12 weeks of ARNi therapy may reduce arterial stiffness and improve endothelial function in HFrEF. Thus, the findings from this pilot study suggest that the benefits of ARNi are beyond blood pressure reduction and include improvements in vascular function. New & Noteworthy: Twelve weeks of ARNi therapy may reduce arterial stiffness (assessed by carotid-femoral PWV) and improve endothelial function (assessed by brachial artery FMD) in HFrEF when compared to conventional treatment. Improvement in vascular function may be a physiological mechanism for the clinical benefit seen with ARNi in HFrEF. Moreover, these pleiotropic benefits of ARNi beyond BP lowering may be vital for the treatment of HFrEF and possibly other cardiovascular diseases.Item Personalized physiologic flow waveforms improve wave reflection estimates compared to triangular flow waveforms in adults(American Journal of Physiology - Heart and Circulatory Physiology, 2021-04-21) Shenouda, Ninette; Stock, Joseph M.; Patik, Jordan C.; Chirinos, Julio A.; Edwards, David G.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.Item Sex differences in microvascular function and arterial hemodynamics in nondialysis chronic kidney disease(American Journal of Physiology - Heart and Circulatory Physiology, 2022-12-01) Kirkman, Danielle L.; Ramick, Meghan G.; Muth, Bryce J.; Stock, Joseph M.; Townsend, Raymond R.; Edwards, David G.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.Item Sleep Variability, Eating Timing Variability, and Carotid Intima‐Media Thickness in Early Adulthood(Journal of the American Heart Association Cardiovascular and Cerebrovascular Disease, 2023-10-03) Hoopes, Elissa K.; Witman, Melissa A.; D'Agata, Michele N.; Brewer, Benjamin; Edwards, David G.; Robson, Shannon M.; Malone, Susan K.; Keiser, Thomas; Patterson, FredaBackground Day‐to‐day variability in sleep patterns and eating timing may disrupt circadian rhythms and has been linked with various adverse cardiometabolic outcomes. However, the extent to which variability in sleep patterns and eating timing relate to atherosclerotic development in subclinical stages remains unclear. Methods and Results Generally healthy adults (N=62, 29.3±7.3 years, 66% female) completed 14 days of sleep and dietary assessments via wrist accelerometry and photo‐assisted diet records, respectively. Variability in sleep duration, sleep onset, eating onset (time of first caloric consumption), eating offset (time of last caloric consumption), and caloric midpoint (time at which 50% of total daily calories are consumed) were operationalized as the SD across 14 days for each variable. Separate regression models evaluated the cross‐sectional associations between sleep and eating variability metrics with end‐diastolic carotid intima‐media thickness (CIMT) measured via ultrasonography. Models adjusted for age, sex, systolic blood pressure, sleep duration, and total energy intake. Each 60‐minute increase in sleep duration SD and sleep onset SD were associated with a 0.049±0.016 mm (P=0.003) and 0.048±0.017 mm (P=0.007) greater CIMT, respectively. Variability in eating onset and offset were not associated with CIMT; however, each 60‐minute increase in caloric midpoint SD was associated with a 0.033±0.015 mm greater CIMT (P=0.029). Exploratory post hoc analyses suggested that sleep duration SD and sleep onset SD were stronger correlates of CIMT than caloric midpoint SD. Conclusions Variability in sleep patterns and eating timing are positively associated with clinically relevant increases in CIMT, a biomarker of subclinical atherosclerosis, in early adulthood.Item Temporal associations between nightly sleep with daytime eating and activity levels in free-living young adults(SLEEP, 2023-04-21) Hoopes, Elissa K.; Brewer, Benjamin; Robson, Shannon M.; Witman, Melissa A.; D’Agata, Michele N.; Malone, Susan K.; Edwards, David G.; Patterson, FredaStudy Objectives This study aimed to quantify the temporal associations between nightly sleep quantity and timing with daytime eating behavior and activity levels in free-living (i.e. non-experimental) settings. Methods Generally healthy young adults (N = 63; 28.9 ± 7.1 years) completed concurrent sleep (wrist actigraphy), eating (photo-assisted diet records), and activity (waist actigraphy) assessments over 14 days. Multilevel models quantified the associations between nightly sleep (total sleep time, timing of sleep and wake onset) with next-day eating behavior (diet quality, caloric intake, timing of eating onset/offset, eating window duration) and activity levels (total physical activity, sedentary time). Associations in the reverse direction (i.e. eating and activity predicting sleep) were explored. Models adjusted for demographic and behavioral confounders and accounted for multiple testing. Results At within- and between-subject levels, nights with greater-than-average total sleep time predicted a shorter eating window the next day (all p ≤ 0.002). Later-than-average sleep and wake timing predicted within- and between-subject delays in next-day eating onset and offset, and between-subject reductions in diet quality and caloric intake (all p ≤ 0.008). At within- and between-subject levels, total sleep time was bidirectionally, inversely associated with sedentary time (all p < 0.001), while later-than-average sleep and wake timing predicted lower next-day physical activity (all p ≤ 0.008). Conclusions These data underscore the complex interrelatedness between sleep, eating behavior, and activity levels in free-living settings. Findings also suggest that sleep exerts a greater influence on next-day behavior, rather than vice versa. While testing in more diverse samples is needed, these data have potential to enhance health behavior interventions and maximize health outcomes. Graphical Abstract: Available at https://doi.org/10.1093/sleep/zsad123