Impaired Endothelium-dependent Vasodilation in Overweight and Obese Adult Humans is Not Limited to Muscarinic Receptor Agonists

Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults. Eighty-six middle-aged and older adults were studied: 42 normal-weight (54 +/- 1 yr, 21 men and 21 women, body mass index = 23.4 +/- 0.3 kg/m(2)) and 44 overweight/obese (54 +/- 1 yr, 28 men and 16 women, body mass index = 30.3 +/- 0.6 kg/m(2)) subjects. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine, methacholine, bradykinin, substance P, isoproterenol, and sodium nitroprusside were measured by strain-gauge plethysmography. FBF responses to each endothelial agonist were significantly blunted in the overweight/obese adults. Total FBF (area under the curve) to acetylcholine (50 +/- 5 vs. 79 +/- 4 ml/100 ml tissue), methacholine (55 +/- 4 vs. 86 +/- 5 ml/100 ml tissue), bradykinin (62 +/- 5 vs. 85 +/- 4 ml/100 ml tissue), substance P (37 +/- 4 vs. 57 +/- 5 ml/100 ml tissue), and isoproterenol (62 +/- 4 vs. 82 +/- 6 ml/100 ml tissue) were 30%-40% lower in the overweight/obese than normal-weight adults. N(G)-monomethyl-l-arginine significantly reduced the FBF response to acetylcholine to the same extent in both groups. There were no differences between the groups in the FBF responses to sodium nitroprusside. These results indicate that agonist-stimulated endothelium-dependent vasodilation is universally impaired with overweight/obesity. Moreover, this impairment appears to be independent of NO

Aging and Endothelial Progenitor Cell Telomere Length in Healthy Men

BACKGROUND: Telomere length declines with age in mature endothelial cells and is thought to contribute to endothelial dysfunction and atherogenesis. Bone marrow-derived circulating endothelial progenitor cells (EPCs) are critical to vascular health as they contribute to both reendothelialization and neovascularization. We tested the hypothesis that EPC telomere length decreases with age in healthy adult humans. METHODS: Peripheral blood samples were collected from 40 healthy, non-obese, sedentary men: 12 young (age 21-34 years), 12 middle-aged (43-55 years) and 16 older (57-68 years). Putative EPCs were isolated from peripheral blood mononuclear cells and telomere length was determined using genomic DNA preparation and Southern hybridization techniques. RESULTS: EPC telomere length (base pairs) was approximately 20% (p=0.01) lower in the older (8492+523 bp) compared to the middle-aged (10,565+572 bp) and young (10,205+501 bp) men. Of note, there was no difference in EPC telomere length between the middle-aged and young men. CONCLUSIONS: These results demonstrate that EPC telomere length declines with age in healthy, sedentary men. Interestingly, telomere length was well preserved in the middle-aged compared to young men, suggesting that EPC telomere shortening occurs after the age of 55 years

Basal Endothelial Nitric Oxide Release is Preserved in Overweight and Obese Adults

OBJECTIVE: Impaired basal nitric oxide release is associated with a number of cardiovascular disorders including hypertension, arterial spasm, and myocardial infarction. We determined whether basal endothelial nitric oxide release is reduced in otherwise healthy overweight and obese adult humans.RESEARCH METHODS AND PROCEDURES: Seventy sedentary adults were studied: 32 normal weight (BMI/m(2)), 24 overweight (BMI \u3e or = 25 \u3c 30 kg/m(2)), and 14 obese (BMI \u3e or = 30 kg/m(2)). Forearm blood flow (FBF) responses to intra-arterial infusions of N(g)-monomethyl-L-arginine (5 mg/min), a nitric oxide synthase inhibitor, were used as an index of basal nitric oxide release.RESULTS: N(g)-monomethyl-L-arginine elicited significant reductions in FBF in the normal weight (from 4.1 +/- 0.2 to 2.7 +/- 0.2 mL/100 mL tissue/min), overweight (4.1 +/- 0.1 to 2.8 +/- 0.2 mL/100 mL tissue/min), and obese (3.9 +/- 0.3 to 2.7 +/- 0.2 mL/100 mL tissue/min) subjects. Importantly, the magnitude of reduction in FBF (approximately 30%) was similar among the groups.DISCUSSION: These results indicate that the capacity of the endothelium to release nitric oxide under basal conditions is not compromised in overweight and obese adults

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

The Effect of Acetaminophen on Running Economy and Performance in Collegiate Distance Runners

Acetaminophen (ACT) may decrease perception of pain during exercise, which could allow runners to improve running economy (RE) and performance. The aim of this study was to determine the effects of ACT on RE and 3 km time trial (TT) performance in collegiate distance runners. A randomized, double blind, crossover study was employed in which 11 track athletes (9M/2F; age: 18.8 ± 0.6 years; VO2 max: 60.6 ± 7.7 mL/kg/min) completed three intervention sessions. Participants ingested either nothing (baseline, BSL), three gelatin capsules (placebo, PLA), or three 500 mg ACT caplets (ACT). One hour after ingestion, participants completed a graded exercise test consisting of 4 × 5 min steady-state stages at ~55–75% of VO2 max followed by a 3 km TT. There was no influence of ACT on RE in any stage. Similarly, ACT did not favorably modify 3 km TT performance [mean ± SD: BSL = 613 ± 71 s; PLA = 617 ± 70 s; ACT = 618 ± 70 s; p = 0.076]. The results indicate that ACT does not improve RE or TT performance in collegiate runners at the 3 km distance. Those wanting to utilize ACT for performance must understand that ACT’s benefits have yet to be significant amongst well-trained runners. Future studies should examine the effects of ACT on well-trained runners over longer trial distances and under more controlled conditions with appropriate medical oversight

Increased Arterial Stiffness in South Dakota American Indian Children

Arterial stiffness has been observed in white American obese children, yet there are no data in American Indian youth, who are affected disproportionately by the cardiovascular consequences of childhood obesity and its accompanying risk factors. The purpose of this study was to determine the association of childhood overweight-obesity and cardiometabolic risk factors with arterial stiffness in South Dakota white American and American Indian children. Thirty-six (28 white American and 8 American Indian) children (age, 13 ± 1 years; grades 6-8) from a rural South Dakota elementary and middle school were studied: 18 had a healthy weight (body mass index (BMI), 19.5 ± 1.9 kg/m(2)) and 18 were overweight-obese (BMI, 26.8 ± 3.5 kg/m(2)). Arterial stiffness was assessed using applanation tonometry via pulse wave analysis to determine carotid-radial pulse wave velocity (crPWV) and aortic augmentation index (AIx). There were no differences (P = 0.94) in crPWV between healthy weight (7.1 ± 1.4 m/s) and overweight-obese (7.3 ± 1.0 m/s) children, even after controlling for risk factors. However, crPWV was markedly elevated (P = 0.002) in overweight-obese American Indian children (7.7 ± 1.1 m/s) compared with white American children (6.8 ± 0.5 m/s), and these differences remained after controlling for blood pressure and more severe obesity in the American Indians. An obesity-matched subgroup analysis indicated that crPWV (7.7 ± 1.1 vs 6.8 ± 0.4 m/s) remained significantly greater in the American Indians (P = 0.03). There were no between-group differences in aortic AIx. These findings indicate an adverse influence of American Indian ethnicity on arterial stiffening in children with elevated adiposity. Arterial stiffness in American Indian children may accelerate early adulthood vascular disease

No Influence of Ischemic Preconditioning on Running Economy

PURPOSE: Many of the potential performance-enhancing properties of ischemic preconditioning suggest that the oxygen cost for a given endurance exercise workload will be reduced, thereby improving the economy of locomotion. The aim of this study was to identify whether ischemic preconditioning improves exercise economy in recreational runners.METHODS: A randomized sham-controlled crossover study was employed in which 18 adults (age 27 ± 7 years; BMI 24.6 ± 3 kg/m(2)) completed two, incremental submaximal (65-85% VO2max) treadmill running protocols (3 × 5 min stages from 7.2-14.5 km/h) coupled with indirect calorimetry to assess running economy following ischemic preconditioning (3 × 5 min bilateral upper thigh ischemia) and sham control. Running economy was expressed as mlO2/kg/km and as the energy in kilocalories required to cover 1 km of horizontal distance (kcal/kg/km).RESULTS: Ischemic preconditioning did not influence steady-state heart rate, oxygen consumption, minute ventilation, respiratory exchange ratio, energy expenditure, and blood lactate. Likewise, running economy was similar (P = 0.647) between the sham (from 201.6 ± 17.7 to 204.0 ± 16.1 mlO2/kg/km) and ischemic preconditioning trials (from 202.8 ± 16.2 to 203.1 ± 15.6 mlO2/kg/km). There was no influence (P = 0.21) of ischemic preconditioning on running economy expressed as the caloric unit cost (from 0.96 ± 0.12 to 1.01 ± 0.11 kcal/kg/km) compared with sham (from 1.00 ± 0.10 to 1.00 ± 0.08 kcal/kg/km).CONCLUSIONS: The properties of ischemic preconditioning thought to affect exercise performance at vigorous to severe exercise intensities, which generate more extensive physiological challenge, are ineffective at submaximal workloads and, therefore, do not change running economy