Search

Our study demonstrates that with aging, female C57BL/6N mice exhibit higher in vivo aortic stiffness, reduced modulus of elasticity, aortic wall structural and extracellular matrix remodeling, and elevations in systemic inflammation. These changes are largely reflective of those that occur with aging in women. Thus, female C57BL/6N mice are a viable model of human aortic aging and the utility of these animals should be considered in future biomedical investigations.

Mounting evidence suggests that myocardial steatosis contributes to left ventricular diastolic dysfunction, but definitive evidence in humans is lacking due to confounding comorbidities. As such, we utilized a 48-hour food restriction model to acutely increase myocardial triglyceride (mTG) content – measured by (1)H magnetic resonance spectroscopy – in 27 young healthy volunteers (13 men/14 women). Forty-eight hours of fasting caused a more than 3-fold increase in mTG content (p < 0.001). Diastolic function – defined as early diastolic circumferential strain rate (CSRd) – was unchanged following the 48-hour fasting intervention, but systolic circumferential strain rate was elevated (p < 0.001), indicative of systolic-diastolic uncoupling. Indeed, in a separate control experiment in 10 individuals, administration of low-dose dobutamine (2 μg/kg/min) caused a similar change in CSRs as was found during 48-hour of food restriction, along with a proportionate increase in CSRd, such that the two metrics remained coupled. Taken together, these data indicate that myocardial steatosis contributes to diastolic dysfunction by impairing diastolic-systolic coupling in healthy adults, and suggest that steatosis may contribute to the progression of heart disease.

Abstract Exercise is a cornerstone of preventive medicine and a promising strategy to intervene on the biology of aging. Variation in the response to exercise is a widely accepted concept that dates back to the 1980s with classic genetic studies identifying sequence variations as modifiers of the VO2max response to training. Since that time, the literature of exercise response variance has been populated with retrospective analyses of existing datasets that are limited by a lack of statistical power from technical error of the measurements and small sample sizes, as well as diffuse outcomes, very few of which have included older adults. Prospective studies that are appropriately designed to interrogate exercise response variation in key outcomes identified a priori and inclusive of individuals over the age of 70 are long overdue. Understanding the underlying intrinsic (e.g., genetics and epigenetics) and extrinsic (e.g., medication use, diet, chronic disease) factors that determine robust versus poor responses to various exercise factors will be used to improve exercise prescription to target the pillars of aging and optimize the clinical efficacy of exercise training in older adults. This review summarizes the proceedings of the NIA-sponsored workshop entitled, “Understanding Heterogeneity of Responses to, and Optimizing Clinical Efficacy of, Exercise Training in Older Adults” and highlights the importance and current state of exercise response variation research, particularly in older adults, prevailing challenges, and future directions.

Endothelial function is reduced across the menopausal stages related to increased oxidative stress associated with estrogen deficiency. In vitro studies demonstrate that coadministration of VITC with BH4 prevents endothelial nitric oxide synthase (eNOS) uncoupling and reductions in NO by peroxynitrite; however, this remains untested in humans. We demonstrate that the coadministration of BH4 + VITC does not restore endothelial function in perimenopausal and postmenopausal women to the level of premenopausal women, suggesting that other mechanisms contribute.

Aging is associated with reductions in cardiovagal baroreflex sensitivity (cBRS), which increases cardiovascular disease risk. Preclinical data indicate that low testosterone reduces cBRS. We determined whether low testosterone is associated with greater age-associated reductions in cBRS in healthy men. Twenty-six men categorized as young (

Context Vascular aging, including endothelial dysfunction secondary to oxidative stress and inflammation, increases the risk for age-associated cardiovascular disease (CVD). Low testosterone in middle-aged/older men is associated with increased CVD risk. Objective We hypothesized that low testosterone contributes to age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. Methods This cross-sectional study included 58 healthy, nonsmoking men categorized as young (N = 20; age 29 ± 4 years; testosterone 500 ± 58 ng/dL), middle-aged/older with higher testosterone (N = 20; age 60 ± 6 years; testosterone 512 ± 115 ng/dL), and middle-aged/older lower testosterone (N = 18; age 59 ± 8 years; testosterone 269 ± 48 ng/dL). Brachial artery flow-mediated dilation (FMDBA) was measured during acute infusion of saline (control) and vitamin C (antioxidant). Markers of oxidative stress (total antioxidant status and oxidized low-density lipoprotein cholesterol), inflammation (interleukin [IL]-6 and C-reactive protein [CRP]), and androgen deficiency symptoms were also examined. Results During saline, FMDBA was reduced in middle-aged/older compared with young, regardless of testosterone status (P < 0.001). FMDBA was reduced in middle-aged/older lower testosterone (3.7% ± 2.0%) compared with middle-aged/older higher testosterone (5.7% ± 2.2%; P = 0.021), independent of symptoms. Vitamin C increased FMDBA (to 5.3% ± 1.6%; P = 0.022) in middle-aged/older lower testosterone but had no effect in young (P = 0.992) or middle-aged/older higher testosterone (P = 0.250). FMDBA correlated with serum testosterone (r = 0.45; P < 0.001), IL-6 (r = −0.41; P = 0.002), and CRP (r = −0.28; P = 0.041). Conclusion Healthy middle-aged/older men with low testosterone appear to have greater age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. These data suggest that low testosterone concentrations may contribute to accelerated vascular aging in men.

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are both independently associated with increased cardiovascular disease (CVD) risk and impaired cognitive function. It is unknown if individuals with both COPD and OSA (i.e., overlap syndrome) have greater common carotid artery (CCA) stiffness, an independent predictor of CVD risk, and lower cognitive performance than either COPD or OSA alone. Elevated CCA stiffness is associated with cognitive impairment in former smokers with and without COPD in past studies. We compared CCA stiffness and cognitive performance between former smokers with overlap syndrome, COPD only, OSA only and former smoker controls using analysis of covariance (ANCOVA) tests to adjust for age, sex, body mass index (BMI), pack years, and postbronchodilator FEV(1)/FVC. We also examined the association between CCA stiffness and cognitive performance among each group separately. Individuals with overlap syndrome (n = 12) had greater CCA β-stiffness index (P = 0.015) and lower executive function-processing speed (P = 0.019) than individuals with COPD alone (n = 47), OSA alone (n = 9), and former smoker controls (n = 21), differences that remained significant after adjusting for age, BMI, sex, pack years, and FEV(1)/FVC. Higher CCA β-stiffness index was associated with lower executive function-processing speed in individuals with overlap syndrome (r = −0.58, P = 0.047). These data suggest that CCA stiffness is greater and cognitive performance is lower among individuals with overlap syndrome compared with individuals with COPD or OSA alone and that CCA stiffening may be an underlying mechanism contributing to the lower cognitive performance observed in patients with overlap syndrome. NEW & NOTEWORTHY Previous studies have demonstrated greater carotid artery stiffness and lower cognitive function among individuals with COPD alone and OSA alone. However, the present study is the first to demonstrate that individuals that have both COPD and OSA (i.e., overlap syndrome) have greater carotid artery stiffness and lower executive function-processing speed than individuals with either disorder alone. Furthermore, among individuals with overlap syndrome greater carotid artery stiffness is associated with lower executive function-processing speed.

Introduction Metabolic acidosis is associated with cardiovascular events, graft function, and mortality in kidney transplant recipients (KTRs). We examined the effect of alkali therapy on vascular endothelial function in KTRs. Methods We performed an 18-week, randomized, double-blind, placebo-controlled crossover pilot study examining the effect of sodium bicarbonate therapy versus placebo on vascular function in 20 adult KTRs at least 1 year from transplant with an estimated glomerular filtration rate (eGFR) ≥45 ml/min per 1.73 m2 and a serum bicarbonate level of 20 to 26 mEq/L. Each treatment period was 8 weeks in duration with a 2-week washout period between treatments. The primary outcome was change in brachial artery flow-mediated dilation (FMD) between sodium bicarbonate treatment and placebo. Results Twenty patients completed the study and were included in the primary analysis. The mean (SD) baseline eGFR of participants was 75 (22) ml/min per 1.73 m2, respectively. Serum bicarbonate levels did not increase significantly with treatment (0.3 [1.5] mEq/L, P = 0.37). Sodium bicarbonate therapy was not associated with worsening blood pressure, weight gain, or hypokalemia. There was no significant increase in FMD after 8 weeks of sodium bicarbonate therapy compared to placebo (mean change in FMD 2.2%, 95% CI –0.1 to 4.6, P = 0.06). There were no significant changes in high-sensitivity C-reactive protein, interleukin-6, eGFR, or urinary albumin-to-creatinine ratio during treatment. Urinary ammonium excretion decreased by 9 mmol/d (P=0.003), with sodium bicarbonate. Conclusions Sodium bicarbonate therapy is safe and feasible in KTRs, and our results strengthen the need for a larger randomized controlled trial., Graphical abstract

Purpose: Up to 1.8% of youth identify as transgender; many will be treated with a gonadotropin-releasing hormone agonist (GnRHa). The impact of GnRHa on insulin sensitivity and body composition in transgender youth is understudied. We aimed to evaluate differences in insulin sensitivity and body composition in transgender youth on GnRHa therapy compared with cisgender youth. Methods: Transgender participants were matched to cisgender participants on age, body mass index, and sex assigned at birth. Transgender males (n=9, ages 10.1–16.0 years) on GnRHa (mean±standard deviation duration of exposure: 20.9±19.8 months) were compared with cisgender females (n=14, ages 10.6–16.2). Transgender females (n=8, ages 12.6–16.1) on GnRHa (11.3±7 months) were compared with cisgender males (n=17, ages 12.5–15.5). Differences in insulin sensitivity (1/[fasting insulin], homeostatic model of insulin resistance [HOMA-IR]), glycemia (hemoglobin A1C [HbA1c], fasting glucose), and body composition (dual-energy X-ray absorptiometry) were evaluated using a mixed linear regression model. Results: Transgender males had lower 1/fasting insulin and higher HOMA-IR (p=0.031, p=0.01, respectively), fasting glucose (89±4 vs. 79±13 mg/dL, p=0.012), HbA1c (5.4±0.2 vs. 5.2±0.2%, p=0.039), and percent body fat (36±7 vs. 32±5%, p=0.042) than matched cisgender females. Transgender females had lower 1/fasting insulin and higher HOMA-IR (p=0.028, p=0.035), HbA1c (5.4±0.1% vs. 5.1±0.2%, p=0.007), percent body fat (31±9 vs. 24±10%, p=0.002), and lower percent lean mass (66±8 vs. 74±10%, p

Objective Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation; however, pulmonary function does not fully account for patients’ functional difficulties. The primary aim of the study was to determine the association between several domains of cognition and daily activity among those with COPD. Method Eighty-nine former smokers completed a neuropsychological battery including measures across multiple domains of cognition, pulmonary function measures, and daily activity questionnaires. Using a cross-sectional design, we compared daily activity between former smokers with and without COPD using two measures (St. George’s Respiratory Questionnaire [SGRQ] Activity Subscale and Lawton Instrumental Activities of Daily Living [IADL] Scale) and examined the association between cognition and daily activity among those with COPD. Results As expected, former smokers with COPD reported more difficulty than those without COPD on both activity measures (SGRQ Activity Subscale p Conclusion The findings suggest that cognition is associated with daily activity in patients with COPD. Future research should examine whether cognitive interventions may help to maximize patients’ engagement in daily activities.

Regular exercise enhances endothelial function in older men, but not consistently in estrogen-deficient postmenopausal women. Estradiol treatment improves basal endothelial function and restores improvements in endothelial function (flow-mediated dilation, FMD) to aerobic exercise training in postmenopausal women; however, estradiol treatment is controversial. Resveratrol, an estrogen receptor ligand, enhances exercise training effects on cardiovascular function and nitric oxide (NO) release in animal models, but impairs exercise training effects in men. We conducted a randomized cross-over, double-blinded, placebo-controlled pilot study to determine whether acute (single dose) resveratrol (250-mg tablet) or estradiol (0.05 mg/day transdermal patch) treatment enhances FMD at rest and after a single bout of moderate-intensity aerobic exercise in healthy estrogen-deficient postmenopausal women ( n = 15, 58.1 ± 3.2 yr). FMD was measured before and after (30, 60, and 120 min) a 40-min bout of moderate-intensity treadmill exercise (60–75% peak heart rate) under the respective conditions (separated by 1-2 wk). FMD was higher ( P < 0.05) before exercise and at all post-exercise time points in the resveratrol and estradiol conditions compared to placebo. FMD was increased from baseline by 120 min postexercise in the estradiol condition ( P < 0.001), but not resveratrol or PL conditions. Consistent with our previous findings, estradiol also enhances endothelial function in response to acute endurance exercise. Although resveratrol improved basal FMD, there was no apparent enhancement of FMD to acute exercise and, therefore, may not act as an estradiol mimetic. NEW & NOTEWORTHY The benefits of endurance exercise training on endothelial function are diminished in estrogen-deficient postmenopausal women, but estradiol treatment appears to restore improvements in endothelial function in this group. We show that basal endothelial function is enhanced with both acute estradiol and resveratrol treatments in estrogen-deficient postmenopausal women, but endothelial function is only enhanced following acute endurance exercise with estradiol treatment.

Peripheral artery disease (PAD) is a prevalent condition that confers substantial morbidity and mortality and remains underdiagnosed as well as undertreated in the overall population. Although PAD prevalence is similar or higher in women compared with men, associations of traditional and nontraditional risk factors with PAD and clinical manifestations of PAD differ by sex and may contribute to delayed or lack of diagnosis in women. Such sex-based differences in the manifestation of PAD may arise from sexual dimorphism in the vascular substrate in health as well as sex variation in the responses to vascular stressors. Despite the availability of proven therapies for improving symptoms and reducing risk of ischemic cardiovascular and limb events among patients with diagnosed PAD, important sex differences in treatment and outcomes have been observed. We provide an overview of current knowledge regarding sex differences in the epidemiology, pathophysiology, clinical presentation, and management of PAD.

BACKGROUND: Attention difficulties are often reported by patients with chronic obstructive pulmonary disease (COPD); however, limited research exists using objective tests designed specifically to measure attention in this population. This study aimed to: 1) identify specific attention deficits in COPD, and 2) determine which demographic/clinical characteristics are associated with reduced attention. METHODS: 84 former smokers (53 COPD, 31 no COPD) completed questionnaires, pulmonary function testing, and the Conner’s Continuous Performance Test II (CPT-II). Participants with and without COPD were compared on CPT-II measures of inattention, impulsivity, and vigilance. CPT-II measures that differed significantly between the two groups were further examined using hierarchical regression modeling. Demographic/clinical characteristics were entered into models with attention as the dependent variable. RESULTS: Participants with COPD performed worse than those without COPD on CPT measures of inattention and impulsivity (i.e., detectability [discrimination of target from non-target stimuli], perseverations [reaction time under 100 ms], omissions [target stimuli response failures], and commissions [responses to non-target stimuli]). More severe COPD (measured by greater airflow limitation) was associated with poorer ability to detect targets vs. foils and perseverative responding after adjusting for age and other covariates in the model. CONCLUSION: Former smokers with COPD experience problems with attention that go beyond slowed processing speed, including aspects of inattention and impulsivity. Clinicians should be aware that greater airflow limitation and older age are associated with attention difficulties, as this may impact functioning.

Context As many as 1.8% of adolescents identify as transgender and many more seek care, yet the impact of gender-affirming hormone therapy (GAHT) on cardiometabolic health is unknown. Objective To determine insulin sensitivity and body composition among transgender females (TF) and males (TM) on estradiol or testosterone, compared with cisgender females (CF) and males (CM). Design Pilot, cross-sectional study conducted from 2016–2018. Setting Academic regional transgender referral center. Participants Transgender adolescents on either testosterone or estradiol for at least 3 months were recruited. Nineteen TM were matched to 19 CM and 42 CF on pubertal stage and body mass index (BMI). Eleven TF were matched to 23 CF and 13 TF to 24 CM on age and BMI. Main Outcome Measures 1/[fasting insulin] and body composition (dual-energy x-ray absorptiometry). Results Total body fat was lower in TM than CF mean ± SD: (29% ± 7% vs 33% ± 7%; P = 0.002) and higher than in CM (28% ± 7% vs 24% ± 9%; P = 0.047). TM had higher lean mass than CF (68% ± 7% vs 64% ± 7%, P = 0.002) and lower than CM (69% ± 7% vs 73% ± 8%; P = 0.029). Insulin sensitivity was not different between the groups. TF had lower body fat than CF (31% ± 7% vs 35% ± 8%; P = 0.033) and higher than CM (28% ± 6% vs 20% ± 10%; P = 0.001). TF had higher lean mass than CF (66% ± 6% vs 62% ± 7%; P = 0.032) and lower than CM (69% ± 5% vs 77% ± 9%; P = 0.001). TF were more insulin resistant than CM (0.078 ± 0.025 vs 0.142 ± 0.064 mL/μU; P = 0.011). Conclusions Transgender adolescents on GAHT have significant differences in body composition compared with cisgender controls, with a body composition intermediate between BMI-matched CMs and CFs. These changes in body composition may have consequences for the cardiometabolic health of transgender adolescents. ClinicalTrials.gov NCT02550431

Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality in both men and women in developed societies. Age is the greatest risk factor for CVD due largely to adverse changes to arteries that include stiffening of the large elastic arteries (aortic and carotid arteries) and endothelial dysfunction. Vascular ageing is driven by oxidative stress, which reduces nitric oxide (NO) bioavailability and stimulates changes in the extracellular matrix. In women, reductions in circulating oestrogens with menopause interact with ageing processes to induce vascular dysfunction. Regular aerobic exercise is the most evidence-based strategy for reducing CVD risk with ageing in both men and women. Much of this cardiovascular-protective effect of aerobic exercise is likely due to its vascular health-enhancing influence. Large elastic artery stiffening with advancing age is attenuated in healthy adults engaged in aerobic exercise training, and aerobic exercise interventions improve arterial stiffness in previously sedentary middle-aged and older men and postmenopausal women. Regular aerobic exercise also enhances endothelial function with ageing in men (by reducing oxidative stress and preserving NO bioavailability), but not consistently in oestrogen-deficient postmenopausal women. In postmenopausal women, treatment with oestradiol appears to restore the ability of aerobic exercise to improve NO-mediated endothelial function by reducing oxidative stress. Several research gaps exist in our understanding of potential sex differences in the vascular adaptations to regular aerobic exercise. More information is needed on the factors that are responsible for sex differences, including the role of circulating oestrogens in transducing the aerobic exercise training 'stimulus'.

Hyperhomocysteinemia is associated with endothelial dysfunction and increased cardiovascular disease (CVD). We determined whether elevated homocysteine (Hcy) and markers of Hcy metabolism were associated with the previously reported endothelial dysfunction across stages of the menopause transition. Brachial artery flow-mediated dilation (FMD) and plasma concentrations of Hcy, cysteine, and methionine were measured in healthy women ( n = 128) 22–70 yr of age categorized as premenopausal ( n = 35), perimenopausal (early: n = 16; late: n = 21), and postmenopausal (early: n = 21; late: n = 35). Dietary intake of micronutrients involved in Hcy metabolism (e.g., vitamins B6, B12, folate) was assessed in a subpopulation of women. Hcy and cysteine concentrations were progressively higher, and methionine was progressively lower across menopausal stages (all P < 0.005). The higher Hcy and cysteine concentrations correlated with lower circulating estradiol levels ( r = −0.49 and −0.50, respectively, both P < 0.001). FMD was inversely correlated with Hcy ( r = −0.25, P = 0.004) and cysteine ( r = −0.39, P < 0.001) and positively correlated with methionine concentrations ( r = 0.25, P = 0.005). Dietary intake of vitamins B6 and B12 (both P < 0.05) were lower in postmenopausal women. Vitamin B12 intake correlated with FMD ( r = 0.22, P = 0.006). These data suggest that declines in estradiol across stages of the menopause transition may lead to elevations in Hcy and cysteine that may contribute to endothelial dysfunction in postmenopausal women. Future studies should examine whether targeting Hcy metabolism during the perimenopausal to early postmenopausal period with interventions, including diet, attenuates or reverses the decline in endothelial function in women.NEW & NOTEWORTHY Declines in circulating estradiol across the stages of the menopausal transition may lead to elevations in Hcy and cysteine concentrations that may contribute to endothelial dysfunction. Abnormalities in the Hcy metabolic pathways, possibly related to dietary deficiencies of vitamins B12 and B6 and folate, may contribute to elevations in Hcy and cysteine concentrations. Findings also suggest that higher cysteine levels may be more damaging to the vascular endothelium than Hcy.

This review summarizes a presentation given during the “Countermeasures to Cardiovascular Aging Symposium” that was part of the American Physiological Society Conference on Cardiovascular Aging: New Frontiers and Old Friends held in Westminster, CO, in August 2017. Endothelial dysfunction, a characteristic of vascular aging, is a major risk factor for age-associated cardiovascular diseases. In women, the decline in endothelial function is attenuated until menopause, whereafter the rate of decline accelerates to match that seen in men. Sex differences in the decline in endothelial function have been attributed to changes in sex hormones with aging. Women have a progressive impairment in endothelial function across the stages of the menopause transition, related in part to declining estradiol levels. In contrast to women, little is known about the impact of declining testosterone levels on endothelial function in men. Some evidence suggests greater endothelial dysfunction in men with low testosterone compared with men with higher testosterone. The underlying causes of endothelial dysfunction with sex hormone deficiency are unknown but may be related to endothelial nitric oxide synthase dysfunction and oxidative stress. Lifestyle behaviors, including habitual endurance exercise, attenuates and reverses the age-associated decline in endothelial function in older men. However, in older women, these exercise adaptations are diminished or absent, possibly related to estrogen deficiency. Understanding how declines in sex hormones contribute to the vascular aging process in both women and men will inform effective sex-specific intervention strategies to preserve vascular health and prevent cardiovascular diseases.

Every year, 2 million women reach menopause in the United States, and they may spend 40% or more of their life in a postmenopausal state. In the years immediately preceding menopause—known as the menopause transition (or perimenopause)—changes in hormones and body composition increase a woman’s overall cardiometabolic risk. In this narrative review, we summarize the changes in weight, body composition, and body fat distribution, as well as the changes in energy intake, energy expenditure, and other cardiometabolic risk factors (lipid profile, glucose metabolism, sleep health, and vascular function), that occur during the menopause transition. We also discuss the benefits of lifestyle interventions in women in the earlier stages of menopause before these detrimental changes occur. Finally, we discuss how to include perimenopausal women in research studies so that women across the life-span are adequately represented.

There is growing evidence that people who are transgender and gender diverse (TGD) are impacted by disparities across a variety of cardiovascular risk factors compared with their peers who are cisgender. Prior literature has characterized disparities in cardiovascular morbidity and mortality as a result of a higher prevalence of health risk behaviors. Mounting research has revealed that cardiovascular risk factors at the individual level likely do not fully account for increased risk in cardiovascular health disparities among people who are TGD. Excess cardiovascular morbidity and mortality is hypothesized to be driven in part by psychosocial stressors across the lifespan at multiple levels, including structural violence (eg, discrimination, affordable housing, access to health care). This American Heart Association scientific statement reviews the existing literature on the cardiovascular health of people who are TGD. When applicable, the effects of gender-affirming hormone use on individual cardiovascular risk factors are also reviewed. Informed by a conceptual model building on minority stress theory, this statement identifies research gaps and provides suggestions for improving cardiovascular research and clinical care for people who are TGD, including the role of resilience-promoting factors. Advancing the cardiovascular health of people who are TGD requires a multifaceted approach that integrates best practices into research, health promotion, and cardiovascular care for this understudied population.

Although estradiol (E2) has been believed to be the most critical factor in the menopause-associated decrease in bone mineral density (BMD), the role of increasing follicle stimulating hormone (FSH) during menopause is relatively unclear. We determined the extent to which hip and lumbar spine BMD differ among the stages of menopause in healthy women, and whether BMD is associated with FSH and E2 levels. A cross-sectional study of 141 healthy women classified as premenopausal (Pre, 38 &plusmn, 6 yrs, mean &plusmn, SD, n = 30), early perimenopausal (EPeri, 50 &plusmn, 3yrs, n = 31), late perimenopausal (LPeri, 4yrs, n = 30), early postmenopausal (EPost, 55 &plusmn, 3yrs, n = 24), or late postmenopausal (LPost, 62 &plusmn, 4 yrs, n = 26), was conducted. Spine/hip BMD and sex hormones were measured using dual-energy X-ray absorptiometry and enzymatic/colorimetric methods, respectively. Compared to EPeri, spine BMD was lower (p &lt, 0.05) in LPeri, EPost, and LPost and hip BMD was lower (p &lt, 0.05) in EPost and LPost. BMD was inversely associated with FSH (spine: r = &minus, 0.341, hip: r = &minus, 0.271, p &lt, 0.05) and directly associated with E2 (spine: r = 0.274, hip: r = 0.256, p &lt, 0.05). The menopause-related loss of spine and hip BMD is associated not only with low E2 but also higher FSH. Future studies are essential to delineating the mechanisms by which FSH regulates bone health in aging women.

Aging is associated with reductions in endothelial function, observations primarily reported using brachial artery ultrasound. There is growing interest in the use of peripheral artery tonometry (PAT) of microvessels in the fingertip to assess endothelial function because it is less technically demanding and has a high sensitivity and specificity for assessing coronary endothelial function. Moreover, similar to brachial artery flow-mediated dilation (FMD), PAT predicts cardiovascular disease outcomes. However, the relationship between PAT and FMD have yet to be examined in the context of aging. To address this question, reactive hyperemic index (RHI) using EndoPAT and FMD using brachial artery ultrasound were assessed after 5 min of forearm ischemia in 20 younger (18–40 yr old; 29 ± 4 yr) and 20 older (60–75 yr old; 65 ± 4 yr) healthy adult men. Higher values of both FMD and RHI indicate better endothelial function. Endothelial function assessed via brachial artery FMD was lower in older (4.8 ± 2.1%), compared with younger (7.5 ± 1.6%) men (P < 0.001). In contrast, the RHI assessed via PAT was greater in older (2.2 ± 0.6), compared with younger (1.8 ± 0.5) men (P = 0.014). FMD and RHI were not correlated (r = –0.15; P = 0.35). We conclude that PAT may not be an appropriate measure to evaluate age-associated changes in endothelial function. NEW & NOTEWORTHY Microvessel endothelial function assessed via finger plethysmography may not reflect age-associated reductions in large artery endothelial function assessed via brachial artery flow-mediated dilation.

Vascular dysfunction plays an important role in the etiology of chronic kidney disease (CKD) and is associated with cardiovascular diseases. Sex differences in vascular function are common in clinical and nonclinical populations. However, no data exist in individuals with CKD. The present study tested the hypothesis that sex and/or aging differences exist in vascular function in patients with CKD. Endothelium-dependent dilation (EDD; measured via brachial artery flow-mediated dilation) and endothelium-independent dilation (EID; measured via nitroglycerin-mediated dilation) were assessed. Analyses were adjusted for several variables that could influence vascular function (diabetes, cardiovascular disease, and blood pressure). Women, in general, had higher EDD values than men (6.5 ± 4.9% vs. 4.4 ± 3.4%); however, EID did not differ among these groups. In younger men and women (

Endothelial function declines progressively across stages of the menopause transition; however, the mechanisms contributing to this decline are unknown. We hypothesized that differences in endothelial function among pre-, peri, and postmenopausal women are related to differences in estradiol and oxidative stress. Brachial artery flow-mediated dilation (FMD) was measured in 87 healthy women categorized by menopause stage (24 premenopausal, 17 early and 21 late perimenopausal, and 25 postmenopausal) before and after 3 days of ovarian hormone suppression (gonadotropin releasing hormone antagonist [GnRH(ant)]) alone, and an additional 3 days of GnRH(ant) with concurrent transdermal estradiol or placebo add-back treatment. In 82 women, FMD during acute vitamin C (antioxidant) infusion was measured before and after GnRH(ant) + add-back. Before GnRH(ant), FMD was different among groups (p < 0.005; reduced across stages of menopause). Vitamin C increased FMD in late peri- and post- (p < 0.005) but not pre- or early perimenopausal women (p > 0.54). After GnRH(ant) alone, FMD decreased in pre- and peri- (p < 0.01), but not postmenopausal women, and was restored to premenopausal levels by estradiol add-back in the pre- and perimenopausal groups. Vitamin C improved FMD in pre-, peri-, and postmenopausal women on GnRH(ant) + placebo. There was no effect of vitamin C on FMD in women on GnRH(ant) + estradiol. These observations support the concept that the decline in endothelial function across the menopause transition is related to the loss of ovarian estradiol. The decline in estradiol may alter redox balance, thereby increasing oxidative stress and impairing endothelial function. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-020-00236-7) contains supplementary material, which is available to authorized users.

Age-related declines in skeletal muscle mass (i.e., sarcopenia) contribute to physical disability in older women. Although a menopause-related increase in fat mass is well documented, whether menopause influences muscle mass and sarcopenia is unclear. We determined the extent to which skeletal muscle mass differs across the stages of the menopause transition in women and whether these differences are associated with estradiol or other sex hormones. This was a cross-sectional study of 144 healthy women (aged 30–70 yr) classified as premenopausal [n = 30, 38 ± 6 yr (means ± SD)], early (n = 31, 50 ± 3 yr) and late (n = 30, 50 ± 4 yr) perimenopausal, and early (n = 26, 55 ± 3 yr) and late (n = 27, 62 ± 4 yr) postmenopausal. Appendicular lean mass (ALM) adjusted by the square of height in meters (ALM index; ALMi) was assessed by dual-energy X-ray absorptiometry. ALMi was lower (P < 0.05) in late perimenopausal and postmenopausal compared with early perimenopausal, with no significant differences between other groups (premenopausal 6.6 ± 0.6, early perimenopausal 6.8 ± 0.8, late perimenopausal 6.1 ± 0.8, early postmenopausal 6.5 ± 1.1, and late postmenopausal 6.2 ± 0.9 kg/m(2)). The prevalence of sarcopenia (ALMi ≤ 5.67 kg/m(2)) was 7%, 3%, 30%, 27%, and 32% in premenopausal, early and late perimenopausal, and early and late postmenopausal groups, respectively. ALMi measured across menopause stages was inversely correlated to follicle-stimulating hormone (FSH; r = −0.28, P = 0.003) but not to estradiol (r = 0.088, P = 0.34). The menopause transition appears to be a vulnerable period for the loss of skeletal muscle mass that may begin during the late perimenopausal transition. Future studies are necessary to investigate the potential effect of FSH on skeletal muscle. NEW & NOTEWORTHY Our data suggest that the late perimenopausal stage may be a vulnerable period for the loss of skeletal muscle, potentially related to elevations in FSH.

Cardiovascular risk is increased in adults with type 1 diabetes (T1D), although the mechanism is poorly understood. Endothelial dysfunction may contribute to increased coronary artery calcium (CAC) in T1D, and CAC severity may be associated with reduced nitric oxide (NO) synthesis and/or increased inflammation. We tested the hypotheses that high CAC and T1D are associated with expression of endothelial NO synthase (eNOS, enzyme that produces NO), phosphorylated eNOS (p-eNOS), and NFκB (pro-inflammatory transcription factor). Participants were categorized as having high (>80 Agatston units [AU]) or low CAC ( Independent t-tests compared protein expression by sex and T1D. Linear regression tested the associations of high vs. low CAC and T1D with the 3 proteins of interest after adjustment for age and sex. In men, eNOS expression differed by T1D: men with T1D had reduced cytoplasmic (0.34 vs.0.52, p=0.03) and nuclear (0.44 vs. 0.60, p=0.02) eNOS expression compared with men without T1D, suggesting reduced NO synthesis. There were no differences in p-eNOS expression, indicating that eNOS levels were likely not due to differential activation. In women, NFκB expression similarly differed by T1D: women with T1D had higher cytoplasmic (0.81 vs. 0.63, p=0.01) and nuclear (0.99 vs. 0.75, p=0.01) NFκB expression compared with women without T1D, suggesting greater inflammation. After adjustment for age and sex, there was no significant association between high vs. low CAC in endothelial expression of any proteins. The data trend suggested that high vs. low CAC is associated with reduced cytoplasmic (0.36 vs. 0.47, p=0.06) and nuclear (0.48 vs. 0.55, p=0.12) eNOS expression. T1D trended in the same direction for both cytoplasmic (0.36 vs. 0.47, p=0.06) and nuclear (0.47 vs. 0.55, p=0.13) eNOS expression. High vs. low CAC also trended towards an association with greater cytoplasmic (0.72 vs. 0.66, p=0.21) and nuclear (0.85 vs. 0.80, p=0.40) NFκB expression, while T1D was significantly associated with greater cytoplasmic (0.76 vs. 0.63, p=0.006) and nuclear (0.92 vs. 0.73, p=0.003) NFκB expression. Neither CAC nor T1D was associated with p-eNOS expression in linear regression. In conclusion, eNOS and NFκB expression are potential mechanisms for increased CAC given their roles in reduced NO synthesis and increased inflammation, and may differ by sex in people with T1D. Regardless of high CAC, inflammation in T1D is increased.

Vascular aging, characterized by endothelial dysfunction and large elastic arterial stiffening, is a major risk factor for age-associated cardiovascular disease (CVD). Although women have a lower prevalence of CVD until midlife, prevalence rates increase rapidly coincident with the menopausal transition to match those observed in men. The menopausal transition, or perimenopause, is a chaotic period that is associated with increased symptoms (e.g., hot flashes, depressed mood, anxiety, sleep disturbances) and CVD risk factors due to changes in the hormonal environment. Because these quality of life factors and CVD risk factors also change with aging, the arteries of women appear to endure a double insult. Our laboratory has been investigating how changes in gonadal function and hormone levels with the menopause transition impacts the vascular aging process in healthy women. Our work has shown that vascular endothelial function progressively declines, and large elastic arterial stiffness is greater across the stages of the menopausal transition. This acceleration in vascular aging may be due to the loss of vasodilatory, antioxidant, anti-inflammatory, and antiproliferative effects of estradiol on the vascular wall. This minireview discusses the impact of changes in gonadal function and hormones with the menopausal transition on vascular aging in women and areas for investigations to further our understanding of the intersection between gonadal function and vascular aging.

Context Little is known about the health of transgender adults in the United States, a growing population. There have been no large reports examining differences in health status and cardiometabolic disease in subgroups of transgender adults [female-to-male (FTM), male-to-female (MTF), and gender nonconforming (GNC)] in the United States. Objective Compare the health status and prevalence of cardiometabolic disease among specific subgroups of transgender adults (FTM, MTF, GNC) with those of cisgender adults in the United States. Design Secondary data analysis based on the 2015 Behavioral Risk Factor Surveillance System survey. Setting The 22 states in the United States that asked about transgender identity. Participants Noninstitutionalized adults age ≥18 years who reside in the United States, identified through telephone-based methods. Main Outcome Measures Data were extracted for respondents who answered the transgender identity question. Weighted percentages are given for all measures. Adjusted odds ratios (ORs) are reported for health status and cardiometabolic disease measures. Results FTM adults have a higher odds of being uninsured than both cisgender women [OR 3.8; 95% confidence interval (CI), 2.1 to 7.1] and cisgender men (OR 2.5; 95% CI, 1.4 to 4.7). MTF adults have a higher odds of reporting myocardial infarction than cisgender women (OR 2.9; 95% CI, 1.6 to 5.3) but not cisgender men. Conclusions There are significant differences in health status measures and cardiometabolic health between subgroups of transgender adults and cisgender adults. There is a need for additional research to understand the societal and medical (e.g., hormone therapy) effects on these outcomes., There are differences in health status and cardiometabolic health among subgroups of transgender adults compared with cisgender adults on the 2015 Behavioral Risk Factor Surveillance System survey.

Ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1) degrades the purines ATP and ADP that are key regulators of inflammation and clotting. We hypothesized that NTPDase1 polymorphisms exist and that they regulate this pathway. We sequenced the ENTPD1 gene (encoding NTPDase1) in 216 subjects then assessed genotypes in 2 cohorts comprising 2213 humans to identify ENTPD1 polymorphisms associated with venous thromboembolism (VTE). The G allele of the intron 1 polymorphism rs3176891 was more common in VTE vs. controls (odds ratio 1.26–1.9); it did not affect RNA splicing, but it was in strong linkage disequilibrium with the G allele of the promoter polymorphism rs3814159, which increased transcriptional activity by 8-fold. Oligonucleotides containing the G allele of this promoter region bound nuclear extracts more avidly. Carriers of rs3176891 G had endothelial cells with increased NTPDase1 activity and protein expression, and had platelets with enhanced aggregation. Thus, the G allele of rs3176891 marks a haplotype associated with increased clotting and platelet aggregation attributable to a promoter variant associated with increased transcription, expression, and activity of NTPDase1. We term this gain-of-function phenotype observed with rs3814159 G “CD39 Denver.”—Maloney, J. P., Branchford, B. R., Brodsky, G. L., Cosmic, M. S., Calabrese, D. W., Aquilante, C. L., Maloney, K. W., Gonzalez, J. R., Zhang, W., Moreau, K. L., Wiggins, K. L., Smith, N. L., Broeckel, U., Di Paola, J. The ENTPD1 promoter polymorphism −860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk.

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

Declines in vascular function occur early in the menopausal transition, as previously demonstrated by a reduction in endothelial function in perimenopausal women (PERI). However, the mechanisms contributing to this decline remain to be elucidated. We have previously shown that vascular impairments in postmenopausal women (POST) are due in part to endothelin-1 (ET-1). Thus, the purpose of this study is to determine if ET-1 contributes to reductions in vascular function across the stages of the menopausal transition. We hypothesized plasma ET-1 levels would be elevated across menopausal stages, and negatively associated with endothelial function. We further hypothesized that ETB receptors would contribute to impaired vascular function in PERI. Methods: We measured vascular endothelial function (flow-mediated dilation, FMD) and plasma ET-1 in 180 women classified as premenopausal (PRE, n=33, 33±7 years), early PERI (n=20, 50±3 years), late PERI (n=25, 50±4 years), early POST (n=36, 55±3 years), and late POST (n=58, 60±4 years) based on the STRAW criteria. In a separate, secondary study, we measured cutaneous microvascular endothelial function via local heating during microdialysis perfusions of lactated Ringers (control) or ETB receptor antagonist (BQ-788, 300 nM) in 6 PRE (22±2 years) and 8 PERI (50±3 years). Results: Plasma ET-1 concentration increased in a step-wise fashion across menopausal stage (PRE 5.4±1.1, early PERI 5.8±1.0, late PERI 6.1±1.6, early POST 6.4±1.6, late POST 6.4±1.5 pg/mL; PP P P Conclusions: These data suggest that elevated ET-1 contributes to impairments in vascular endothelial function across the menopausal transition. Furthermore, the decline in endothelial function is evident in the macro- and micro- circulation during the perimenopausal transition, due in part to a loss of ETB mediated dilation.

ContextUp to 1.8% of adolescents identify as transgender and many more seek care, yet the impact of gender affirming hormone therapy (GAHT) on cardiometabolic health is unknown.ObjectiveTo determine insulin sensitivity and body composition among transgender females (TF) and males (TM) on estradiol or testosterone, compared to cisgender females (CF) and males (CM).DesignPilot, cross-sectional study conducted from 2016-2018.Setting. Academic regional transgender referral center.ParticipantsTransgender adolescents on either testosterone or estradiol for at least 3 months were recruited. Nineteen TM were matched to 19 CM and 42 CF on pubertal stage and body mass index (BMI). Eleven TF were matched to 23 CF and 13 TF to 24 CM on age and BMI.Main Outcome Measure(s)1/[fasting insulin] and body composition (dual-energy absorptiometry, DXA).ResultsTotal body fat was lower in TM than CF (29±7 vs. 33±7%, p=0.002) and higher than CM (28±7 vs. 24±9%, p=0.047). TM had higher lean mass than CF (68±7 vs. 64±7%, p=0.002) and lower than CM (69± vs. 73±8%, p=0.029). Insulin sensitivity was not different between the groups.TF had lower body fat than CF (31±7 vs. 35±8%, p=0.033) and higher than CM (28±6 vs. 20±10, p=0.001). TF had higher lean mass than CF (66±6 vs. 62±7%, p=0.032) and lower than CM (69±5 vs. 77±9%, p=0.001). TF were more insulin resistant than CM (0.078±0.025 vs. 0.142±0.064, p=0.011).ConclusionsTransgender adolescents on GAHT have significant differences in body composition compared to cisgender controls, with a body composition intermediate between BMI-matched cisgender males and females. These changes in body composition may have consequences for the cardiometabolic health of transgender adolescents.PrecisTransgender youth on gender affirming hormone therapy have differences in their percent fat and lean mass compared to cisgender (non-transgender) youth.

Background and Objectives: Among youth, 0.7% identify as transgender. Markers of cardiometabolic health and body composition in transgender youth undergoing gender-affirming hormone therapy have not been rigorously studied. Our objectives were to evaluate differences in body composition, insulin sensitivity, lipid profile, and aspartate and alanine aminotransferases (AST, ALT) in male-to-female (MTF) youth treated with estradiol (E2) compared to non-transgender female (FC) and male controls (MC). Methods: Fourteen MTF E2-treated (mean + SD E2 dose 1.5 + 1.0 mg/day, duration 1 + 0.8 years) participants (aged 14.5-19.4 years) were compared to BMI percentile-category-matched and age-matched (within 1 year) FC (n=23, aged 14.2-18.3) and MC (n=24, aged 14.5-19.8). Three MTF participants were also on a gonadotropin releasing-hormone analogue (GnRHa) for suppression of endogenous testicular function. Participants had fasted morning laboratory testing and body composition measured by dual-energy X-ray absorptiometry (DXA). Differences (mean + SD) in body composition, insulin sensitivity (estimated from 1/[fasting insulin]), lipids, leptin, AST, ALT and blood pressure (BP) were evaluated using a mixed linear regression model with a random effect for the matched set. A spearman correlation was performed to evaluate for a correlation between 1/[fasting insulin] and % lean mass. Results: MTF vs. FC: Total testosterone was higher in MTF vs. FC (224 + 182 vs. 43 + 10 ng/dL, respectively, p

Study objective A phase 1/2 clinical trial was performed in individuals with cystathionine β synthase (CBS) deficient homocystinuria with aims to: (a) assess pharmacokinetics and safety of taurine therapy, (b) evaluate oxidative stress, inflammation, and vascular function in CBS deficiency, and (c) evaluate the impact of short-term taurine treatment. Methods Individuals with pyridoxine-nonresponsive CBS deficiency with homocysteine >50 μM, without inflammatory disorder or on antioxidant therapy were enrolled. Biomarkers of oxidative stress and inflammation, endothelial function (brachial artery flow-mediated dilation [FMD]), and disease-related metabolites obtained at baseline were compared to normal values. While maintaining current treatment, patients were treated with 75 mg/kg taurine twice daily, and treatment response assessed after 4 hours and 4 days. Results Fourteen patients (8-35 years; 8 males, 6 females) were enrolled with baseline homocysteine levels 161 ± 67 μM. The study found high-dose taurine to be safe when excluding preexisting hypertriglyceridemia. Taurine pharmacokinetics showed a rapid peak level returning to near normal levels at 12 hours, but had slow accumulation and elevated predosing levels after 4 days of treatment. Only a single parameter of oxidative stress, 2,3-dinor-8-isoprostaglandin-F2α, was elevated at baseline, with no elevated inflammatory parameters, and no change in FMD values overall. Taurine had no effect on any of these parameters. However, the effect of taurine was strongly related to pretreatment FMD values; and taurine significantly improved FMD in the subset of individuals with pretreatment FMD values 125 μM, pertinent to endothelial function. Conclusion Taurine improves endothelial function in CBS-deficient homocystinuria in patients with preexisting reduced function.

OBJECTIVES: Menopause and decline in estradiol (E(2)) may contribute to sarcopenia (i.e., age-related decline in muscle mass and strength) in women. E(2) may directly impact skeletal muscle protein breakdown via estrogen receptor (ER) signaling, primarily ERα. It is not yet known whether: 1) E(2) regulates pathways of skeletal muscle protein breakdown; 2) E(2)-mediated changes in protein breakdown markers are associated with ERα activation and insulin sensitivity; and 3) the effects of E(2) on protein breakdown markers differ by increasing time since menopause. STUDY DESIGN: We studied 27 women who were ≤6 years past menopause (early postmenopausal, EPM; n=13) or ≥10 years past menopause (late postmenopausal, LPM; n=14). Fasted skeletal muscle samples were collected following 1 week of transdermal E(2) or placebo treatment in a randomized cross-over design. MAIN OUTCOME MEASURES: We analyzed for cytosolic protein content of the: 1) structural proteins myosin heavy chain (MHC) and tropomyosin; and 2) protein regulatory markers: protein kinase B (Akt), muscle-specific ring finger protein1 (MuRF1), atrogin1, and forkhead box O3 (FOXO3) using Western blot. RESULTS: In response to acute E(2), FOXO3 activation (dephosphorylation) and MuRF1 protein expression decreased in EPM but increased in LPM women (p