The Association Between Testosterone and Vascular Function in Reproductive-Aged Females With Chronic Kidney Disease.

Cardiovascular disease is the leading cause of death in women, and women with chronic kidney disease (CKD) experience especially elevated risk. This study examined the association between testosterone and vascular function in 61 reproductive-aged females with CKD. Testosterone levels and measures of vascular function were assessed, including pulse wave velocity, aortic augmentation, flow-mediated dilation (FMD), and velocity time integral. Multivariable linear regression analyses assessed the relationship between testosterone and each measure of vascular function. No associations were observed between testosterone and vascular function outcomes, although a significant positive association between testosterone-to-estradiol ratio and FMD was demonstrated. Although testosterone levels were not independently predictive of vascular function, the level of testosterone relative to estradiol was associated with FMD and may therefore influence endothelial function in the high-risk population of reproductive-aged female patients with CKD.

Alors que les maladies cardiovasculaires sont la cause principale de décès chez les femmes, les femmes atteintes d'une maladie rénale chronique (MRC) sont exposées à un risque particulièrement élevé. La présente étude vise à examiner l'association entre la testostérone et la fonction vasculaire de 61 femmes en âge de procréer atteintes d'une MCV. Nous avons évalué les concentrations de testostérone et les mesures de la fonction vasculaire, soit la vélocité de l'onde de pouls, l'augmentation de l'aorte, la dilatation médiée par le flux (DMF) et l'intégrale temps-vitesse. Les analyses multivariées de régression linéaire ont permis d'évaluer la relation entre la testostérone et chacune des mesures de la fonction vasculaire. Aucune association n'a été observée entre la testostérone et les résultats de la fonction vasculaire, bien qu'une association positive significative entre le ratio testostérone/œstradiol et la DMF ait été démontrée. Bien que les concentrations de testostérone n'étaient pas indépendamment prédictives de la fonction vasculaire, les concentrations de la testostérone relativement à l'œstradiol ont été associées à la DMF et peuvent par conséquent influencer la fonction endothéliale au sein de la population exposée à un risque élevé composée de patientes en âge de procréer atteintes d'une MRC.

Awareness of Hypertension in Reproductive-Aged Women Living With Chronic Kidney Disease.

Background: Hypertension is the most important modifiable cardiovascular risk factor among women. Chronic kidney disease (CKD), which affects 1 in 10 reproductive-aged women, increases the risk of hypertension; however, awareness of hypertension in this population is unknown. This study aimed to determine hypertension awareness among reproductive-aged women living with chronic kidney disease. Methods: Women aged 18 to 50 years with CKD were recruited from nephrology clinics in Calgary, Alberta, Canada. Participants completed a semistructured interview and focused chart review, serum and urine laboratory assessment, and a physical examination that included anthropomorphic measurements and 2 automated office blood pressure readings. Hypertension was defined according to the use of ≥ 1 antihypertensive medications and/or an automated office blood pressure reading of ≥ 135/85 mm Hg. Data were stratified by hypertension status, as well as by awareness, and descriptively presented as mean ± standard deviation, numerical values, and percentages. Results: Sixty-three participants with CKD were included. Thirty-eight (60%) participants had hypertension according to study definitions. Of those with hypertension, 30 participants (79%) were aware of their hypertension status. Conclusions: Hypertension awareness is relatively high in reproductive-aged women living with CKD. However, hypertension awareness is the critical component for hypertension management, and further work is necessary to optimize reduction of cardiovascular risk in this important population.

Contexte: L'hypertension est le principal facteur de risque cardiovasculaire modifiable chez les femmes. La néphropathie chronique, qui touche une femme en âge de procréer sur 10, augmente le risque d'hypertension, mais le niveau de sensibilisation de cette population à ce sujet est inconnu. La présente étude visait à déterminer le niveau de sensibilisation à l'hypertension chez les femmes en âge de procréer atteintes de néphropathie chronique. Méthodologie: Des femmes âgées de 18 à 50 ans atteintes de néphropathie chronique ont été recrutées dans les cliniques de néphrologie de Calgary, en Alberta (Canada). Les participantes ont été soumises à des entrevues semi-structurées, un examen ciblé du dossier médical, des analyses de laboratoire du sérum et de l'urine et un examen physique incluant des mesures anthropométriques et deux lectures automatisées de la pression artérielle réalisées en cabinet. L'hypertension a été définie de la façon suivante : (1) l'utilisation de ≥ 1 agent antihypertenseur, et/ou (2) une lecture automatisée de la pression artérielle en cabinet ≥ 135/85 mmHg. Les données ont été stratifiées selon le statut d'hypertension et le niveau de sensibilisation, et elles sont présentées de façon descriptive par la moyenne ± l'écart-type, les valeurs numériques et les pourcentages. Résultats: Soixante-trois participantes atteintes de néphropathie chronique ont été incluses dans l'étude. Trente-huit (60 %) participantes étaient atteintes d'hypertension selon la définition utilisée dans l'étude. Parmi les participantes hypertendues, 30 (79 %) étaient conscientes de leur statut d'hypertension. Conclusions: Le niveau de sensibilisation à l'hypertension est relativement élevé parmi les femmes en âge de procréer atteintes de néphropathie chronique. Toutefois, la sensibilisation à l'hypertension est un élément clé pour sa prise en charge, et d'autres travaux sont nécessaires pour optimiser la réduction du risque cardiovasculaire dans cette population importante.

Sex differences in body fluid composition in humans with obstructive sleep apnea before and after CPAP therapy.

Obstructive sleep apnea (OSA) is common in heart and kidney disease, both conditions prone to fluid retention. Nocturnal rostral fluid shift contributes to the pathogenesis of OSA in men more than women, suggesting a potential role for sex differences in body fluid composition in the pathogenesis of OSA, with men having a predisposition to more severe OSA due to an underlying volume expanded state. Continuous positive airway pressure (CPAP) increases intraluminal pressure in the upper airway and mitigates the rostral fluid shift; this, in turn, may prevent fluid redistribution from other parts of the body to the upper airway. We sought to determine the impact of CPAP on sex differences in body fluid composition. Twenty-nine (10 women, 19 men) incident, sodium replete, otherwise healthy participants who were referred with symptomatic OSA (oxygen desaturation index >15/h) were studied pre- and post-CPAP (>4 h/night × 4 weeks) using bioimpedance analysis. Bioimpedance parameters including fat-free mass (FFM, %body mass), total body water (TBW, %FFM), extracellular and intracellular water (ECW and ICW, %TBW), and phase angle (°) were measured and evaluated for sex differences before and after CPAP. Pre-CPAP, despite TBW being similar between sexes (74.6 ± 0.4 vs. 74.3 ± 0.2%FFM, p = 0.14; all values women vs. men), ECW (49.7 ± 0.7 vs. 44.0 ± 0.9%TBW, p < 0.001) was increased, while ICW (49.7 ± 0.5 vs. 55.8 ± 0.9%TBW, p < 0.001) and phase angle (6.7 ± 0.3 vs. 8.0 ± 0.3°, p = 0.005) were reduced in women compared to men. There were no sex differences in response to CPAP (∆TBW -1.0 ± 0.8 vs. 0.7 ± 0.7%FFM, p = 0.14; ∆ECW -0.1 ± 0.8 vs. -0.3 ± 1.0%TBW, p = 0.3; ∆ICW 0.7 ± 0.4 vs. 0.5 ± 1.0%TBW, p = 0.2; ∆Phase Angle 0.2 ± 0.3 vs. 0.0 ± 0.1°, p = 0.7). Women with OSA had baseline parameters favoring volume expansion (increased ECW, reduced phase angle) compared to men. Changes in body fluid composition parameters in response to CPAP did not differ by sex.

The Effect of Biological Sex on Arterial Stiffness and Renin-Angiotensin-Aldosterone System Activity in Response to Cyclooxygenase-2 (COX-2) Inhibition.

Background: Cardiovascular disease is the leading cause of death globally. Cyclooxygenase (COX)-derived prostaglandins play an important role in cardiovascular health regulation. Animal studies suggest a greater vascular dependence on prostaglandins in female subjects, but whether this extends to humans is unknown. We aimed to assess the effect of COX-2 inhibition on blood pressure and arterial stiffness, validated markers of cardiovascular risk, in human adults. Methods: Healthy premenopausal females and males were studied in high-salt balance before and after 14 days of daily oral celecoxib, 200 mg ingestion, on 2 identical study days. Blood pressure (BP) and pulse-wave velocity (PWV) were measured at baseline and in response to an Angiotensin II (AngII) challenge, a validated marker of renin-angiotensin-aldosterone system activity. Results: Thirteen females (age [mean ± standard deviation], 38 ± 13 years) and 11 males (age, 34 ± 9 years) were studied. Pre-COX-2 inhibition, resting measures of systolic (S)BP (P = 0.2) and diastolic (D)BP (P = 0.1) were similar between sexes. Post-COX-2 inhibition, resting SBP (P < 0.001) and DBP (P = 0.02) were significantly lower in females than in males. COX-2 inhibition was not associated with changes in arterial parameters by sex (change in DBP: P = 0.54; change in PWV: P = 0.55; females vs males). COX-2 inhibition was associated with increased SBP (P = 0.039 vs pre-COX-2 inhibition), but no change in DBP (P = 0.16) or PWV (P = 0.52) response to AngII challenge in females. Measures did not differ in response to AngII pre- vs post-COX-2 inhibition in males (SBP: P = 0.88; DBP: P = 0.93; PWV: P = 0.97). Conclusions: The effects of COX-2 inhibition on arterial function may differ by sex, but further studies are needed. Given the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk, increased attention regarding sex-specific pathophysiology is warranted.

Contexte: Les maladies cardiovasculaires sont la principale cause de décès dans le monde. Les prostaglandines dérivées de la cyclo-oxygénase (COX) jouent un rôle important dans la régulation de la santé cardiovasculaire. Des études menées chez l'animal suggèrent une plus grande dépendance vasculaire aux prostaglandines chez les femelles, mais on ne sait pas si ces observations s'appliquent à l'humain. Notre objectif était d'évaluer les effets de l'inhibition de la COX-2 sur la pression artérielle et la rigidité artérielle, des marqueurs validés du risque cardiovasculaire, chez l'humain adulte. Méthodologie: Des mâles et des femelles non ménopausées en bonne santé ayant un équilibre salin élevé ont été examinés lors de deux jours identiques de l'étude avant et après 14 jours de traitement par le célécoxib à raison de 200 mg par jour par voie orale. La pression artérielle (PA) et la vitesse de l'onde de pouls (VOP) ont été mesurées au départ et en réponse à une épreuve de provocation à l'angiotensine II, un marqueur validé de l'activité du système rénine-angiotensine-aldostérone. Résultats: Treize femelles (âge moyen ± écart-type, 38 ± 13 ans) et 11 mâles (âgé, 34 ± 9 ans) ont été étudiés. Avant l'inhibition de la COX-2, la PA systolique (PAS) (p = 0,2) et la PA diastolique (PAD) (p = 0,1) au repos étaient comparables chez les deux sexes. Après l'inhibition de la COX-2, la PAS (p < 0,001) et la PAD (p = 0,02) au repos étaient significativement plus basses chez les femelles que chez les mâles. L'inhibition de la COX-2 n'a pas été associée à des modifications des paramètres artériels en fonction du sexe (modification de la PAD : p = 0,54; modification de la VOP : p = 0,55; femelles vs mâles). L'inhibition de la COX-2 a été associée à une augmentation de la PAS (p = 0,039 vs avant l'inhibition de la COX-2), mais à aucun changement de la PAD (p = 0,16) ou de la VOP (p = 0,52), après une épreuve de provocation à l'angiotensine II chez les femelles. Les résultats en réponse à une épreuve de provocation à l'angiotensine II ne différaient pas avant et après l'inhibition de la COX-2 chez les mâles (PAS : p = 0,88; PAD : p = 0,93; VOP : p = 0,97). Conclusions: Les effets de l'inhibition de la COX-2 sur la fonction artérielle pourraient varier en fonction du sexe, mais d'autres études sont requises. Compte tenu du lien entre les anti-inflammatoires non stéroïdiens (AINS) et le risque cardiovasculaire, une attention accrue doit être accordée à la physiopathologie en fonction du sexe.

Healthcare provider and patient/family perceptions of continuous pressure imaging technology for prevention of pressure injuries: A secondary analysis of patients enrolled in a randomized control trial.

INTRODUCTION: Despite the availability of various pressure injury (PI) prevention strategies (e.g., risk identification, use of pressure re-distribution surfaces, frequent repositioning), they persist as a significant issue for healthcare systems worldwide. Continuous pressure imaging (CPI) is a novel technology that could be integrated within a comprehensive approach to the prevention of PIs. We studied the perceptions of healthcare providers and patients/families to identify facilitators and barriers to the use of this technology. METHODS: Hospitalized patients/family members from a randomized controlled trial assessing the efficacy of CPI in preventing PIs completed a survey after 72 hours (or upon discharge from hospital) of CPI monitoring. They were asked questions about prior and current experience with CPI technology. For healthcare providers, perceptions on the use of the device and its impact on care were explored through a survey distributed by email or hard copies. RESULTS: A total of 125 healthcare providers and 525 patients/family members completed the surveys. Of the healthcare providers, 95% either agreed/strongly agreed that the CPI technology was easy to use and 65% stated that the device improved how they provided pressure relief for patients. Identified issues with the device were cost, the fitting of the mattress cover, and the fixation of the patients/families on the device. Over a quarter of the patient/family respondents agreed/strongly agreed that the device influenced how pressure relief was provided. This response was statistically associated with whether the monitor was turned on (intervention arm; 52.7%) or off (control arm; 4.2%). DISCUSSION AND CONCLUSION: CPI technology was positively perceived by healthcare providers. Most patients/families felt it influenced care when the CPI monitor was turned on. Concerns raised around cost and the ease of use of these devices by healthcare providers may affect the decisions of healthcare system administrators to adopt and implement this technology.

Gender-affirming estrogen therapy route of administration and cardiovascular risk: a systematic review and narrative synthesis.

Transgender women (individuals assigned male sex at birth who identify as women) and nonbinary and gender-diverse individuals receiving gender-affirming estrogen therapy (GAET) are at increased cardiovascular risk. Nonoral (i.e., patch, injectable) compared with oral estrogen exposure in cisgender women (individuals assigned female sex at birth who identify as women) may be associated with lower cardiovascular risk, though whether this applies to transgender women and/or gender-diverse individuals is unknown. We sought to determine the association between the route of estrogen exposure (nonoral compared with oral) and cardiovascular risk in transgender women and gender diverse individuals. Bibliographic databases (MEDLINE, Embase, PsycINFO) and supporting relevant literature were searched from inception to January 2022. Randomized controlled trials and observational studies reporting cardiovascular outcomes, such as all-cause and cardiovascular mortality, adverse cardiovascular events, and cardiovascular risk factors in individuals using nonoral compared with oral gender-affirming estrogen therapy were included. The search strategy identified 3,113 studies, 5 of which met inclusion criteria (3 prospective cohort studies, 1 retrospective cohort study, and 1 cross-sectional study; n = 259 participants, range of duration of exposure of 2 to 60 mo). One out of five studies reported on all-cause and cardiovascular mortality or adverse cardiovascular events. All five studies reported lipid levels [low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and total cholesterol (TC)], whereas only two studies reported systolic blood pressure (SBP) and diastolic blood pressure (DBP). Limited studies have examined the effect of the route of GAET on all-cause cardiovascular mortality, morbidity, and risk factors. In addition, there is significant heterogeneity in studies examining the cardiovascular effects of GAET.NEW & NOTEWORTHY This study is the first to summarize the potential effect of nonoral versus oral gender-affirming estrogen therapy use on cardiovascular risk factors in transgender women or nonbinary or gender-diverse individuals. Heterogeneity of studies in reporting gender-affirming estrogen therapy formulation, dose, and duration of exposure limits quantification of the effect of gender-affirming estrogen therapy on all-cause and cardiovascular mortality, adverse cardiovascular events, and cardiovascular risk factors. This systematic review highlights the needs for large prospective cohort studies with appropriate stratification of gender-affirming estrogen therapy by dose, formulation, administration route, and sufficient follow-up and analyses to limit selection bias to optimize the cardiovascular care of transgender, nonbinary, and gender-diverse individuals.

Heart rate variability as a function of menopausal status, menstrual cycle phase, and estradiol level.

Low estradiol status is associated with increased cardiovascular risk. We sought to determine the association between heart rate variability (HRV), a marker of cardiovascular risk, at baseline and in response to stressor as a function of menopausal status, menstrual cycle phase and estradiol level. Forty-one healthy women (13 postmenopausal, 28 premenopausal) were studied. Eleven premenopausal women were additionally studied in the high and low estradiol phases of the menstrual cycle. HRV was calculated by spectral power analysis (low Frequency (LF), high frequency (HF) and LF:HF) at baseline and in response to graded Angiotensin II (AngII) infusion. The primary outcomes were differences in HRV at baseline and in response to AngII. Compared to premenopausal women in the low estradiol phase, postmenopausal women demonstrated lower baseline LF (p = 0.01) and HF (p < 0.001) measures, which were not significant after adjustment for age and BMI. In response to AngII, a decrease in cardioprotective HRV (ΔHF = -0.43 ± 0.46 ln ms2 , p = 0.005 vs. baseline) was observed in postmenopausal women versus premenopausal women. Baseline HRV parameters did not differ by menstrual phase in premenopausal women. During the low estradiol phase, no differences were observed in the HRV response to AngII challenge. In contrast, women in the high estradiol phase were unable to maintain HRV (ΔLF = -0.07 ± 0.46 ln ms2 , p = 0.048 response vs. baseline, ΔHF = -0.33 ± 0.74 ln ms2, p = 0.048 response vs. baseline). No association was observed between any measure of HRV and estradiol level. Menopausal status and the high estradiol phase in premenopausal women were associated with reduced HRV, a marker of cardiovascular risk. Understanding the role of estradiol in the modulation of cardiac autonomic tone may help guide risk reduction strategies in women.

Sex influences the effect of adiposity on arterial stiffness and renin-angiotensin aldosterone system activity in young adults.

INTRODUCTION: Sex influences the cardiovascular risk associated with body mass index (BMI) in older adults. Whether this risk differs by sex in younger adults is unknown. We aimed to evaluate the association between measures of adiposity and arterial stiffness and reninangiotensin-aldosterone system (RAAS) activity in younger adults, stratified by sex. METHODS: Body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and fat mass% (FM%) were measured in healthy participants in a fasting, high-salt state. Arterial stiffness [pulse wave velocity (PWV) and aortic augmentation index (AIx)] were measured at baseline and in response to angiotensin II challenge, a validated marker of RAAS activity. Associations were evaluated using linear regression analysis and stratified by sex. RESULTS: Ninety-five healthy, normotensive, non-diabetic females (n = 67, 37 ± 2 y, BMI 25 ± 1 kg/m2 ) and males (n = 28, 39 ± 3 y, BMI 27 ± 1 kg/m2 ) participated in the study. No association was observed between any measure of adiposity and PWV, either at baseline or in response to angiotensin II challenge in premenopausal females. In contrast, all measures of adiposity except HC were associated with PWV at baseline (BMI r = 0.32; WC r = 0.18; WHtR r = 0.34; FM r = 0.21; all values p < .05) and in response to AngII (BMI r = -0.39; WC r = -0.42; WHR r = -0.39; and WHtR r = -0.55) in males. Most adiposity measures were positively associated with baseline AIx (BMI r = 0.33; WC r = 0.27; WHtR r = 0.35; FM% r = 0.25; p < .05) in females, while only WHtR was associated with baseline AIx (r = 0.39; p = .04) in males. All measures of adiposity were positively associated with a blunted Aix response to Ang II (all values p < .001) in females. BMI, WC, WHR and WHtR were associated with a blunted AIx response to Ang II (ΔAIx: BMI r = -0.37; WC r = -0.31; WHR r = -0.16; and WHtR r = -0.22; all values p < .05) in males. CONCLUSION: The associations between adiposity measures and cardiovascular risk differ by sex in a young population. These factors should be considered when managing cardiovascular risk.

Nocturnal hypoxemia severity influences the effect of CPAP therapy on renal renin-angiotensin-aldosterone system activity in humans with obstructive sleep apnea.

STUDY OBJECTIVES: Nocturnal hypoxemia (NH) in obstructive sleep apnea (OSA) is associated with renal renin-angiotensin-aldosterone system (RAAS) up-regulation and loss of kidney function. Continuous positive airway pressure (CPAP) therapy is associated with RAAS down-regulation, though the impact of NH severity remains unknown. We sought to determine whether NH severity alters the effect of CPAP on renal hemodynamics and RAAS activity in humans. METHODS: Thirty sodium-replete, otherwise healthy, OSA participants (oxygen desaturation index ≥ 15 h-1) with NH (SpO2 < 90% ≥ 12%/night) were studied pre- and post-CPAP (>4 h/night∙4 weeks). NH severity was characterized as moderate (mean SpO2[MSpO2] ≥ 90%; N = 15) or severe (MSpO2 < 90%; N = 15). Glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF) were measured at baseline and in response to angiotensin-II (3 ng/kg/min∙30 min, 6 ng/kg/min∙30 min), a marker of RAAS activity. RESULTS: Pre-CPAP, baseline renal hemodynamics did not differ by NH severity. Pre-CPAP, severe NH participants demonstrated blunted GFR (Δ30 min, -9 ± 4 vs 1 ± 3 mL/min, p = 0.021; Δ60 min, -5 ± 5 vs 8 ± 5 mL/min, p = 0.017) and RPF (Δ30 min, -165 ± 13 vs -93 ± 19 mL/min, p = 0.003; Δ60 min, -208 ± 18 vs -112 ± 22 mL/min, p = 0.001; moderate vs severe) responses to angiotensin-II. Post-CPAP, severe NH participants demonstrated maintained GFR (112 ± 5 vs 108 ± 3 mL/min, p = 0.9), increased RPF (664 ± 35 vs 745 ± 34 mL/min, p = 0.009), reduced FF (17.6 ± 1.4 vs 14.9 ± 0.6%, p = 0.009), and augmented RPF responses to Angiotensin-II (Δ30 min, -93 ± 19 vs -138 ± 16 mL/min, p = 0.009; Δ60 min, -112 ± 22 vs -175 ± 20 mL/min, p = 0.001; pre- vs post-CPAP), while moderate participants were unchanged. CONCLUSIONS: Correction of severe, but not moderate, NH with CPAP therapy was associated with improved renal hemodynamics and decreased renal RAAS activity in humans with OSA.

Sex differences in renal hemodynamics and renin-angiotensin system activity post-CPAP therapy in humans with obstructive sleep apnea.

Men have faster loss of kidney function and greater renal renin-angiotensin system (RAS) activity compared with women. Obstructive sleep apnea (OSA) is common in chronic kidney disease; the vascular effects of OSA differ by sex, and OSA-associated glomerular hyperfiltration can be reversed by continuous positive airway pressure (CPAP) therapy. We evaluated sex differences in the effect of CPAP on renal hemodynamics and the renal RAS in OSA. Twenty-nine Na+-replete, otherwise healthy study participants with OSA (10 women and 19 men) with nocturnal hypoxemia were studied pre- and post-CPAP (>4 h/night for 4 wk). Renal hemodynamics [renal plasma flow (RPF), glomerular filtration rate (GFR), and filtration fraction(FF)] were measured at baseline and in response to ANG II challenge, as a marker of renal RAS activity, pre- and post-CPAP therapy for 1 mo. In women, CPAP was associated with increased RPF (626 ± 22 vs. 718 ± 43 mL/min, P = 0.007, pre- vs. post-CPAP), maintained GFR (108 ± 2 vs. 105 ± 3 mL/min, P = 0.8), and reduced FF (17.4 ± 0.8% vs. 15.0 ± 0.7%, P = 0.017). In men, CPAP was associated with maintained RPF (710 ± 37 vs. 756 ± 38 mL/min, P = 0.1), maintained GFR (124 ± 8 vs. 113 ± 6 mL/min, P = 0.055), and reduced FF (18.6 ± 1.7% vs. 15.5 ± 1.1%, P = 0.035). Pre-CPAP, there were no sex differences in renal hemodynamic responses to ANG II. CPAP use was associated with a greater renovasoconstrictive response to ANG II in women (RPF at Δ30 min: -100 ± 27 vs. -161 ± 25 mL/min, P = 0.007, and RPF at Δ60 min: -138 ± 27 vs. -206 ± 32 mL/min, P = 0.007) but not men. CPAP use was associated with improved renal hemodynamics in both sexes and downregulated renal RAS activity in women but not men.

CPAP Therapy Delays Cardiovagal Reactivation and Decreases Arterial Renin-Angiotensin System Activity in Humans With Obstructive Sleep Apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. The effect of OSA treatment with continuous positive airway pressure (CPAP) on the cardiovascular response to a stressor is unknown. We sought to determine the effect of CPAP therapy on heart rate variability (HRV) and arterial stiffness, at baseline, in response to, and recovery from a physiological stressor, Angiotensin II (AngII), in humans with OSA. METHODS: Twenty-five incident healthy subjects (32% female; 49 ± 2 years) with moderate-severe OSA and nocturnal hypoxia were studied in high-salt balance, a state of maximal renin-angiotensin system (RAS) suppression, before CPAP, and after 4 weeks of effective CPAP therapy (usage > 4 h/night) in a second identical study day. HRV was calculated by spectral power and time domain analysis. Aortic augmentation index (AIx) and carotid-femoral pulse-wave velocity (PWVcf) were measured by applanation tonometry. HRV and arterial stiffness were measured at baseline and in response to AngII challenge (3 ng/ kg/min·30 minutes, 6 ng/kg/min·30 minutes, recovery·30 minutes). The primary outcome was the association between CPAP treatment and HRV and arterial stiffness responses to, and recovery from, AngII challenge. In an exploratory analysis subjects were stratified by sex. RESULTS: CPAP corrected OSA and nocturnal hypoxemia. CPAP treatment was associated with increased sensitivity and delayed recovery from AngII (Δln HF [high frequency; recovery: -0.09 ± 0.19 versus -0.59 ± 0.17 ms2, P = .042; ΔrMSSD [root mean successive differences; recovery: -0.4 ± 2.0 versus -7.2 ± 1.9 ms, P = .001], ΔpNN50 [percentage of normal waves differing ≥ 50 ms compared to the preceding wave; AngII: 1.3 ± 2.3 versus -3.0 ± 2.4%, P = .043; recovery: -0.4 ± 1.4 versus -6.0 ± 1.9%, P = .001], all values pre-CPAP versus post-CPAP treatment). No differences were observed by sex. There was increased AIx sensitivity to AngII after CPAP among men (8.2 ± 1.7 versus 11.9 ± 2.2%, P = .046), but not women (11.4 ± 1.5 versus 11.6 ± 2.1%, P = .4). No change in PWVcf sensitivity was observed in either sex. CONCLUSIONS: CPAP therapy was associated with delayed cardiovagal reactivation after a stressor and down-regulation of the arterial RAS. These findings may have important implications in mitigating cardiovascular risk in both men and women with OSA.

Cyclooxygenase-2 Inhibition Limits Angiotensin II-Induced DNA Oxidation and Protein Nitration in Humans.

Compared to other cyclooxygenase-2 inhibitors, celecoxib is associated with a lower cardiovascular risk, though the mechanism remains unclear. Angiotensin II is an important mediator of oxidative stress in the pathophysiology of vascular disease. Cyclooxygenase-2 may modify the effects of angiotensin II though this has never been studied in humans. The purpose of the study was to test the effects of selective cyclooxygenase-2 inhibition on plasma measures of oxidative stress, the vasoconstrictor endothelin-1, and nitric oxide metabolites, both at baseline and in respose to Angiotensin II challenge in healthy humans. Measures of 8-hydroxydeoxyguanosine, advanced oxidation protein products, nitrotyrosine, endothelin-1, and nitric oxide metabolites were assessed from plasma samples drawn at baseline and in response to graded angiotensin II infusion (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min) before and after 14 days of cyclooxygenase-2 inhibition in 14 healthy subjects (eight male, six female) in high salt balance, a state of maximal renin angiotensin system suppression. Angiotensin II infusion significantly increased plasma oxidative stress compared to baseline (8-hydroxydeoxyguanosine; +17%; advanced oxidation protein products; +16%), nitrotyrosine (+76%). Furthermore, levels of endothelin-1 levels were significantly increased (+115%) and nitric oxide metabolites were significantly decreased (-20%). Cycloxygenase-2 inhibition significantly limited the increase in 8-hydroxydeoxyguanosine, nitrotyrosine and the decrease in nitric oxide metabolites induced by angiotensin II infusion, though no changes in advanced oxidation protein products and endothelin-1 concentrations were observed. Cyclooxygenase-2 inhibition with celecoxib partially limited the angiotensin II-mediated increases in markers of oxidative stress in humans, offering a potential physiological pathway for the improved cardiovascular risk profile of this drug.

Sex differences in associations between insulin resistance, heart rate variability, and arterial stiffness in healthy women and men: a physiology study.

Diabetes confers greater cardiovascular risk to women than to men. Whether insulin-resistance-mediated risk extends to the healthy population is unknown. Measures of insulin resistance (fasting insulin, homeostatic model assessment, hemoglobin A1c, quantitative insulin sensitivity check index, glucose) were determined in 48 (56% female) healthy subjects. Heart rate variability (HRV) was calculated by spectral power analysis and arterial stiffness was determined using noninvasive applanation tonometry. Both were measured at baseline and in response to angiotensin II infusion. In women, there was a non-statistically significant trend towards increasing insulin resistance being associated with an overall unfavourable HRV response and increased arterial stiffness to the stressor, while men demonstrated the opposite response. Significant differences in the associations between insulin resistance and cardiovascular physiological profile exist between healthy women and men. Further studies investigating the sex differences in the pathophysiology of insulin resistance in cardiovascular disease are warranted.

The VITAH Trial-Vitamin D Supplementation and Cardiac Autonomic Tone in Patients with End-Stage Kidney Disease on Hemodialysis: A Blinded, Randomized Controlled Trial.

End-stage kidney disease (ESKD) patients are at increased cardiovascular risk. Vitamin D deficiency is associated with depressed heart rate variability (HRV), a risk factor depicting poor cardiac autonomic tone and risk of cardiovascular death. Vitamin D deficiency and depressed HRV are highly prevalent in the ESKD population. We aimed to determine the effects of oral vitamin D supplementation on HRV ((low frequency (LF) to high frequency (HF) spectral ratio (LF:HF)) in ESKD patients on hemodialysis. Fifty-six subjects with ESKD requiring hemodialysis were recruited from January 2013-March 2015 and randomized 1:1 to either conventional (0.25 mcg alfacalcidol plus placebo 3×/week) or intensive (0.25 mcg alfacalcidol 3×/week plus 50,000 international units (IU) ergocalciferol 1×/week) vitamin D for six weeks. The primary outcome was the change in LF:HF. There was no difference in LF:HF from baseline to six weeks for either vitamin D treatment (conventional: p = 0.9 vs. baseline; intensive: p = 0.07 vs. baseline). However, participants who remained vitamin D-deficient (25-hydroxyvitamin D < 20 ng/mL) after treatment demonstrated an increase in LF:HF (conventional: n = 13, ∆LF:HF: 0.20 ± 0.06, p < 0.001 vs. insufficient and sufficient vitamin D groups; intensive: n = 8: ∆LF:HF: 0.15 ± 0.06, p < 0.001 vs. sufficient vitamin D group). Overall, six weeks of conventional or intensive vitamin D only augmented LF:HF in ESKD subjects who remained vitamin D-deficient after treatment. Our findings potentially suggest that while activated vitamin D, with or without additional nutritional vitamin D, does not appear to improve cardiac autonomic tone in hemodialysis patients with insufficient or sufficient baseline vitamin D levels, supplementation in patients with severe vitamin D deficiency may improve cardiac autonomic tone in this higher risk sub-population of ESKD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01774812.

Nocturnal hypoxemia severity and renin-angiotensin system activity in obstructive sleep apnea.

RATIONALE: Obstructive sleep apnea (OSA) and nocturnal hypoxemia are associated with chronic kidney disease and up-regulation of the renin-angiotensin system (RAS), which is deleterious to renal function. The extent to which the magnitude of RAS activation is influenced by the severity of nocturnal hypoxemia and comorbid obesity has not been determined. OBJECTIVES: To determine the association between the severity of nocturnal hypoxemia and RAS activity and whether this is independent of obesity in patients with OSA. METHODS: Effective renal plasma flow (ERPF) response to angiotensin II (AngII) challenge, a marker of renal RAS activity, was measured by paraaminohippurate clearance technique in 31 OSA subjects (respiratory disturbance index, 51 ± 25 h(-1)), stratified according to nocturnal hypoxemia status (mean nocturnal SaO2, ≥90% [moderate hypoxemia] or <90% [severe hypoxemia]) and 13 obese control subjects. MEASUREMENTS AND MAIN RESULTS: Compared with control subjects, OSA subjects demonstrated decreased renovascular sensitivity (ERPF, -153 ± 79 vs. -283 ± 31 ml/min; P = 0.004) (filtration fraction, 5.4 ± 3.8 vs. 7.1 ± 2.6%; P = 0.0025) in response to 60 minutes of AngII challenge (mean ± SD; all P values OSA vs. control). The fall in ERPF in response to AngII was less in patients with severe hypoxemia compared with those with moderate hypoxemia (P = 0.001) and obese control subjects after 30 minutes (P < 0.001) and 60 minutes (P < 0.001) of AngII challenge, reflecting more augmented renal RAS activity. Severity of hypoxemia was not associated with the blood pressure or the systemic circulating RAS component response to AngII. CONCLUSIONS: The severity of nocturnal hypoxemia influences the magnitude of renal, but not the systemic, RAS activation independently of obesity in patients with OSA.

Testosterone is associated with the cardiovascular autonomic response to a stressor in healthy men.

OBJECTIVE: Men have high cardiovascular risk and unfavourable cardiac autonomic tone compared to premenopausal women. The role of sex hormones in control of autonomic tone is unclear. We sought to determine the association between sex hormones and cardiosympathovagal tone at baseline and in response to a physiological stressor. METHODS: Forty-eight healthy subjects (21 men, 27 premenopausal women) were studied in high-salt balance. Cardiac autonomic tone was assessed by heart rate variability, calculated by spectral power analysis (low frequency (LF, a measure of sympathetic modulation), high frequency (HF, a measure of vagal modulation) and LF:HF (a measure of cardiosympathovagal balance)) at baseline and in response to graded Angiotensin II (AngII) infusion (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min) were measured. The primary outcome was association between endogenous sex hormone levels and measures of cardiac autonomic tone. RESULTS: All subjects had sex hormone levels in the normal range. No associations were observed between sex hormones and baseline cardiac autonomic tone in men or women. Men with lower testosterone levels, however, were unable to maintain both cardiosympathetic (p = 0.045) and cardiovagal tone (p = 0.035) in response to AngII even after adjustments for covariates. No association was observed between estradiol and progesterone and cardiac autonomic response to AngII in either sex. CONCLUSION: An unfavourable shift in the cardiac autonomic tone in men with lower testosterone levels was observed in response to a stressor. Understanding the role of sex hormones in modulation of cardiac autonomic tone may help guide risk reduction strategies in men.

Serum uric acid level, blood pressure, and vascular angiotensin II responsiveness in healthy men and women.

Uric acid is associated with hypertension and increased renin-angiotensin system activity, although this relationship diminishes after chronic exposure to high levels. Uric acid is more strongly associated with poor outcomes in women compared to men, although whether this is due to a sex-specific uric acid-mediated pathophysiology or reflects sex differences in baseline uric acid levels remains unknown. We examined the association between uric acid and vascular measures at baseline and in response to angiotensin-II challenge in young healthy humans. Fifty-two subjects (17 men, 35 premenopausal women) were studied in high-salt balance. Serum uric acid levels were significantly higher in men compared to women (328 ± 14 µmol/L vs. 248 ± 10 µmol/L, P < 0.001), although all values were within normal sex-specific range. Men demonstrated no association between uric acid and blood pressure, either at baseline or in response to angiotensin-II. In stark contrast, a significant association was observed between uric acid and blood pressure at baseline (systolic blood pressure, P = 0.005; diastolic blood pressure, P = 0.02) and in response to angiotensin-II (systolic blood pressure, P = 0.035; diastolic blood pressure, P = 0.056) in women. However, this sex difference lost significance after adjustment for baseline uric acid. When all subjects were stratified according to high (>300 µmol/L) or low (≤300 µmol/L) uric acid levels, only the low uric acid group showed a positive association between uric acid and measures of vascular tone at baseline and in response to angiotensin-II. Differences in uric acid-mediated outcomes between men and women likely reflect differences in exposure to increased uric acid levels, rather than a sex-specific uric acid-mediated pathophysiology.

Evaluation of continuous positive airway pressure therapy on renin-angiotensin system activity in obstructive sleep apnea.

RATIONALE: Obstructive sleep apnea (OSA) has been associated with kidney function loss, which may be related to changes in the renin-angiotensin system (RAS). OBJECTIVES: We sought to determine the effect of continuous positive airway pressure (CPAP) of patients with OSA on renal hemodynamics at baseline and in response to angiotensin II (AngII), which reflects RAS activity. METHODS: Twenty normotensive, nondiabetic, newly diagnosed OSA subjects (15 men, 5 women, 50 ± 2 yr, respiratory disturbance index [RDI] > 15 h(-1)) with nocturnal hypoxemia (SaO2 < 90% for >12% of the night) were studied in high-salt balance pre- and post-CPAP therapy (>4 h CPAP use/night for 1 mo). Glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF) (a surrogate marker for intraglomerular pressure) were measured pre- and post-CPAP using inulin and para-aminohippurate clearance techniques at baseline and in response to graded AngII infusion (3 ng/kg/min × 30 min and 6 ng/kg/min × 30 min, respectively). MEASUREMENTS AND MAIN RESULTS: CPAP corrected OSA and hypoxemia (RDI: 42 ± 4 vs. 4 ± 1 h(-1), P < 0.001; duration SaO2 < 90%: 36% ± 5% vs. 6 ± 2%, P < 0.001). CPAP reduced GFR (124 ± 8 ml/min vs. 110 ± 6 ml/min, P = 0.014), increased RPF (692 ± 36 ml/min vs. 749 ± 40 ml/min, P = 0.059), and reduced baseline FF (18.9 ± 1.6% vs. 15.3 ± 1.0%, P = 0.004). Post-CPAP demonstrated a blunted GFR response (-9 ± 3 ml/min vs. -2 ± 2 ml/min, P = 0.033) and augmented RPF response (-182 ± 22 ml/min vs. -219 ± 25 ml/min, P = 0.024) to AngII. FF response was maintained (P = 0.4). CPAP reduced baseline mean arterial pressure (94 ± 2 vs. 89 ± 2 mm Hg, P = 0.002), plasma aldosterone (149 ± 18 vs. 109 ± 10 pmol/L, P = 0.003), and urinary protein excretion (61 [39-341] mg/day vs. 56 [22-204] mg/d, P = 0.003). CONCLUSIONS: CPAP therapy was associated with improved renal hemodynamics and down-regulation of renal RAS activity, suggesting a potential therapeutic benefit for kidney function.

25-Hydroxyvitamin D status, arterial stiffness and the renin-angiotensin system in healthy humans.

Vitamin D deficiency is associated with increased arterial stiffness. We sought to clarify the influence of vitamin D in modulating angiotensin II-dependent arterial stiffness. Thirty-six healthy subjects (33 ± 2 years, 67% female, mean 25-hydroxyvitamin D 69 ± 4 nmol/L) were studied in high salt balance. Arterial stiffness, expressed as brachial pulse wave velocity (bPWV) and aortic augmentation index (AIx), was measured by tonometry at baseline and in response to angiotensin II infusion (3 ng/kg/min × 30 min then 6 ng/kg/min × 30 min). The primary outcome was change in bPWV after an angiotensin II challenge. Results were analyzed according to plasma 25-hydroxyvitamin D status: deficient (<50 nmol/L) and sufficient (≥ 50 nmol/L). There were no differences in baseline arterial stiffness between vitamin D deficient (25-hydroxyvitamin D 40 ± 2 nmol/L) and sufficient (25-hydroxyvitamin D 80 ± 4 nmol/L) groups. Compared with sufficient vitamin D status, vitamin D deficiency was associated with a decreased arterial response to angiotensin II challenge (Δbrachial pulse wave velocity: 0.48 ± 0.44 m/s versus 1.95 ± 0.22 m/s, p=0.004; Δaortic augmentation index: 9.4 ± 3.4% versus 14.2 ± 2.7%, p=0.3), which persisted for brachial pulse wave velocity response after adjustment for covariates (p=0.03). Vitamin D deficiency is associated with increased arterial stiffness in healthy humans, possibly through an angiotensin II-dependent mechanism.