Stiffness In Females Research Articles

Severity and frequency of menopausal hot flash symptoms are not associated with arterial stiffness in females

Background: Females who experience menopausal hot flashes ([MHF]; episodes of sudden warmth and sweating) have greater risk of developing hypertension than females without MHF. MHF symptom severity and frequency are positively associated with hypertension. Considering that augmented arterial stiffness contributes to hypertension, this work aimed to investigate the relations between MHF severity and frequency with arterial stiffness. We hypothesized that females with moderate to severe MHF symptoms would exhibit greater arterial stiffness compared to females without MHF symptoms. Further, we hypothesized that there would be a positive relation between MHF frequency and arterial stiffness. Methods: Twenty-five females (51±5 [SD] years) with no history of hypertension or cardiovascular disease participated. The Menopausal Rating Scale was used to categorize participants by symptom severity (None MHF: n=7, Mild MHF: n=9, Moderate/Severe MHF: n=9). Participants self-reported MHF frequency over three consecutive days in real time using a hot flash diary (4±5 MHF/day, Range: 0-16). After 15 minutes of supine rest, brachial cuff blood pressures (sphygmomanometer) and heart rate (electrocardiogram) were recorded. Arterial stiffness was measured as pulse wave velocity ([PWV]; SphygmoCor®). PWV was measured using a carotid tonometer simultaneously with a leg cuff to capture blood pressure waveforms at the carotid and femoral sites. Aortic systolic pressure, aortic diastolic pressure, and augmentation index (AIx) were measured via pulse wave analysis ([PWA]; SphygmoCor®) using a brachial cuff. Data were analyzed using one-way analysis of variance (ANOVA) and Spearman Rho (ρ). Results: Age, body mass index, resting mean blood pressure, and resting heart rate were not different among MHF severity groups (P>0.05 for all). PWV was not different among severity groups (None: 6.2±0.67 vs. Mild: 6.4±1.0 vs. Moderate/Severe: 6.6±1.0 cm/s, P=0.72). MHF frequency did not correlate with PWV (P=0.42). Aortic systolic pressure (None: 110±6 vs. Mild: 114±5 vs. Moderate/Severe: 112±11 mmHg, P=0.66), aortic diastolic pressure (None: 76±9 vs. Mild: 77±6 vs. Moderate/Severe: 76±10 mmHg, P=0.93), and AIx (None: 31.9±9.0 vs. Mild: 38.7±11.1 vs. Moderate/Severe: 30.4±7.4 %, P=0.16) were not different among severity groups. MHF frequency did not correlate with metrics of PWA (Systolic: P=0.61; Diastolic: P=0.89, AIx: P=0.42). Conclusion: Arterial stiffness and metrics of PWA were not different among females with varying MHF symptom severity. MHF frequency was also not correlated with aortic stiffness and metrics of PWA. Other mechanisms of vascular function (e.g., autonomic function, vasodilation, and/or vasoconstriction) should be investigated to determine potential contributors of hypertension risk in females with MHF. AHA 898649, NIH T32 DK07352, K01 HL148144, NCATS UL1 TR002377. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Evaluating the Role of LOXL2 in Post-menopausal Arterial Stiffening

Introduction: Cardiovascular disease (CVD) is the number one cause of death for both men and women. Even though pre-menopausal women are relatively protected from CVD, a disproportionate increase in CVD risk and incidence occurs after menopause. Aortic stiffening, as occurs in aging, is predictive of major adverse cardiovascular events, independent from the traditional CVD risk factors. Epidemiological studies have shown that older, post-menopausal women exhibit an accelerated pace of aortic stiffening, eventually surpassing age-matched men, with exacerbated isolated systolic hypertension, diastolic dysfunction, and left ventricular remodeling. The hormonal shift, particularly loss of estrogen, present in post-menopausal women has also been widely studied; however, it is increasingly clear that estrogen loss alone is not responsible for the elevated CVD risk. More recently, a shift to androgen signaling has emerged as a key facet in post-menopausal women's health. Thus, mechanistic differences and manifestations of arterial stiffness in men and women require further investigation to help identify and develop novel risk assessment tools and therapeutic targets. Here we propose LOXL2, a key matrix remodeling enzyme, as a potential therapeutic target. In this study, we determined if post-menopausal females present accelerated arterial stiffening, and an abrupt and larger increase in LOXL2. We also studied the effect of sex hormones in LOXL2 activation. Methods and results: Male and female C57Bl/6J mice were used. Female mice underwent ovariectomy (OVX) or sham surgery at 10 weeks old. Three groups were compared: 1) OVX, 2) sham control females, and 3) age-matched males. Body weight, pulse wave velocity (PWV, the gold-standard index of in vivo arterial stiffening), and blood pressure (BP) were measured non-invasively from 12 to 53 weeks old. Results showed a significant increase in both body weight and PWV in the OVX females compared to sham females and males. BP remained similar for all groups, with a slight increase in OVX females. Mice were dissected, and aorta and heart were extracted and prepared for Western blotting measurements. OVX mice showed a low heart to body weight ratio. Western blotting (pilot data) revealed an increasing trend in LOXL2, ERα, and ERβ in the aorta and heart of OVX females. To test LOXL2 activation by sex hormones in vitro, human aortic smooth muscle cells (HASMC) and human aortic endothelial cells (HAEC) were exposed to dihydrotestosterone (DHT) and estradiol (E2) concentrations that mimic the hormonal levels of menstruating women, post-menopausal women, and men (post-puberty) for 16h. Western blotting showed highest levels of LOXL2 when mimicking the post-menopausal women hormonal levels in HASMCs but not in HAECs. Conclusion: Vascular stiffness is exacerbated in OVX females compared to sham females and males. OVX mice present a higher LOXL2 protein abundance in the aorta and heart, as well as increased ERα and ERβ. LOXL2 is modulated by sex hormones, showing significant increase when mimicking post-menopausal women’ hormonal levels. Future studies will continue to: 1) determine the molecular mechanisms underlaying increased arterial stiffness in females after menopause, 2) identify and test novel targets to stop and/or reverse this increase in vascular stiffening, and 3) study the role of hormonal shift in old females in arterial aging. NHLBI grant R01HL148112 01 (L.S.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

FRI131 Abrogation Of Transglutaminase 2 In Myeloid Cells Ameliorates Angiotensin II Induced Vascular Stiffness In Female Mice

Abstract Disclosure: H. Naz: None. A.R. Aroor: None. A.T. Whaley-Connell: None. J. Guanghong: None. J.L. Hulse: None. C.M. Manrique Acevedo: None. G. Lastra: None. Introduction: Chronic low-grade inflammation and vascular stiffening contribute to cardiovascular disease (CVD) in obese and insulin-resistant women. Under these conditions, inappropriate activation of the renin angiotensin aldosterone system (RAAS) stimulates Transglutaminase 2 (TG2), a ubiquitously expressed enzyme that promotes vascular stiffening and remodeling. Additionally, Th17 cells contribute to CVD development in the setting of RAAS activation. However, it is unclear how TG2 activation mediates maladaptive immune responses associated with vascular stiffening in women. In this study, we hypothesize that TG2 abrogation inhibits Ang II-induced vascular stiffness in females by modulating Th17 immunity. Methods: 12-week-old female mice lacking TG2 expression (MyTG2KO) in myeloid cells, and control littermates (LM) were infused with Ang-II (1.4 mg/kg/day) for 2 weeks (n=4-8 per group). Prior to sacrifice, systolic blood pressure (SBP) was measured by tail-cuff method. Aortic stiffness was assessed by atomic force microscopy of thoracic aorta explants, and TG2 activity was examined by Alexa FluorTM 488 cadaverine. Analysis of Th17 cells in blood, spleen and epididymal fat (epi-fat) was done by flow cytometry. Cytokine bead array was used to measure cytokine levels in serum, RT-PCR was used to analyze cytokines in aortic tissue and TG2 knockdown efficiency in myeloid cells. Immunohistochemistry was used to examine fibrosis in aorta. Results: SBP was decreased in MyTG2KO-Ang-II as compared to LM-Ang-II cohort (129.6±5.6 vs 152.5 ±2 mmHg; p=0.04). TG2 mRNA expression in macrophages was lower in MyTG2KO mice as compared to LM (p=0.002). TG2 activity in aortic tissue increased in LM-Ang-II as compared to LM-saline (p=0.004) but was significantly lower in MyTG2KO-Ang-II mice (p=0.02). Aortic stiffness was lower in MyTG2KO-Ang-II mice relative to LM-Ang-II (4.0±0.6 vs 10.3±2.4 kPa; p=0.02). Compared to LM-Ang-II, MyTG2KO-Ang-II mice also had decreased Th17 lymphocytes (CD4+IL-17A+) in blood (3.5±0.2 vs 5.8 ±0.4 %; p=<0.0001), spleen (4.7±0.4 vs 7.1 ±0.5 %; p=0.004) and epi-fat (4.7±0.6 vs 6.8 ±0.5 %; p=0.02). MyTG2KO-Ang II mice also had significant lower levels of proinflammatory cytokines (TNF-a, IL6, IL17A, INF-g) in serum and mRNA expression of proinflammatory cytokines compared to LM-Ang-II mice and decreased total macrophage infiltration (CD68+) in the aorta. Ang-II treated MyTG2KO mice group also exhibited reduced fibrosis in the aorta relative to LM-Ang-II (p=0.003). Conclusion: The results demonstrate that abrogating TG2 in myeloid cells in female mice substantially reduces blood pressure, proinflammatory cytokines, and Th17 immune responses induced by Ang-II. Our findings have potential clinical implications for the prevention and management of CVD in women. Presentation: Friday, June 16, 2023

Abstract 055: Estrogen And Smooth Muscle Cell Estrogen Receptor Alpha Modulate Arterial Stiffness

Background: Arterial stiffness increases with age and contributes to cardiovascular disease. Although sex differences in arterial stiffness are clinically observed, the underlying mechanisms are unknown. Specifically, the role of estrogen (E2) and estrogen receptor alpha (ERα) in sex-dependent differences in arterial stiffness have not been defined. We hypothesize that E2 and ERα contribute to sex differences in arterial stiffness. Methods/Results: We measured aortic pulse wave velocity, an index of arterial stiffness, at 3, 12, and 18 months old, in male and female mice. Arterial stiffness increased in males at 12 and 18m but was delayed until 18m in females (p<0.05). Circulating E2 decreased with age in females (p<0.05), suggesting a link between estrogens and arterial stiffness. In young female mice, arterial stiffness increased with ovariectomy (OVX) versus sham surgery but was restored in OVX mice plus E2 pellet (p<0.05). Aortic gene expression for the vasoprotective angiotensin II type 2 receptor (AT2R) decreased with OVX versus sham and was restored in OVX mice plus E2 pellet (p<0.05). These data suggest a link between arterial stiffness, E2, and AT2R. We therefore created novel SMC-specific ERα knockout (SMC-ERα-KO) mice to assess the role of SMC-ERα in sex differences in arterial stiffness. Differences in arterial stiffness with age persist in ERα-intact mice, but 18m SMC-ERα-KO males and females exhibited less stiffness vs. age-matched ERα-intact littermates (p<0.05). Trends persist in repeat PWV measures at 12 and 16-18m in individual males and females. Blood pressure (via telemetry) did not differ between 18m intact and KO males or females (p=0.73). In young ERα-intact females, OVX increased stiffness and decreased aortic AT2R expression, while OVX had no effect in SMC-ERα-KO females (all p<0.05), supporting a role for E2 and SMC-ERα in arterial stiffness. Conclusion: These data suggest that estrogen contributes to sex differences in arterial stiffness and that with advancing age, SMC-ERα is unliganded due to the loss of estrogen and contributes to arterial stiffness in females, potentially via alterations in vascular AT2R function. These results also suggest a detrimental role for SMC-ERα in aging-associated arterial stiffness in males.

An Evolutionarily Conserved Olfactory Receptor Is Required for Sex Differences in Blood Pressure

Olfactory receptor 558 (Olfr558) is expressed in the kidney where its functional role is unknown. Using RNAScope, we find that Olfr558 localizes to vascular smooth muscle, including the renal afferent arteriole. Thus, we measured blood pressure (BP) in Olfr558 wild-type (WT) and knockout (KO) mice. Systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP) were measured in whole-body Olfr558 wild-type (WT) and knockout (KO) via telemetry. It is known that males have a higher BP than premenopausal females in both humans and mice; indeed, we find Olfr558WT males (M) have higher BP than females (F, n=7-9 per group), including MAP (M:101.0±1.6 vs. F:89.0±0.9 mmHg, p<0.0001), SBP (M:113±2 vs. F:102±1mmHg, p=0.0025), and DBP (M: 89±2 vs. F:75±01mmHg, p<0.0001). However, sex differences in BP are entirely absent in Olfr558 KO (MAP M: 96±2 vs. F: 95±1mmHg; SBP M: 110±2 vs. F: 108±2mmHg; DBP M: 81±2 vs. F: 82±2mmHg). Of note, other sex differences (body weight) are intact in KO, and KO males and females are fertile. To characterize this phenotype, renin expression was analyzed by qPCR, plasma renin activity (PRA) was measured by ELISA, and vasoreactivity was examined ex vivo by wire myography (responses to potassium chloride (KCl), phenylephrine (PE), acetylcholine (Ach), and sodium nitroprusside (SNP) in aortic and mesenteric rings). In male KOs (n=10-12), there was a decrease in kidney renin mRNA (0.4±0.1 vs WT: 1±0.1 p=0.001) and PRA (201±21 vs WT: 402±15, p=0.001); these parameters were unchanged in female KOs. Male KO aortic rings exhibit less constriction to PE, male KO mesenterics exhibit more relaxation to SNP, and female KO aortic rings exhibit more constriction to KCl. In females, pulse wave velocity (PWV) and tensile testing revealed that KO females have increased PWV (KO: 4.6±0.4 vs WT: 3.2±0.2 m/s, p=0.0069, n=8-11), but no changes in tensile testing. The human ortholog of Olfr558, OR51E1, was previously identified as a locus associated with DBP. Using UK Biobank data (N~450k), we find that a rare OR51E1 missense variant has a statistically significant sex interaction effect with DBP ( p=0.015), increasing DBP (+6.28mmHg) in women but decreasing it (-4.77mmHg) in men (similar to the phenotype in M and F Olfr558 KO mice). Finally, we express OR51E1 variants in HEK 293T cells and characterize how two different clinically relevant OR51E1 variants influence OR51E1 signaling. In sum, our findings demonstrate that an evolutionarily conserved olfactory receptor is required for sex differences in BP. Olfr558 regulates BP in males via renin and vascular reactivity, but via arterial stiffness in females. Funding: R56DK107726 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Application of Shear-Wave Elastography in the Evaluation of Hamstring Stiffness in Young Basketball Athletes.

Previous literature has postulated a relationship between greater hamstring stiffness and a higher risk of sustaining injury. Shear wave elastography (SWE) presents a relatively new means for non-invasive evaluation of soft tissue elasticity pre- and post- injury or intervention. 1. To establish baseline hamstring stiffness measures for young competitive athletes and (2) determine effect of targeted neuromuscular training (TNMT) on shear wave stiffness of the hamstring. Un-blinded, prospective, non-randomized, cohort study. Six-hundred forty-two lower extremities from 321 high school and collegiate basketball athletes (177 F: 139 M) were examined for hamstring stiffness prior to the start of their competitive basketball season. Teams were cluster assigned to either the control or intervention (TNMT) group. Subjects in the control group underwent regular season activities as directed, with no influence from the research team. For the TNMT group, the research team introduced a hamstring targeted dynamic warm-up program as an intervention focused on activating the hamstring musculature. Collegiate status was significant to hamstring stiffness for both sexes (p ≤ 0.02), but hamstring stiffness did not correlate to age or sex (r2 ≤ 0.08). Intervention was a significant factor to hamstring stiffness when the hip was positioned in extension (p ≤ 0.01), but not in deeper flexion (p = 0.12). This effect was sex-specific as TNMT influenced hamstring stiffness in females (p = 0.03), but not in males (p ≥ 0.13). Control athletes suffered three HAM injuries; TNMT athletes suffered 0 hamstring injuries. Higher SWE measurements correlated with increased risk of injury, male sex, and collegiate athletics. TNMT intervention can lessen muscle stiffness which may reduce relate to injury incidence. Intervention effectiveness may be sex specific. II.

Validation of shear wave elastography as a noninvasive measure of pelvic floor muscle stiffness.

To investigate the validity of shear wave elastography (SWE) as a measure of stiffness of the puborectalis muscle by examining: (1) the relationship between puborectalis muscle stiffness and pelvic floor muscle (PFM) activation at different intensities; and (2) the relationship between puborectalis stiffness and pelvic floor morphometry during contractions at different intensities. Fifteen healthy asymptomatic women performed 6-s isometric PFM contractions at different intensities (0, 10%, 20%, 30%, 50%, 75%, and 100% of maximal voluntary contraction) guided by intravaginal electromyography (EMG). Stiffness of the puborectalis muscle was measured using SWE by calculating the average shear modulus in regions of interest that contained puborectalis muscle fibers parallel to the transducer. Pelvic floor morphometry was assessed in the mid-sagittal plane using transperineal B-mode ultrasound imaging. Shear modulus, EMG (root mean square amplitude) and pelvic floor morphometry parameters were normalized to the value recorded during maximal voluntary contraction. To assess the relationship between stiffness and pelvic floor activation/morphometry, coefficient of determination (r2 ) was calculated for each participant and a group average was computed. Shear modulus and EMG were highly correlated (average r2 ; left 0.90 ± 0.08, right 0.87 ± 0.15). Shear modulus also strongly correlated with bladder neck position (x-axis horizontal coordinates relative to the pubic symphysis), anorectal rectal angle and position, levator plate angle, and antero-posterior diameter of the levator hiatus (average r2 : range 0.62-0.78). These findings support the validity of SWE to assess puborectalis muscle stiffness in females. Stiffness measures were strongly associated with PFM EMG and pelvic floor morphometry and may be used to indirectly assess the level of activation of the puborectalis muscle without the use of more invasive techniques. By overcoming limitations of current assessment tools, this promising noninvasive and real-time technique could enable important breakthrough in the pathophysiology and management of pelvic floor disorders.

Sexually dimorphic role of smooth muscle cell estrogen receptor alpha in aging‐associated arterial stiffness

BackgroundAging is associated with rising arterial stiffness (AS), an independent risk factor for cardiovascular disease. The development of aging‐associated AS follows a sexually dimorphic pattern with women developing AS later in life. Estrogen and estrogen receptor alpha (ERα) are protective in the premenopausal state, potentially due to the regulation of the vasoprotective angiotensin II type 2 receptor (AT2R), however, the role of estrogen/ERα in aging‐associated AS has not been defined and the mechanisms of the sexually‐dimorphic development of aging‐associated AS are unknown.Methods/ResultsAll studies were conducted in accordance with the FASEB Statement of Principles for the use of Animals in Research and Education. We generated novel smooth muscle cell‐specific ERα‐KO mice and measured aortic pulse wave velocity (PWV), an index of AS, in 3, 12, and 18 month old male and female intact and KO mice. Male mice develop increases in AS from 3 to 12 months compared to 3 to 18 months in females (p<0.05). SMC‐ERα‐KO protected females from the aging‐associated increase in AS (p<0.05). Circulating estrogens also declined in 18 month old females vs. 3 mo. (p<0.05), suggesting a role for unliganded SMC‐ERα in aging‐associated AS. SMC‐ERα‐KO females were also protected from the aging‐associated decline in aortic AT2R expression observed in intact females (p<0.05). To further investigate the potential role of unliganded SMC‐ERα in AS, we performed ovariectomy (OVX) or sham surgeries in young female SMC‐ERα‐Intact and KO mice and measured PWV. Results demonstrated an OVX‐driven increase in AS that was prevented by SMC‐ERα‐KO (p<0.05). This was also associated with an OVX‐mediated decrease in aortic expression of the AT2R, which was prevented by SMC‐ERα‐KO. To determine the in vivo role of AT2R in the vascular protection observed in 12 month old female mice, we treated 12 month old male and female mice with AT2R antagonist PD‐123319 (3mg/kg/day) or vehicle via osmotic minipumps for 4 weeks. Chronic inhibition of the AT2R increased AS in 12 month old females (p<0.05), but not males, suggesting that AT2R‐mediated protection contributes to the delay in aging‐associated AS in female mice. In vitro studies also demonstrated that estrogen upregulates AT2R mRNA and protein in female mouse aortic SMC, supporting an estrogen‐mediated mechanism of AT2R driven vascular protection in females.ConclusionThese data indicate sex differences in the time course of the development of aging‐associated arterial stiffness and suggest the presence of unliganded SMC‐ERα contributes specifically to aging‐associated arterial stiffness in females via reductions in vascular AT2R. Further, these results implicate that AT2R agonist therapy may improve cardiovascular outcomes in aging women to retain the beneficial downstream effects of estrogen signaling, without the potential detrimental effects of hormone replacement therapy.

Clinical Relevance of Selenium with Liver Stiffness and Steatosis Detected by Transient Elastography in Adults.

The associations between selenium and liver stiffness and steatosis remain uncertain. This study aimed to explore the clinical relevance of selenium with liver stiffness and steatosis in adults from the 2017-2018 National Health and Nutrition Examination Survey. Subjects with excessive alcohol consumption and hepatitis B or C infection were excluded. Liver stiffness and steatosis were detected by transient elastography. Dietary selenium intakes and blood selenium concentrations were included as exposures. In multivariate analysis without adjustment for obesity, higher dietary selenium intakes (tertile 3 vs. tertile 1) were positively associated with liver stiffness in females (odds ratio (95% confidence interval): 2.64 (1.88-3.70)), and were positively associated with liver steatosis overall (1.54 (1.20-1.97)) and also in males (1.55 (1.06-2.26)). In multivariate analysis without adjustment for obesity, higher blood selenium concentrations (tertile 3 vs. tertile 1) were positively associated with liver steatosis overall (1.33 (1.02-1.76)) and also in males (1.56 (1.13-2.16)). After further adjustment for obesity, the abovementioned associations remain significant between dietary selenium intakes and liver stiffness in females (2.29 (1.69-3.12)) and liver steatosis overall (1.37 (1.01-1.86)), and between blood selenium concentrations and liver steatosis in males (1.67 (1.25-2.21)). Dose-response analysis showed that the abovementioned associations were linear. However, dietary selenium intakes meeting the recommended daily allowance (≥ 55µg/day) were not associated with liver stiffness (0.99 (0.62-1.55)) and steatosis (1.01 (0.69-1.49)). In conclusion, higher dietary selenium intakes and blood selenium concentrations were positively associated with liver stiffness and steatosis, and obesity may partially account for the observed associations.

Characteristics of the Passive Muscle Stiffness of the Vastus Lateralis: A Feasibility Study to Assess Muscle Fibrosis.

Skeletal muscle fibrosis occurs with aging and has been suggested to impair muscle performance, thereby decreasing quality of life. Recently, muscle stiffness, a surrogate measure of muscle fibrosis, was noninvasively quantified as the shear modulus using ultrasound shear wave elastography (SWE) in humans. We aimed to investigate thigh muscle stiffness in females and males, respectively, across a broad range of ages by using SWE. Eighty-six community-dwelling Japanese people who were aged 30 to 79 years and did not regularly exercise participated in this study. The vastus lateralis (VL) shear modulus was measured at three different knee joint angles: full extension, 90° of flexion, and full flexion. There were no significant main effects of sex or age on the VL shear modulus in full extension or 90° of flexion of the knee. However, the VL shear modulus in knee full flexion was significantly smaller in females than in males and increased with age from 47.9 years. The results suggest that the accelerated increase in VL stiffness that occurs after an individual passes their late 40s may be an important therapeutic target for developing effective treatments and programs that preserve and improve quality of life.

The Effects of a 11‐Week Resistance Training Program on Arterial Stiffness in Females

Arterial stiffness is an indicator of disease and is an independent predictor of cardiovascular events. There have been inconsistencies from previous investigations examining the effect of resistance training on arterial stiffness in female participants. Objective This study was conducted to examine the effect of two resistance training models on arterial stiffness in females. Hypothesis We tested the hypothesis that 11 weeks of either high-intensity or high-volume resistance training would not increase indices of arterial stiffness in young, healthy females. Methods 24 female, untrained college students aged 18-22 years were randomized into one of three groups: control (CON) group (n = 8), high-intensity resistance exercise (HI) group (n = 8), and high-volume resistance exercise (HV) group (n = 8). Subjects randomized to resistance training groups were required to perform strength training exercises three to five days a week for 11 weeks. The exercise regimen consisted of 2-3 sets of 3-8 repetitions (80-90% of 1-repetition maximum (1 RM)) for the HI group and 3-4 sets of 10-15 repetitions (50%-70% of 1 RM) for the HV group. All subjects were instructed to continue their normal diet and avoid cardiovascular exercise during the study. Results Following the intervention, there was a significant increase in carotid femoral pulse wave velocity (C-F PWV) (6.39±0.73 to 8.4±2.31; P < 0.05) and carotid radial (C-R) PWV (9.77±1.74 to 12.58±2.09; P < 0.05) in the CON group only. Both CON and HI groups had significantly decreased central pulse pressure (cPP) (-15.3±12.4 vs. -13.11±12.0 percent change; P < 0.05), respectively. Both the HI and HV groups increased their maximum squat (36.6±7.9 vs.41.3±31.8 percent change; P < 0.05), bench press (34.4±12.6 vs. 23.4±11.1 percent change; P < 0.05), and seated row (22.0±12.6 vs. 21.9±12.5 percent change; P < 0.05), respectively. Conclusion Our findings support the use of resistance training exercise without undue impact on vascular compliance in healthy, young females.

A Low-Calorie Diet with or without Exercise Reduces Postprandial Aortic Waveform in Females with Obesity.

Arterial stiffness is considered a predictor of cardiovascular disease. Females have higher values of arterial stiffness than males, suggesting a greater risk of heart-related complications. Although a low-calorie diet (LCD) reduces fasting arterial stiffness, in part through weight loss, it is unknown if interval exercise (INT) adds to the benefit of LCD on fasting and postprandial arterial stiffness in females with obesity. Twenty-five females (47 ± 2.6 yr, 37.6 ± 1.3 kg·m-2) were randomized to 13 d of LCD (n = 12; mixed meals of ~1200 kcal·d-1) or LCD + INT (n = 13; 60 min·d-1 of supervised 3-min intervals at 90% HRpeak and 50% HRpeak). Arterial stiffness (augmentation index [AIx] and carotid-femoral pulse wave velocity [cfPWV]) and blood biochemistries were measured during a 75-g oral glucose tolerance test before and after the intervention to determine fasting and postprandial arterial stiffness as well as insulin sensitivity (simple index of insulin sensitivity [SIIS]) and inflammation (C-reactive protein, interleukin 8, and tumor necrosis factor alpha). Although LCD + INT increased V˙O2peak and HDL compared with LCD (P = 0.04 and P < 0.01, respectively), both interventions decreased body fat, LDL, total cholesterol, and triglycerides (all P < 0.01) and increased SIIS (P = 0.03). Despite no effect on fasting AIx (P = 0.27), LCD and LCD + INT decreased AIx60min (-7.4% ± 4.3% vs -7.0% ± 5.0%, P = 0.04) and tAUC120min (-663 ± 263 vs -457 ± 406, P = 0.03). There were no changes in fasting cfPWV (P = 0.91) or cfPWV120min (P = 0.62). Increased SIIS and decreased interleukin 8 were associated with reduced fasting AIx (r = -0.44, P = 0.03, and r = 0.40, P = 0.055), whereas decreased C-reactive protein correlated with reduced postprandial AIx60min (r = 0.43, P = 0.04). Independent of exercise, 13 d of LCD reduces postprandial AIx in females with obesity. Insulin sensitivity and inflammation correlated with improved arterial stiffness, suggesting unique mechanisms regulate fasted versus postprandial arterial stiffness.

Abstract P068: Endothelial Mineralocorticoid Receptor Activation Promotes Endothelial And Vascular Stiffening In Western Diet Fed Female Mice Through Sgk1 Mediated Activation Of The Endothelial Sodium Channel

Over-nutrition/obesity predisposes persons, particularly women, to endothelial dysfunction and vascular stiffening. We have employed a clinically relevant model using female mice fed a high fat and high fructose diet (western diet, WD). These mice display high plasma aldosterone levels, endothelial stiffness and dysfunction and increased mineralocorticoid receptor (MR) expression in the vasculature. One potential mechanism by which MR activation may promote endothelial stiffness is through increased expression and activation of epithelial sodium channel (EnNaC) in endothelial cells (ECs) through mTOR2 mediated activation of serum and glucocorticoid regulated kinase 1(SGK1). In this investigation we observed that WD feeding in female mice for 16 wks caused endothelial (atomic force microscopy (AFM)), and aortic stiffening (PW analysis) in concert with increased expression of EnNaC and SGK1 in the endothelium and EnNaC activation in ECs. Further, amelioration of WD induced EC and vascular stiffness was accomplished by EnNaC inhibition with low dose amiloride (1mg/kg/day in drinking water) over the 16 wks of WD. We then explored the idea that inhibition of SGK1 as well as specific deletion of ECMR and EnNaC decreases vascular EC stiffness accompanied by decreased sodium current in isolated lung ECs. Accordingly, female wild type and ECMR and EnNaC KO mice were fed a WD or control diet (CD) for 16 wks. Aortic and coronary artery EC stiffness, measured ex vivo by AFM, was increased in WD fed mice and this was prevented in ECMR and EnNaC KO models. Both ECMR and EnNaC KO mice fed a WD showed decreased amiloride sensitive sodium current in isolated ECs. Further, in cultured ECs , inhibition of SGK1 by a chemical inhibitor attenuated aldosterone mediated sodium currents. Collectively, these findings support the notion that a WD promotes ECMR mediated increases in SGK1 and associated EnNaC activity in ECs together with increased endothelial and vascular stiffness in females.

1.6 Individual and Neighborhood Deprivation and Carotid Stiffness: The Paris Prospective III Study

BackgroundLarge artery stiffness is an index of vascular ageing associated with cardiovascular mortality. While traditional risk factors for arterial stiffness are known, the contribution of socioeconomic factors are less reported. We sought to determine the relationship between arterial stiffness and socioeconomic deprivation (at the individual and neighborhood levels) in healthy males and females.MethodsIn 7803 adults, carotid stiffness was determined by high-precision carotid echotracking. Individual deprivation data included education, living alone, occupation and Evaluation of the Deprivation and Inequalities of Health in Healthcare Centers (EPICES) score. Neighborhood deprivation was determined from commune level data (smallest administrative sub-division) available from French National Institute of statistics and Economic Studies (2011) using principal component analysis. The separate and combined associations between individual and neighborhood deprivation (main exposures) and carotid stiffness (outcome) were quantified using linear and multilevel model adjusted for traditional risk factors including age, mean blood pressure, body mass index, fasting glucose, high density lipoprotein, triglycerides, heart rate, history of cardiovascular disease, smoking, alcohol, and physical activity. Analyses were conducted separately in males and females.ResultsIndividual deprivation (lower education and occupation in males, and living alone and higher EPICES in both populations) was adversely related to carotid stiffness, independently of potential confounders (p < 0.05). Neighborhood deprivation was adversely related to carotid stiffness in males (p < 0.05) but not in females.ConclusionSocioeconomic deprivation, both at the individual and, to a lesser extent, neighborhood level are associated with carotid stiffness in males. Only individual deprivation is associated with carotid stiffness in females.

Individual and Neighborhood Deprivation and Carotid Stiffness.

Large artery stiffness is an index of vascular aging associated with cardiovascular mortality. Whereas traditional risk factors for arterial stiffness are known, the contribution of socioeconomic factors is less reported. We sought to determine the relationship between arterial stiffness and socioeconomic deprivation (at the individual and neighborhood levels) in healthy males and females. In 7803 adults, carotid stiffness was determined by high-precision carotid echo-tracking. Individual deprivation data included education, living alone, occupation, and Evaluation of the Deprivation and Inequalities of Health in Healthcare Centers score. Neighborhood deprivation was determined from commune level data (smallest administrative subdivision) available from French National Institute of Statistics and Economic Studies (2011) using principal component analysis. The separate and combined associations between individual and neighborhood deprivation (main exposures) and carotid stiffness (outcome) were quantified using linear and multilevel model adjusted for traditional risk factors. Analyses were conducted separately in males and females. Individual deprivation (lower education and occupation in males and living alone and higher Evaluation of the Deprivation and Inequalities of Health in Healthcare Centers in both populations) was adversely related to carotid stiffness, independently of potential confounders ( P<0.05). Neighborhood deprivation was adversely related to carotid stiffness in males ( P<0.05), but not in females. Socioeconomic deprivation, both at individual and, to a lesser extent, neighborhood level are associated with carotid stiffness in males. Only individual deprivation is associated with carotid stiffness in females.

The Relationship Between Body Mass Index and Aortic Stiffness in Females Across the Lifespan

Obesity, classified by a body mass index (BMI) >30 kg/m2, continues to be a health concern for women in the United States across all ages. Obesity is a traditional risk factor for the development of cardiovascular disease (CVD). One novel non-traditional predictor of future CVD risk is aortic stiffness. Obese individuals have increased aortic stiffness compared to those of normal body size. PURPOSE: Determine the relationship between BMI and aortic stiffness in 476 women between the ages of 9-83 years old. METHODS: Girls (n= 123, age 9-12 years (yrs), BMI 21 ± 5 g/m2), young women (n= 138, age 18-39 yrs, BMI 24.89 ± 4.46 kg/m2), middle age women (n= 137, age 40-59 yrs, BMI 26.73 ± 4.22 kg/m2) and older women (n= 78, age 60-83 yrs, BMI 26.34 ± 4.26 kg/m2) participated in the study. BMI was calculated as weight (kg) / height (m)2. Aortic stiffness was measured as carotid-femoral pulse wave velocity (PWV) using applanation tonometry (SphygmoCor; Sydney, Australia). RESULTS: According to results from linear regression, BMI was a significant predictor of PWV for the female children (β= 0.387, p<0.01, 95% CI 0.03 – 0.076), young women (β= 0.635, p<0.01, 95% CI 0.156 – 0.237) and middle age women (β= 0.508, p<0.01, 95% CI 0.113 – 0.210). BMI was not a significant predictor of PWV in the older women (β= 0.107, p= 0.20, 95% CI -0.073 – 0.178). When exploring age-group by BMI interaction terms, significant group differences were detected in the relation between BMI and PWV. Using the young women as a reference group – there was no significant difference between the slopes of the regression lines for BMI and PWV between the young and middle age women (β= -0.03, p=0.36, 95% CI -0.11 – 0.04). There were significant differences between the slopes of the regression lines between the young women and girls (β= -0.14, p<0.01, 95% CI -0.21 – -0.08) and between the young women and older women (β= -0.14, p<0.01, 95% CI -0.23 – -0.06). CONCLUSION: Our data suggest that the relationship between BMI and aortic stiffness changes with advancing age. BMI is a significant predictor of aortic stiffness in females between the ages of 9-59 yrs, but not in elderly females (>60 yrs). In older females changes in body composition (i.e. increases in body fat and decrease in muscle mass) may change the relationship between BMI and aortic stiffness. FUNDING SOURCES: NIH, DRI, AHA, ACSM

Patient-Specific Parameters Associated with Traction Stiffness in Primary and Revision Hip Arthroscopy

Objectives:To quantify the force of traction required for adequate distraction of the hip during arthroscopy and explore the relationship between hip joint stiffness and patient-specific demographics, flexibility, and anatomy.Methods:101 primary arthroscopy patients (61 females) and 23 patients undergoing revision arthroscopy for capsular repair (all female) were prospectively enrolled. A load cell attached to the traction boot continuously measured traction force. Fluoroscopy images were obtained before and after traction to measure joint displacement. The stiffness coefficient was calculated as the force of traction divided by joint displacement. Primary patients were analyzed in a univariable regression model and re-analyzed separately by gender. Variables significant at p<0.05 were included in a multivariable regression model. Stiffness was compared between female primary and revision patients using independent t-tests.Results:For primary arthroscopy, instantaneous peak force averaged 80 ± 18 kgf, after which the force required to maintain distraction decreased to 57 ± 13 kgf. In univariable regression analysis, gender, alpha angle, hamstring flexibility and Beighton hypermobility score were each correlated to stiffness. However, gender was the only significant variable in the multivariable regression model. Intragender analysis demonstrated increased hamstring flexibility correlated with decreased stiffness in males and higher Beighton scores correlated with decreased stiffness in females. Stiffness was significantly less in the revision cases than the primary cases (p=0.006).Conclusion:A substantial force is required to achieve and maintain hip distraction, with males requiring higher forces. Males with increased hamstring flexibility and females with higher Beighton scores are less stiff than their same gender counterparts. Patients indicated for revision capsule repair were less stiff, supporting the importance of the hip capsule on hip stability. These data may be used to identify patients with microinstability and patients where specific focus on capsular repair and/or plication may be warranted.

Xanthine oxidase inhibition protects against Western diet-induced aortic stiffness and impaired vasorelaxation in female mice.

Consumption of a high-fat, high-fructose diet [Western diet (WD)] promotes vascular stiffness, a critical factor in the development of cardiovascular disease (CVD). Obese and diabetic women exhibit greater arterial stiffness than men, which contributes to the increased incidence of CVD in these women. Furthermore, high-fructose diets result in elevated plasma concentrations of uric acid via xanthine oxidase (XO) activation, and uric acid elevation is also associated with increased vascular stiffness. However, the mechanisms by which increased xanthine oxidase activity and uric acid contribute to vascular stiffness in obese females remain to be fully uncovered. Accordingly, we examined the impact of XO inhibition on endothelial function and vascular stiffness in female C57BL/6J mice fed a WD or regular chow for 16 wk. WD feeding resulted in increased arterial stiffness, measured by atomic force microscopy in aortic explants (16.19 ± 1.72 vs. 5.21 ± 0.54 kPa, P < 0.05), as well as abnormal aortic endothelium-dependent and -independent vasorelaxation. XO inhibition with allopurinol (widely utilized in the clinical setting) substantially improved vascular relaxation and attenuated stiffness (16.9 ± 0.50 vs. 3.44 ± 0.50 kPa, P < 0.05) while simultaneously lowering serum uric acid levels (0.55 ± 0.98 vs. 0.21 ± 0.04 mg/dL, P < 0.05). In addition, allopurinol improved WD-induced markers of fibrosis and oxidative stress in aortic tissue, as analyzed by immunohistochemistry and transmission electronic microscopy. Collectively, these results demonstrate that XO inhibition protects against WD-induced vascular oxidative stress, fibrosis, impaired vasorelaxation, and aortic stiffness in females. Furthermore, excessive oxidative stress resulting from XO activation appears to play a key role in mediating vascular dysfunction induced by chronic exposure to WD consumption in females.

Sleep disorder, an independent risk associated with arterial stiffness in menopause

As women age and go through menopause, they suffer a higher incidence of sleep disorder, cardiovascular morbidity and mortality. In addition, evidences suggested that sleep disorder was an important pathological indicator for coronary heart disease. However, the relationship between different menopausal status, sleep disorder and cardiovascular diseases was unclear. Thus, we aim to assess the association between sleep disorder with arterial stiffness in females of 40–60 years free of cardiovascular diseases through self-administered Pittsburgh Sleep Quality Index (PSQI) and brachial-ankle pulse wave velocity (baPWV). Logistic regression revealed that sleep disorder (PSQI score ≥ 8) was an independent indicator for higher risk of elevated arterial stiffness (baPWV ≥ 1465.5 cm/s, upper tertile) beyond other established cardiovascular confounders in peri-postmenopause (OR 2.83, 95% confidence interval (CI) 2.00–4.00, p < 0.001), but not in premenopause (OR 1.67, 95% CI 0.71–3.90, p = 0.223). Collectively, it clearly indicates that sleep disorder in menopausal women is of prominent value to predict arterial stiffness.

Sex Differences in the Influence of Leg Strength on Arterial Stiffness.

INTRODUCTION: Acute resistance exercise has been associated with increased central artery stiffness and muscle strength has been shown to be inversely associated with arterial stiffness. However, many studies have only included males with little research conducted including females. Pre-menopausal females typically have lower resting arterial stiffness, yet the relationship between strength and arterial stiffness responses is unknown for females. PURPOSE: To determine the relationship between quadriceps and hamstring strength and the acute arterial stiffness response following resistance exercise. METHODS: Eleven males (28 ± 5 yrs; 24.6 ± 2.0 kg/m2) and eight females (26 ± 4 yrs; 22.5 ± 2.3 kg/m2) completed maximal isokinetic knee extension and flexion (3 sets of 10 repetitions) on a force dynamometer. Central pulse wave velocity (PWV) was estimated by brachial oscillometric blood pressure waveforms at baseline and 5 min post-exercise. Bivariate correlations were performed to examine the linear relationship between leg strength and change in PWV. Relative leg strength data was adjusted for lean body mass measured by dual-energy X-ray absorptiometry. RESULTS: Only females exhibited positive correlations between changes in PWV and peak flexor torque (p < 0.05), relative peak flexor torque (p < 0.05), relative flexor power (p < 0.05) and relative average power (p < 0.05). PWV did not change from rest to 5 min post-exercise in females (5.2 ± 0.2 to 5.2 ± 0.3 m/s) but did significantly increase in males (5.2 ± 0.6 to 5.4 ± 0.6 m/s). CONCLUSION: The results suggest that leg strength is positively associated with changes in arterial stiffness in females, but not males, despite the group mean for females showing no change in stiffness. Therefore, females with higher leg strength have greater changes in stiffness after a bout of resistance exercise.Table: No title available.