Harvey, Ronée E.

Background: Females with uterine fibroids (UF), benign tumors of the myometrium, have a higher risk of hypertension than females without UF. The relationship between UF and hypertension is not fully understood. Case studies have reported hypertension in patients with large UF that compress the ureters, resulting in hydronephrosis. However, this pathophysiology is not present in all females with UF and hypertension. It is unknown if UF volume is correlated with blood pressure in the absence of renal compromise. Therefore, the goal of this study was to determine the potential associations between blood pressure and 1) volume of the largest UF and 2) volume of the uterus (a surrogate for total UF volume) in females with UF. Methods: We utilized the Mayo Clinic Data Explorer to identify patients, who had pelvic ultrasound or magnetic resonance imaging (MRI) studies performed at Mayo Clinic-Rochester in 2021 that reported the presence of UF, and who were ages 18-65 years old. From this system, we collected brachial blood pressure data (systolic, diastolic, and mean), assessed in the outpatient setting within 14 days of imaging. For each patient, dimensions of the largest UF and the uterus were abstracted from radiology reports. The largest UF was assessed, as it reliably had all three dimensions reported. Volume of the uterus was used as a surrogate for total UF volume to consider the possibility of multiple UF that were not detailed in the radiology report. Volumes of the largest UF and uterus were each calculated as for ellipsoid structures, (length✕depth✕width)✕0.523 in cm3. The Pearson correlation coefficient (r) was calculated to assess the linear relationship between blood pressure and largest UF volume, and blood pressure and uterine volume. A p-value <0.05 denoted statistical significance. Results: One hundred thirteen females (48±9 years old) were included in the analysis, 88 with ultrasound and 25 with MRI reports. Average blood pressures were as follows, systolic: 121±16 mmHg (range: 92-185 mmHg), diastolic: 76±9 mmHg (52-101 mmHg), and mean: 91±11 mmHg (67-129 mmHg). Twenty-nine females (25.7%) had a diagnosis of hypertension. Hydronephrosis was not reported in any of the imaging reports. A mean of 2±2 UF were present per uterus (range: 1-15). Average volume of the largest UF was 75.0±115.9 cm3. Largest UF volume was not associated with systolic (r=0.023, p=0.812), diastolic (r=-0.040, p=0.677), or mean (r=-0.014, p=0.881) blood pressures. Average volume of the uterus was 219.6±215.6 cm3. Volume of the uterus was not associated with systolic (r=0.040, p=0.688), diastolic (r=0.102, p=0.305), or mean (r=0.071, p=0.475) blood pressures. Conclusion: In females with UF, blood pressure is not associated with the largest UF or uterine volumes. These data suggest that in the absence of hydronephrosis, the association between UF and blood pressure is not related to UF size. It is unknown if these findings differ based on factors, such as race. AHA 898649, NIH K01 HL1148144 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.

The central neural mechanisms affecting sympathetic neuronal discharge strategies supporting homeostatic adjustments in human muscle sympathetic nerve activity (MSNA) remain unclear. This study investigated the hypothesis that central alpha-2 adrenergic mechanisms affect sympathetic action potential (AP) discharge, recruitment, and latency patterns within human MSNA (peroneal nerve microneurography and continuous wavelet transform). An alpha-2 adrenergic agonist (dexmedetomidine) was infused in eight healthy male and female participants (5 females; 28 ± 7years). Data were recorded during a 5-minute resting control condition, a 10-minute intravenous dexmedetomidine loading dose (0.225 μg/kg), and a dexmedetomidine maintenance dose (~0.1 μg/kg/hr). Data are reported as mean (SD) for the 5-minute control condition and 2-minutes of the dexmedetomidine infusion when MSNA bursting activity was demonstrably reduced. Two-tailed paired t-tests were performed. Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg; P < 0.01) but did not affect heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.75). Dexmedetomidine reduced integrated MSNA burst frequency (14 ± 6 to 4 ± 3 bursts/min; P < 0.01), sympathetic AP frequency (75 ± 46 to 16 ± 14 AP/min; P < 0.01), APs per burst (5 ± 1 to 4 ± 1 AP/burst; P = 0.01), AP clusters per burst (3.5 ± 0.7 to 3.0 ± 0.7 clusters/burst; P = 0.03), and de-recruited the largest AP clusters (12 ± 3 to 7 ± 2 AP clusters; P < 0.01). Despite de-recruiting large AP clusters with short conduction times, dexmedetomidine elicited shorter sympathetic AP conduction times (1.18 ± 0.12 to 1.14 ± 0.13 s; P = 0.03). Six participants performed a Valsalva Maneuver (20 s, 40 mmHg mouth pressure) during the control condition and during the dexmedetomidine maintenance dose. Data are reported as mean (SD) change (Δ) from the 2-minute period preceding the Valsalva Maneuver to the Valsalva Maneuver for each condition. During the control condition, Valsalva Maneuver increased AP frequency (Δ 311 ± 317 AP/min; P = 0.048), recruited larger previously silent AP clusters (Δ 2 ± 1 AP clusters; P < 0.01), and elicited shorter AP conduction times (Δ ‑0.09 ± 0.07 s; P = 0.02). Compared to the control condition, Valsalva Maneuver performed during the dexmedetomidine maintenance dose condition elicited lesser increases in AP frequency (Δ 116 ± 189 AP/min; P vs. control = 0.02) and lesser recruitment of larger previously silent AP clusters (Δ 0 ± 1 AP clusters; P vs. control = 0.02). Dexmedetomidine did not affect the latency reduction elicited by Valsalva Maneuver (Δ ‑0.07 ± 0.14 s; P vs. control = 0.61). These data suggest that human central alpha-2 adrenergic mechanisms affect: i) sympathetic postganglionic neuronal discharge and recruitment patterns, and ii) synaptic delays within the sympathetic neurocircuitry influencing AP latency. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). 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.

Background: Hypertension prevalence increases in females following menopause. Poor endothelial microvascular function increases risk of hypertension. Endothelial-mediated vasodilation is dependent on nitric oxide (NO). Estrogen enhances NO production; therefore, reduced estrogen levels in postmenopausal females may result in a reduced contribution of NO to endothelial-mediated vasodilation, although studies are limited. Herein, we aimed to investigate the contribution of NO to endothelial-mediated vasodilation in premenopausal and postmenopausal females. We hypothesized that postmenopausal females would have attenuated endothelium-mediated vasodilation and reduced contribution of NO compared to premenopausal females. Methods: Ten premenopausal (27±3 yrs) and eleven postmenopausal (59±4 yrs) normotensive females were studied. Resting brachial blood pressures were measured using a standard arm cuff. Brachial arterial catheters were placed for continuous blood pressure measurement and pharmacologic infusions. Forearm blood flow (FBF) was measured using venous occlusion plethysmography at baseline (saline) and during infusion of an endothelium-dependent vasodilator (acetylcholine; 1.0, 2.0, 4.0, and 8.0 μg/100mL tissue/min) with and without a NO synthase inhibitor (L-NG-monomethylarginine [L-NMMA]; 1.0 mg/min) co-infusion. Forearm vascular conductance (FVC) was calculated as FBF/mean arterial pressure✕100. Data were analyzed using a two-way repeated-measures ANOVA. Results: Resting systolic blood pressure (SBP) but not diastolic blood pressure (DBP) was greater in postmenopausal compared to premenopausal females (SBP: 121±15 vs. 103±9 mmHg, respectively; P<0.01; DBP: 72±11 vs. 65±5 mmHg, respectively; P=0.07). FBF responses to acetylcholine did not differ between premenopausal and postmenopausal females (Group Main Effect: P=0.11). When correcting for blood pressure, premenopausal females exhibited greater FVC responses to acetylcholine compared to postmenopausal females (Group Main Effect: P=0.04). In premenopausal females, FBF and FVC responses to acetylcholine were reduced with co-infusion of L-NMMA compared to acetylcholine infusion only (L-NMMA Main Effect: P=0.02 and P=0.01, respectively). In postmenopausal females, the FBF and FVC responses to acetylcholine were unaffected by L-NMMA (L-NMMA Main Effect: P=0.79 and P=0.76, respectively). Conclusion: Compared to premenopausal females, postmenopausal females have impaired endothelial microvascular function. Attenuated NO contribution during endothelium-mediated vasodilation in postmenopausal women may partially contribute to the increased hypertension risk in this population. AHA 14PRE18040000, AHA 898649, NIH HL083947, NIH HL148144, NCATS UL1 TR000135 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.

Early menopause (prior to age 46 years) due to bilateral oophorectomy results in an abrupt loss of estrogen and other ovarian hormones and an increased risk of cardiovascular disease (CVD). Administration of estrogen partially mitigates this increased CVD risk; however, optimal dosing strategies for lowering CVD risk have not been studied. Current standard care is to use a dose of estrogen higher than that used for vasomotor symptom treatment in women after natural menopause in order to approximate the physiologic estradiol levels in premenopausal women (standard care); however, estradiol levels are not generally measured. An individualized approach that titrates estradiol levels to premenopausal hormone levels (individualized dosing) may be better for CVD risk mitigation in this younger population. The goal of this study was to compare the effect of estradiol dosing strategies (standard care vs. individualized dosing) on subclinical predictors of CVD in women with early menopause due to bilateral oophorectomy. We studied a total of 18 women at baseline and 6 months following surgical and medical intervention: 6 women underwent bilateral oophorectomy and were treated with standard care (age 41±2 years), 7 women underwent bilateral oophorectomy followed by estrogen therapy dosage based on individualized dosing (39±2 years), and 5 women served as time controls (did not undergo bilateral oophorectomy and were studied during the early‐follicular phase of the menstrual cycle at both visits; 34±3 years). At each time point, we assessed parameters of subclinical CVD including resting aortic blood pressure, carotid‐femoral pulse wave velocity, and blood pressure changes during a handgrip test and a cold pressor test. At baseline, serum estradiol levels were similar amongst groups (p>0.05). After 6 months, women who received individualized dosing of estrogen therapy had higher serum estradiol levels (179±23 pg/ml) than women who received standard care (53±25 pg/ml, p=0.01) and women in the control group (78±27 pg/ml, p=0.03). Systolic and diastolic aortic blood pressures did not change between baseline and 6 months, nor did they differ amongst groups at any time point (p>0.05 for all). There were no group or time differences in the change in mean blood pressure during the handgrip exercise or cold pressor test across 6 months (p>0.05 for all). Over a 6‐month follow‐up, despite differences in serum estradiol levels following two different estradiol dosing strategies after bilateral oophorectomy, there were no group differences or detrimental changes in subclinical CVD parameters across time. It is yet to be seen if differences in these parameters will be apparent following a longer duration after bilateral oophorectomy.

Background During the menopause transition, women are at an increased risk of developing hypertension, which is a key marker of cardiovascular disease (CVD). Although historically hot flashes have been considered a quality‐of‐life issue, emerging data provides a link between hot flashes and risk of CVD. Poor renal function is suggested to be one of the key physiological contributors to increased risk of hypertension and CVD among women with hot flashes. Thus, the aim of this study was to characterize the relationship between hot flashes and renal function in peri‐ and post‐menopausal women using a retrospective chart review. We hypothesized that women with hot flashes would demonstrate reduced renal function compared to women without hot flashes. Methods We performed a chart review using serum creatinine and estimated glomerular filtration rate (eGFR) as proxies to assess renal function. Electronic health records for Mayo Clinic patients across multiple sites were abstracted for female patients who were diagnosed with peri‐ or post‐menopause between 2016 and 2020, between 45 and 55 years of age, and had available creatinine laboratory test results. Data regarding demographics, anthropometrics, systemic blood pressure, menopausal stage, occurrence of hot flashes, and comorbidities were extracted from electronic health records. Differences between women with and without hot flashes were evaluated using two‐tailed, independent samples t‐tests. We completed a univariate analysis of variance testing the main effects of menopausal status (peri‐ or post‐menopausal) and presence of hot flashes (yes or no). Given the potential modifying effects of menopause, analytical models were performed in duplicate with and without models separated by menopausal status (peri‐and post‐menopause). Results Data from 83 medical charts were assessed, including 57 women with hot flashes and 26 women without hot flashes. Without separating by menopausal status, there were no hot flash‐related differences in age (51 ± 3 vs. 51 ± 3 years, P = 0.64) or body mass index (30 ± 7 vs. 33 ± 11, P = 0.19) between women with and without hot flashes. Additionally, there were no hot flash‐related differences in metrics of blood pressure, including systolic (120 ± 13 vs. 125 ± 20, P = 0.19), diastolic (75 ± 11 vs. 77 ± 13, P = 0.54), and mean arterial pressure (90 ± 11 vs. 92 ± 14, P = 0.62). There were also no hot flash‐related differences in indicators of renal function, including creatinine (0.8 ± 0.1 vs. 0.8 ± 0.2, P = 0.65) and eGFR (88 ± 11 vs. 85 ± 16, P = 0.36). The clinical characteristics of the perimenopausal versus postmenopausal women are summarized in Table 1 by hot flash status . There were no main effects of hot flash or menopausal status on creatinine (menopausal stage: p=0.810, hot flash status: p=0.659, interaction effect: p=0.983) or eGFR (menopausal stage: p=0.508, hot flash status: p=0.405, interaction effect: p=0.834). Conclusions In this retrospective chart review of peri‐ and post‐menopausal women, there were no differences in systemic blood pressure or renal function between groups. Future investigations may include longitudinal markers of renal function and metrics describing frequency and severity of hot flashes.

A history of preeclampsia (PE) places women at higher risk for future cardiovascular disease and cognitive decline. We have previously shown that postmenopausal women with a history of PE demonstrated a reduced cerebral blood flow response to hypercapnia compared with postmenopausal women with a history of a normotensive pregnancy (NP). These findings suggest cerebrovascular effects of PE 30+ years postpartum. In addition, we have reported that women with a history of PE did not have an exaggerated pressor response to a sympathoexcitatory stimulus. However, it is possible that women with a history of PE may have an altered cerebral blood flow response to a sympathoexcitatory stimulus. In this study, middle cerebral artery blood velocity (MCAv) and beat‐to‐beat mean arterial blood pressure (MAP) were measured during isometric handgrip to fatigue (IHG) at 30% of maximal voluntary contraction followed by post‐exercise ischemia (PEI) for 90 seconds and a two minute recovery period (REC). Participants were postmenopausal women with a history of PE (n = 21; age at study = 58±5 y; years since last pregnancy = 35±3 y) and NP (n = 27; age at study = 58±5 y; years since last pregnancy = 35±3 y). Baseline MAP and MAP responses to IHG and PEI were similar between groups (p>0.05). PE women demonstrated lower MCAv at baseline (NP: 72±3 cm/s vs. PE: 57±4 cm/s), IHG (NP: 78±4 cm/s vs. PE: 63±4 cm/s), PEI (NP: 74±4 cm/s vs. PE: 60±4 cm/s), and REC (NP: 70±3 cm/s vs. PE: 58±4 cm/s) compared with NP women (p<0.05 for all). MCAv, when calculated as a percent change from baseline, was elevated during IHG in both PE and NP women as expected (p<0.05); however, PE women had an augmented MCAv response during the last third of IHG compared with NP women (NP: 9±2 % vs. PE: 13±2 %; p<0.05). PE women also had a higher MCAv response during REC compared with NP women (NP:−2±2% vs. PE: 3±2%; p<0.05). Importantly, these elevated MCAv responses occurred despite the fact that MAP was not different between groups. In summary, PE women demonstrated a lower basal cerebral blood velocity but an elevated cerebrovascular response to a sympathoexcitatory stimulus compared with NP women. This suggests that in postmenopausal women, there is an effect of pregnancy history on the sensitivity of the cerebral blood flow response to a sympathoexcitatory stimulus. Support or Funding Information NIH: AG 044170. This investigation was supported by the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32 HL 007936 from the National Heart Lung and Blood Institute to the University of Wisconsin‐Madison Cardiovascular Research Center. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Hypertensive pregnancy (HP) is considered a risk factor for cardiovascular disease. Blood pressure (BP) response to physical stressor is an independent marker of cardiovascular risk. However, there is limited data regarding the pressor response to acute physical stress in women with a history of HP. Hence, the aim of the study was to compare BP responses in women with a history of HP to age and parity matched controls. Beat to beat BP was recorded in postmenopausal women (age = 59 ± 1 yrs, BMI = 31 ± 2 kg/m2) with and without a history of HP at baseline and during isometric handgrip (HG) exercise (30% of MVC) to fatigue. Isometric handgrip exercise was followed by 90 seconds of supra‐systolic cuff occlusion on the exercising arm. In both groups combined (N=31), systolic blood pressure (SBP) increased significantly from baseline to HG to cuff inflation (143 ± 3 to 161 ± 3 to 167 ± 4 mmHg). Similarly, mean arterial pressure (MAP) increased significantly from baseline to HG to cuff inflation (106 ± 2 to 119 ± 2 to 122 ± 2 mmHg). Diastolic pressure (DBP) increased significantly only from baseline to HG (80 ± 1 to 88 ± 1 mmHg) and baseline to cuff inflation (89 ± 2 mmHg). However, there were no significant differences in SBP, DBP and MAP between women with and without a history of HP (p>0.05). Even though both groups had an increase in BP variables in response to HG and cuff occlusion, there was no difference in the BP response to acute physical stressors in women with a history of HP as compared to control participants. Funding: National Institute of Aging 1P50AG044170‐01 and CTSA UL1 TR000135 and HL 118154 (JNB)

<a name=“OLE_LINK2”></a><a name=“OLE_LINK1”>Hypertensive pregnancy (HP) disorders have been linked to a four‐fold increased risk for development of future cardiovascular diseases. We examined whether history of HP in postmenopausal women (N=20, 59±5 yr) influenced the risk factors for cardiovascular disease as assessed by aortic pulse wave characteristics, compared to age and parity matched controls (N=18, 60±4 yr). Non‐invasive aortic pressure waveforms were synthesized from high‐fidelity pressure waveforms obtained from SphygmoCor applanation tonometry using the radial artery. Aortic systolic and diastolic blood pressure (ASBP, ADBP), aortic augmentation index (AI x ), augmented pressure (AP), aortic pulse pressure (APP), and left ventricular wasted energy (E w ) were calculated from the generated aortic pressure waveform. There were no differences in ASBP (125±4 vs. 129±4 mmHg), ADBP (79±2 vs. 81±2 mmHg), AP (17±2 vs. 17±2 mmHg), AI x (35±2 vs. 29±1%), AI x @75BPM (31±2 vs. 29±1%), E w (3313±338 vs. 3364±432 dynes/cm 2 /s), between women with a history of HP vs. matched controls, respectively (P>0.05 for all). Body mass index was significantly higher in women with a history of HP (30.6±1 vs. 26.7±1 kg/m 2 , P<0.05), however it did not statistically influence any of the indices (P>0.05 for all). Our results suggest that postmenopausal women with a history of HP do not demonstrate elevated aortic blood pressure or altered aortic pulse wave characteristics in comparison to matched controls. </a> Supported by: National Institute of Aging 1P50AG044170‐01 and CTSA UL1 TR000135 and HL 118154