Pruter, Wyatt W.

Introduction: Severe menopausal hot flash symptoms are linked to the development of cardiovascular disease. Exaggerated blood pressure responses to exercise are also associated with an increased risk of hypertension and cardiovascular disease. It is unclear if females with more severe hot flash symptoms exhibit greater blood pressure responses to exercise compared to those with minimal menopausal hot flashes. We aimed to determine if there is a difference in the pressor response to isometric exercise between females with severe hot flash symptoms compared to females with no/low hot flash symptoms. We hypothesized that there will be exaggerated blood pressure responses to isometric handgrip exercise (IHG) and post-exercise ischemia (PEI) in females who have severe menopausal hot flashes compared to females with no/low hot flashes. Methods: We studied 19 female participants (age: 51±5yrs) with no history of cardiovascular disease or hypertension. The Menopausal Rating Scale (MRS) was used to assess the hot flash symptom severity and to group the participants into no/low (no-or-mild on MRS) or high (moderate-or-severe on MRS) hot flash symptom groups. Continuous blood pressure (BP) was measured via photoplethysmography and calibrated relative to a brachial arm cuff pressure. After 2 minutes of quiet rest, participants performed 2 minutes of IHG at 30% of maximal voluntary contraction, followed by 2 minutes of PEI on the exercising arm to isolate the metaboreflex. The severity groups were compared via independent samples t-tests. Results: There were 13 females in the no/low group and 6 females in the high group. Baseline heart rate (HR, no/low: 60±11 vs high: 58±8bpm), systolic (SBP, no/low:129±18 vs high: 120±14mmHg), diastolic (DBP, no/low: 72±12 vs high: 63±7mmHg) and mean BP (MBP, no/low: 91±11 vs high 82±9mmHg) were not different between groups. There were no differences in the pressor responses to IHG between groups (HR: no/low: Δ6±5 vs high: 5±4bpm, p=0.425; SBP: no/low: Δ9±5 vs high: 11±6mmHg, p=0.408; DBP: no/low: Δ5±3 vs high: 7±4mmHg, p=0.182; MBP: no/low: Δ6±3 vs high: 8±4mmHg, p=0.253). There was also no difference in the pressor response to PEI between groups (HR: no/low: Δ6±6 vs high: 4±2bpm, p=0.554; SBP: no/low: Δ11±6 vs high: 16±9mmHg, p=0.191; DBP: no/low: Δ5±3 vs high: 8±6mmHg, p=0.298; MBP: no/low: Δ7±4 vs high: 11±7mmHg, p=0.280). Conclusion: The current data show no differences in the blood pressure responses to IHG or PEI between females with different menopausal hot flash symptom severities. This suggests that pressor responses to an IHG exercise and the metaboreflex may not be notable contributors to the increased cardiovascular risk in females with severe menopausal hot flashes. NIH: K01 HL148144, NCATS UL1 TR000135, UL1 TR002377; AHA: 898649. 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.

Menopausal females who experience frequent hot flashes (episodes of increased body temperature and sweating) have a greater risk of hypertension and cardiovascular disease than females without hot flashes. Individuals with exaggerated blood pressure (BP) responses to cold stress have a higher risk of hypertension than those with lower responses. It is unknown if females who experience hot flashes have exaggerated pressor responses to cold stress, indicating their greater risk of hypertension. The aim of this study was to determine the pressor responses to cold stress in females who experience hot flashes and those who do not. An additional goal was to understand the relation between daily hot flash frequency and pressor responses. We hypothesized that females with hot flashes would have exaggerated pressor responses to cold stress compared to females without hot flashes. We also hypothesized that pressor responses would be positively correlated to daily hot flash frequency. We recruited 17 females, ages 45-60 years, without hypertension or cardiovascular disease, who did and did not have hot flashes. They reported hot flash frequency in a 3-day written diary. On the study day, continuous BP (finger photoplethysmography, calibrated to brachial cuff BP) and heart rate (HR; 3-lead ECG) were recorded while the participant rested during a 2-minute baseline period, then subsequently had an ice-water pack placed on their forehead for 3 minutes. The changes in mean BP (MBP) and HR are calculated as the change in MBP or HR during the cold pressor test minus the average MBP or HR during baseline. Data were analyzed using the Student’s t-test and Pearson correlation. Twelve females reported hot flashes (age: 51±4 years; average number of hot flashes: 3 per day) and five did not (age: 49±5 years). These groups did not differ in age, body mass index, resting MBP, or resting HR (p>0.05 for all). The change in MBP from baseline to the cold pressor test did not differ between females with and without hot flashes (Δ17±10 vs. Δ19±14 mmHg, respectively; p=0.860). The change in HR with the cold pressor test also did not differ between females who did and did not report hot flashes (Δ10±6 vs. Δ12±8 mmHg, respectively; p=0.647). In females with hot flashes, the number of hot flashes reported per day (range: 1-12 per day) was not correlated with the change in MBP (p=0.824) or HR (p=0.460) during the cold pressor test. These current data show that menopausal females who experience hot flashes do not exhibit exaggerated BP or HR responses to cold stress in comparison to females who do not experience hot flashes. In addition, BP and HR responses are not correlated with daily hot flash frequency. There are likely other vascular mechanisms that place menopausal females with hot flashes at an increased risk for hypertension. In addition, incorporating information on the age at which hot flashes began, as well as hot flash severity, might help us to further understand cardiovascular risk in this population. 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.

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.

Background: The compensatory reserve metric (CRM) provides a novel marker of hemodynamic status in prediction of sudden cardiovascular decompensation during central hypovolemia. The CRM has previously been calculated using arterial waveforms obtained from a photoplethysmographic volume-clamp technique. However, the in-field use of pulse oximetry is becoming more prominent in research and medicine. To improve in-field applicability of the CRM, this project aimed to validate pulse-oximetry derived CRM values relative to physiologic data during simulated hemorrhage through application of lower body negative pressure (LBNP). Methods: Forty-nine healthy adults (25 females) underwent a graded LBNP protocol with the following 5-minute stages: -0, -15, -30, -45, -60, -70, -80, -90, and 100 mmHg, or until the onset of pre-syncopal symptoms (tolerance) was reached. Arterial waveforms were sampled using pulse oximetry (Massimo Radical 7). The CRM was calculated using a validated one-dimensional convolutional neural network. A brachial artery catheter was used to measure intraarterial pressure. A 3-lead ECG was used to measure heart rate. SpO2 was measured using pulse oximetry. Cardiac output and stroke volume were estimated using the photoplethysmographic volume-clamp. Data were binned for the last thirty seconds of each completed stage, and at tolerance. Fixed-effect linear mixed models with repeated measures were used to examine the association between CRM values and physiologic variables. A priori significance was set at P<0.05. Results: The median LBNP stage reached was 70 mmHg (Range: 45-100 mmHg). Relative to baseline, at tolerance there was a 50±12% ( P<0.001) mean reduction in stroke volume, 65±27% ( P<0.001) increase in heart rate, 18±8% ( P<0.001) reduction in mean arterial pressure, 21±7% ( P<0.001) systolic blood pressure, 8±9% ( P<0.001) diastolic blood pressure, and 39±12% ( P<0.001) pulse pressure. The CRM obtained using pulse oximetry was significantly associated with a reduction in stroke volume ( P<0.001), increase in heart rate ( P<0.001), and reductions in systolic ( P=0.033), diastolic ( P=0.036), and pulse pressure ( P=0.002). There was no statistically significant association between CRM and cardiac output ( P=0.421), SpO2 ( P=0.408), or mean arterial pressure ( P=0.214). Conclusion: The CRM obtained using pulse oximetry may be a valid, reliable marker of hemodynamic status with promising in-field applications. Future studies warrant investigation of feasibility and applicability within various contexts ranging from the operating room to the battlefield. The presented work was funded in part by the Congressionally Directed Medical Research Program (Award No. DM180240) and Offce of Naval Research (Awards No. N00014-18-D-7001 and N00014-19-C-2017). 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.

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.

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.

During hypoxic exposure, humans with high-affinity hemoglobin (and compensatory polycythemia) have blunted increases in heart rate compared with healthy humans with typical oxyhemoglobin dissociation curves. This response may be associated with altered autonomic control of heart rate. Our hypothesis-generating study aimed to investigate cardiac baroreflex sensitivity and heart rate variability among nine humans with high-affinity hemoglobin [6 females, O2 partial pressure at 50% [Formula: see text] (P50) = 16 ± 1 mmHg] compared with 12 humans with typical affinity hemoglobin (6 F, P50 = 26 ± 1 mmHg). Participants breathed normal room air for a 10-min baseline, followed by 20 min of isocapnic hypoxic exposure, designed to lower the arterial partial pressure O2 ([Formula: see text]) to ∼50 mmHg. Beat-by-beat heart rate and arterial blood pressure were recorded. Data were averaged in 5-min periods throughout the hypoxia exposure, beginning with the last 5 min of baseline in normoxia. Spontaneous cardiac baroreflex sensitivity and heart rate variability were determined using the sequence method and the time and frequency domain analyses, respectively. Cardiac baroreflex sensitivity was lower in humans with high-affinity hemoglobin than controls at baseline and during isocapnic hypoxic exposure (normoxia: 7 ± 4 vs. 16 ± 10 ms/mmHg, hypoxia minutes 15–20: 4 ± 3 vs. 14 ± 11 ms/mmHg; group effect: P = 0.02, high-affinity hemoglobin vs. control, respectively). Heart rate variability calculated in both the time (standard deviation of the N-N interval) and frequency (low frequency) domains was lower in humans with high-affinity hemoglobin than in controls (all P < 0.05). Our data suggest that humans with high-affinity hemoglobin may have attenuated cardiac autonomic function.

Background Humans with high O 2 affinity hemoglobin (HAH) have a markedly lower partial pressure of O 2 at which 50% of hemoglobin is saturated (P 50 ) and a leftward shift of the oxy‐hemoglobin dissociation curve. Humans with HAH have attenuated heart rate responses during both acute and chronic hypoxic exposure relative to humans with typical P 50 . Despite the attenuated heart rate responses to hypoxia, there are typically no blood pressure differences found in humans with HAH relative to humans with typical P 50 . Due to the blunted heart rate and normal blood pressure responses to hypoxia in humans with HAH, this study aimed to investigate the impact of HAH on cardiac autonomic function during normoxia and hypoxia. We hypothesized that humans with HAH would have lower cardiac baroreflex sensitivity (cBRS) and heart rate variability (HRV) during normoxia and hypoxia relative to individuals with typical P 50. Methods Nine humans with a HAH mutation (6 female, Age: 40±12yrs, P 50 : 16±1 mmHg) and 12 controls with typical affinity hemoglobin (6 female, Age: 40±10yrs, P 50 : 26±1 mmHg) laid supine for 10‐minutes prior to 20‐minutes of isocapnic hypoxia, titrated to reduce arterial O 2 pressure to ~50 mmHg (Avg. F i O 2 = 11.9±0.0%). Beat‐to‐beat arterial pressures (arterial catheter) and heart rate (electrocardiogram) were continuously recorded. Data were averaged in five‐minute segments starting with the last five minutes of supine normoxic rest. Spontaneous cBRS was quantified using the sequence method. HRV was measured in time and frequency domains. Standard deviation of the RR interval (SDRR) was calculated as the standard deviation of all RR intervals in a data segment. Low frequency (LF) HRV was calculated using Fast Fourier Transformation and assessed as absolute spectral intensity in the LF band (0.04‐0.15Hz). Results Arterial oxygen (P a O 2 ) and carbon dioxide (P a CO 2 ) pressures were not different between humans with HAH and controls during normoxia or isocapnic hypoxia [P a O 2 : (HAH vs. Control): 48±3 vs. 47±2 mmHg, p=0.612; P a CO 2 : (HAH vs. Control): 40±3 vs. 39±1 mmHg, p=0.328] exposure. cBRS was lower in humans with HAH compared to controls in normoxia and throughout isocapnic hypoxia [normoxia (HAH vs. Control): 7±4 vs. 16±10 ms/mmHg; hypoxia minutes 15‐20 (HAH vs. Control): 4±3 vs. 14±11 ms/mmHg; Hb type, p=0.024]. Several metrics of HRV were lower in humans with HAH relative to control (SDRR: Hb type, p≤0.001; LF: Hb type, p=0.030) and HRV was blunted to a similar extent in both groups with hypoxia (SDRR: time effect, p=0.009). Conclusion The findings of this study are twofold. Compared to controls, humans with HAH have: 1) attenuated cardiac baroreflex sensitivity and 2) lower heart rate variability in both normoxia and isocapnic hypoxia.