Blood pressure responses to handgrip exercise but not apnea or mental stress are enhanced in women with a recent history of preeclampsia.

Preeclampsia is a risk factor for future cardiovascular diseases. However, the mechanisms underlying this association remain unclear, limiting effective prevention strategies. Blood pressure responses to acute stimuli may reveal cardiovascular dysfunction not apparent at rest, identifying individuals at elevated cardiovascular risk. Therefore, we compared blood pressure responsiveness with acute stimuli between previously preeclamptic (PPE) women (34 ± 5 yr old, 13 ± 6 mo postpartum) and women following healthy pregnancies (Ctrl; 29 ± 3 yr old, 15 ± 4 mo postpartum). Blood pressure (finger photoplethysmography calibrated to manual sphygmomanometry-derived values; PPE: n = 12, Ctrl: n = 12) was assessed during end-expiratory apnea, mental stress, and isometric handgrip exercise protocols. Integrated muscle sympathetic nerve activity (MSNA) was assessed in a subset of participants (peroneal nerve microneurography; PPE: n = 6, Ctrl: n = 8). Across all protocols, systolic blood pressure (SBP) was higher in PPE than Ctrl (main effects of group all P < 0.05). Peak changes in SBP were stressor specific: peak increases in SBP were not different between PPE and Ctrl during apnea (8 ± 6 vs. 6 ± 5 mmHg, P = 0.32) or mental stress (9 ± 5 vs. 4 ± 7 mmHg, P = 0.06). However, peak exercise-induced increases in SBP were greater in PPE than Ctrl (11 ± 5 vs. 7 ± 7 mmHg, P = 0.04). MSNA was higher in PPE than Ctrl across all protocols (main effects of group all P < 0.05), and increases in peak MSNA were greater in PPE than Ctrl during apnea (44 ± 6 vs. 27 ± 14 burst/100 hb, P = 0.04) and exercise (25 ± 8 vs. 13 ± 11 burst/100 hb, P = 0.01) but not different between groups during mental stress (2 ± 3 vs. 0 ± 5 burst/100 hb, P = 0.41). Exaggerated pressor and sympathetic responses to certain stimuli may contribute to the elevated long-term risk for cardiovascular disease in PPE.NEW & NOTEWORTHY Women with recent histories of preeclampsia demonstrated higher systolic blood pressures across sympathoexcitatory stressors relative to controls. Peak systolic blood pressure reactivity was exacerbated in previously preeclamptic women during small muscle-mass exercises, although not during apneic or mental stress stimuli. These findings underscore the importance of assessing blood pressure control during a variety of experimental conditions in previously preeclamptic women to elucidate mechanisms that may contribute to their elevated cardiovascular disease risk.

Sex as a biological variable for cardiovascular physiology.

There have been ongoing efforts by federal agencies and scientific communities since the early 1990s to incorporate sex and/or gender in all aspects of cardiovascular research. Scientific journals provide a critical function as change agents to influence transformation by encouraging submissions for topic areas, and by setting standards and expectations for articles submitted to the journal. As part of ongoing efforts to advance sex and gender in cardiovascular physiology research, the American Journal of Physiology-Heart and Circulatory Physiology recently launched a call for papers on Considering Sex as a Biological Variable. This call was an overwhelming success, resulting in 78 articles published in this collection. This review summarizes the major themes of the collection, including Sex as a Biological Variable Within: Endothelial Cell and Vascular Physiology, Cardiovascular Immunity and Inflammation, Metabolism and Mitochondrial Energy, Extracellular Matrix Turnover and Fibrosis, Neurohormonal Signaling, and Cardiovascular Clinical and Epidemiology Assessments. Several articles also focused on establishing rigor and reproducibility of key physiological measurements involved in cardiovascular health and disease, as well as recommendations and considerations for study design. Combined, these articles summarize our current understanding of sex and gender influences on cardiovascular physiology and pathophysiology and provide insight into future directions needed to further expand our knowledge.

Sympathetic determinants of resting blood pressure in males and females.

Discharge of postganglionic muscle sympathetic nerve activity (MSNA) is related poorly to blood pressure (BP) in adults. Whether neural measurements beyond the prevailing level of MSNA can account for interindividual differences in BP remains unclear. The current study sought to evaluate the relative contributions of sympathetic-BP transduction and sympathetic baroreflex gain on resting BP in young adults. Data were analyzed from 191 (77 females) young adults (18-39 years) who underwent continuous measurement of beat-to-beat BP (finger photoplethysmography), heart rate (electrocardiography), and fibular nerve MSNA (microneurography). Linear regression analyses were computed to determine associations between sympathetic-BP transduction (signal-averaging) or sympathetic baroreflex gain (threshold technique) and resting BP, before and after controlling for age, body mass index, and MSNA burst frequency. K-mean clustering was used to explore sympathetic phenotypes of BP control and consequential influence on resting BP. Sympathetic-BP transduction was unrelated to BP in males or females (both R2 < 0.01; P > 0.67). Sympathetic baroreflex gain was positively associated with BP in males (R2 = 0.09, P < 0.01), but not in females (R2 < 0.01; P = 0.80), before and after controlling for age, body mass index, and MSNA burst frequency. K-means clustering identified a subset of participants with average resting MSNA, yet lower sympathetic-BP transduction and lower sympathetic baroreflex gain. This distinct subgroup presented with elevated BP in males (P < 0.02), but not in females (P = 0.10). Sympathetic-BP transduction is unrelated to resting BP, while the association between sympathetic baroreflex gain and resting BP in males reveals important sex differences in the sympathetic determination of resting BP.NEW & NOTEWORTHY In a sample of 191 normotensive young adults, we confirm that resting muscle sympathetic nerve activity is a poor predictor of resting blood pressure and now demonstrate that sympathetic baroreflex gain is associated with resting blood pressure in males but not females. In contrast, signal-averaged measures of sympathetic-blood pressure transduction are unrelated to resting blood pressure. These findings highlight sex differences in the neural regulation of blood pressure.

Guidelines on the use of sex and gender in cardiovascular research.

In cardiovascular research, sex and gender have not typically been considered in research design and reporting until recently. This has resulted in clinical research findings from which not only all women, but also gender-diverse individuals have been excluded. The resulting dearth of data has led to a lack of sex- and gender-specific clinical guidelines and raises serious questions about evidence-based care. Basic research has also excluded considerations of sex. Including sex and/or gender as research variables not only has the potential to improve the health of society overall now, but it also provides a foundation of knowledge on which to build future advances. The goal of this guidelines article is to provide advice on best practices to include sex and gender considerations in study design, as well as data collection, analysis, and interpretation to optimally establish rigor and reproducibility needed to inform clinical decision-making and improve outcomes. In cardiovascular physiology, incorporating sex and gender is a necessary component when optimally designing and executing research plans. The guidelines serve as the first guidance on how to include sex and gender in cardiovascular research. We provide here a beginning path toward achieving this goal and improve the ability of the research community to interpret results through a sex and gender lens to enable comparison across studies and laboratories, resulting in better health for all.

Commentary: importance of considering sex and gender when designing cancer care programs.

Due to perceived methodological complications, scientific studies have often excluded females. As a result, male-based findings have been generalized to females, despite physiological and biological differences between sexes. Gender has been even less considered in the literature, with little exploration specifically beyond traditional man/woman representation. This practice is compounded by a lack of what sex and gender encompass, including their erroneous use as synonyms. Sex- and gender-based differences, which are not clearly defined and recognized in scientific literature, are disregarded in health care delivery and, specifically relevant to the focus of this commentary, the development of cancer care programs. Conversely, accounting for sex- and gender in anti-cancer treatments and pathways can help create effective and personalized programming which could lead to an increased likelihood of adoption and adherence to treatment protocols. Although sex- and gender-specific programming may not be necessary in all situations, awareness of the concepts and possible impact on cancer care programs is paramount as more inclusive and personalized methodologies take shape. The goals of this commentary are to (a) clarify the terms sex and gender and (b) raise awareness of their applications and considerations for cancer care program design.

Health-related physical fitness in women with polycystic ovary syndrome versus controls: a systematic review and meta-analysis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common endocrinopathy associated with cardiometabolic dysfunction. PURPOSE: (1) To compare HRPF indices, including cardiorespiratory fitness (CRF), muscle strength, and muscle endurance, between women with and without PCOS (i.e., controls). (2) To explore the impact of moderating factors, i.e., insulin sensitivity, androgen levels, physical activity levels, and body mass index, on these indices. METHODS: Articles comparing HRPF between PCOS and control groups were identified until February 27th, 2022. Random-effects meta-analyses were conducted and moderating factors were explored with subgroup and meta-regression analyses. RESULTS: Twenty studies were included. Compared to controls, CRF was lower in women with PCOS (n = 15, - 0.70 [- 1.35, - 0.05], P = 0.03, I2 = 95%). Meta-regression analyses demonstrated that fasting insulin (P = 0.004) and homeostatic model assessment of insulin resistance (P = 0.006) were negatively associated with CRF, while sex-hormone binding globulin levels (P = 0.003) were positively associated. Absolute muscle strength was not different between PCOS and controls (n = 7, 0.17 [- 0.10, 0.45], P = 0.22, I2 = 37%). One study evaluated muscle endurance and reported lower core endurance in PCOS subjects compared to controls. CONCLUSION: These data suggest that PCOS may be associated with impaired CRF. It remains unclear whether muscle strength and endurance differ between women with PCOS and controls. As this data set was limited by a small sample size, potential for bias, and inconsistent findings, additional studies accounting for the heterogeneous presentation of PCOS as well as improved matching between PCOS and controls for characteristics known to affect HRPF would help elucidate the impact of PCOS on indices of HRPF. PROSPERO REGISTRATION NUMBER: CRD42020196380.

Correlations between salivary- and blood-derived gonadal hormone assessments and implications for inclusion of female participants in research studies.

Even in the 21st century, female participants continue to be underrepresented in human physiology research. This underrepresentation is attributable in part to the perception that the inclusion of females is more time consuming, less convenient, and more expensive relative to males because of the need to account for the menstrual cycle in cardiovascular study designs. Accounting for menstrual cycle-induced fluctuations in gonadal hormones is important, given established roles in governing vascular function and evidence that failure to consider gonadal hormone fluctuations can result in misinterpretations of biomarkers of cardiovascular disease. Thus, for cardiovascular researchers, the inclusion of females in research studies implies a necessity to predict, quantify, and/or track indexes of menstrual cycle-induced changes in hormones. It is here that methodologies are lacking. Gold standard measurement requires venous blood samples, but this technique is invasive and can become both expensive and technically preclusive when serial measurements are required. To this end, saliva-derived measures of gonadal hormones provide a means of simple, noninvasive hormone tracking. To investigate the feasibility of this technique as a means of facilitating research designs that take the menstrual cycle into account, the purpose of this review was to examine literature comparing salivary and blood concentrations of the primary gonadal hormones that fluctuate across the menstrual cycle: estradiol and progesterone. The data indicate that there appear to be valid and promising applications of salivary gonadal hormone monitoring, which may aid in the inclusion of female participants in cardiovascular research studies.

Is polycystic ovary syndrome associated with elevated muscle sympathetic nerve activity?

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by reproductive abnormalities, cardiometabolic disturbances and a heightened risk of cardiovascular disease. A small but compelling body of research demonstrates that females with PCOS present with elevated muscle sympathetic nerve activity (MSNA) at rest. Heightened MSNA is present in lean, overweight and obese females with PCOS, but limited evidence suggests that androgens may be more strongly linked to elevated MSNA in lean females with PCOS than in obese females with PCOS. Although the specific mechanisms underlying elevated MSNA in PCOS remain elusive, sympathetic activation is implicated in the progression of several cardiovascular diseases and may contribute to the cardiovascular pathophysiology of PCOS. Encouragingly, MSNA appears responsive to non-pharmacological intervention, making the sympathetic nervous system a promising therapeutic target to mitigate cardiovascular risk in PCOS. This brief review summarizes the existing evidence regarding elevated MSNA, cardiovascular risk profile and vascular function, as well as the potential for clinical intervention and future research directions in females with PCOS. NEW FINDINGS: What is the topic of this review? The presence of elevated muscle sympathetic nerve activity in females with polycystic ovary syndrome and the implications for cardiovascular health. What advance does it highlight? The sympathetic nervous system likely contributes to elevated cardiovascular disease risk in females with polycystic ovary syndrome. Moreover, it presents as a promising therapeutic target for mitigating cardiovascular disease and merits further investigation.

Sex differences in sympathetic neurovascular and neurohemodynamic relationships during cold pressor test.

Muscle sympathetic nerve activity (MSNA) affects vascular resistance differently in women and men. However, whether this sex difference persists during pronounced increases in MSNA remains unclear. Therefore, the purpose of this study was to examine sex differences in neurovascular transduction during cold pressor test (CPT)-mediated sympathoexcitation. Integrated peroneal MSNA (microneurography) was measured at rest and during a 3-min CPT in young healthy women (n = 11) and men (n = 10). Mean arterial pressure (MAP) was measured beat-by-beat (Finometer), and superficial femoral artery blood flow was measured using duplex ultrasound. Femoral vascular resistance (FVR) was quantified as MAP/femoral blood flow (mmHg/mL/min). Baseline MSNA was similar between women and men (14 ± 9 vs. 15 ± 9 bursts/100 heartbeat, respectively; P = 0.83), whereas MAP was lower (86 ± 7 vs. 92 ± 4 mmHg; P = 0.047), and FVR was greater in women than men (0.54 ± 0.16 vs. 0.36 ± 0.15 mmHg/mL/min; P = 0.02). CPT-induced increases in MSNA were similar between the sexes (19 ± 11 vs. 26 ± 14 bursts/100 heartbeat; P = 0.26) whereas increases in MAP (7 ± 3 vs. 10 ± 3 mmHg; P = 0.03) and FVR (3.2 ± 18.6 vs. 26.8 ± 12.8%; P < 0.01) were smaller in women than in men. Within men, CPT- induced increases in MSNA predicted increases in MAP (R2 = 0.51, P = 0.02) and FVR (R2 = 0.49, P = 0.02). However, MSNA did not predict MAP (R2 = 0.11, P = 0.35) or FVR (R2 = 0.07, P = 0.46) in women. Our findings demonstrate that men experience robust CPT-induced MAP responses that are driven by both neurovascular (MSNA-FVR) and neurohemodynamic (MSNA-MAP) coupling. These relationships were not observed in women, indicating that even during pronounced increases in sympathetic outflow, MSNA is not predictive of vascular nor blood pressure outcomes in young healthy women.

Heterogeneous baroreflex control of sympathetic action potential subpopulations in humans.

KEY POINTS: Emission patterns in muscle sympathetic nerve activity stem from differently sized action potential (AP) subpopulations that express varying discharge probabilities. The mechanisms governing these firing behaviours are unclear. This study investigated the hypothesis that the arterial baroreflex exerts varying control over the different AP subpopulations. During baseline, medium APs expressed the greatest baroreflex slopes, while small and large APs exhibited weaker slopes. On going from baseline to lower body negative pressure (LBNP; simulated orthostatic stress), baroreflex slopes for some clusters of medium APs expressed the greatest increase, while slopes for large APs also increased but to a lesser degree. A subpopulation of previously silent larger APs was recruited with LBNP but these APs expressed weak baroreflex slopes. The arterial baroreflex heterogeneously regulates sympathetic AP subpopulations, exerting its strongest effect over medium APs. Weak baroreflex mechanisms govern the recruitment of latent larger AP subpopulations during orthostatic stress. ABSTRACT: Muscle sympathetic nerve activity (MSNA) occurs primarily in bursts of action potentials (AP) with subpopulations that differ in size and discharge probabilities. The mechanisms determining these discharge patterns remain unclear. This study investigated the hypothesis that variations in AP discharge are due to subpopulation-specific baroreflex control. We employed multi-unit microneurography and a continuous wavelet analysis approach to extract sympathetic APs in 12 healthy individuals during baseline (BSL) and lower body negative pressure (LBNP; -40, -60, -80 mmHg). For each AP cluster, the baroreflex threshold slope was measured from the linear regression between AP probability (%) and diastolic blood pressure (mmHg). During BSL, the baroreflex exerted non-uniform regulation over AP subpopulations: medium-sized AP clusters expressed the greatest slopes while clusters of small and large APs expressed weaker slopes. On going from BSL to LBNP, the baroreflex slopes for each AP subpopulation were modified differently. Baroreflex slopes (%/mmHg) for some medium APs (cluster 5: -4.4 ± 4 to -9.1 ± 5) expressed the greatest increase with LBNP, while slopes for large APs (cluster 9: -1.3 ± 1 to -2.6 ± 2) also increased, but to a lesser degree. Slopes for small APs present at BSL exhibited reductions with LBNP (cluster 2: -3.9 ± 3 to -2.2 ± 3). Larger previously silent AP clusters recruited with LBNP expressed weak baroreflex regulation (cluster 14: -0.9 ± 1%/mmHg). The baroreflex exerts the strongest control over medium-sized APs. Augmenting baroreflex gain and upward resetting of discrete AP subpopulations active at BSL, as well as recruiting larger previously silent APs with weak baroreflex control, facilitates elevated MSNA during orthostatic stress.

Sex differences in dynamic blood pressure regulation: beat-by-beat responses to muscle sympathetic nerve activity.

It has been suggested that sex differences in acute blood pressure fluctuations occur during the periods of time between bursts of muscle sympathetic nerve activity. Therefore, we tested the hypothesis that men experience more dynamic changes in mean arterial pressure (Finometer MIDI) than women during acute sympathoinhibition (i.e., slow breathing) in which bursts of sympathetic activity occur more infrequently than at rest. We tested healthy women (n = 9) and men (n = 9) of similar age (22 ± 2 vs. 23 ± 3 yr, P = 0.6). Custom software was used to calculate beat-by-beat changes in blood pressure following sympathetic burst and nonburst sequences (recorded using microneurography) during 10 min of supine rest and a 15-min bout of slow breathing. During slow breathing following nonburst sequences, women demonstrated smaller overall reductions in mean arterial pressure compared with men over the subsequent 15 cardiac cycles (P < 0.01). In addition, following a burst of sympathetic activity, women experienced greater overall increases in mean arterial pressure compared with men over the following 15 cardiac cycles (P < 0.01). Despite these differences, the peak and nadir changes in arterial pressure following burst and nonburst sequences were not different between the sexes (P = 0.45 and P = 0.48, burst and nonburst sequences, respectively). As such, these data suggest that women respond to a burst of sympathetic activity with more sustained increases in blood pressure than men, coupled with improved maintenance of blood pressure during acute periods of sympathetic quiescence. In other words, these findings suggest that men rely more on frequent bursts of sympathetic activity to acutely regulate arterial pressure than women.NEW & NOTEWORTHY We demonstrate that during acute sympathoinhibition, women demonstrate more sustained increases in blood pressure following sympathetic bursts of activity than men. Likewise, during prolonged sympathetic quiescence, blood pressure is less labile in women than men. This suggests that lower overall blood pressure in young women may not be mediated by smaller beat-by-beat changes in blood pressure in response to sympathetic outflow but may instead be mediated by a lower frequency of sympathetic bursts.

A recent history of preeclampsia is associated with elevated central pulse wave velocity and muscle sympathetic outflow.

Preeclampsia is associated with the development of cardiovascular diseases later in life. To investigate this phenomenon, we compared established markers of cardiovascular dysregulation between previously preeclamptic women (PPE; n = 12, 13 ± 6 mo postpartum, 34 ± 6 yr) and women who had previously had an uncomplicated pregnancy [control (CTRL); n = 12, 15 ± 4 mo postpartum; 29 ± 3 yr]. We hypothesized that PPE would present with elevated arterial stiffness (assessed as central and peripheral pulse wave velocity) and muscle sympathetic nerve activity (MSNA; microneurography) and blunted baroreflex sensitivity (BRS) relative to CTRL. Blood pressure (Finometer) was similar between PPE and CTRL (mean arterial pressure: 94 ± 11 vs. 89 ± 9, P = 0.16). Central (6.92 ± 0.21 vs. 6.24 ± 0.22 m/s, P = 0.04) but not peripheral arterial stiffness (7.52 ± 0.19 vs. 7.09 ± 0.19 m/s, P = 0.13) was elevated in PPE versus CTRL (values normalized to MAP). MSNA was also elevated in PPE versus CTRL (22 ± 7 vs. 13 ± 5 bursts/min, P = 0.01), although this was independent of arterial stiffness (central: r2 = 0.01, P = 0.74; peripheral: r2 = 0.01, P = 0.74). Cardiovagal BRS was blunted in PPE versus CTRL (15 ± 5 vs. 28 ± 1 ms/mmHg, P = 0.01), whereas sympathetic vascular BRS was similar (-3.2 ± 0.9 vs. -3.1 ± 1.4 bursts·100 hb-1·mmHg-1, P = 0.88). Cardiovagal and sympathetic BRS were inversely correlated in both CTRL (r2 = 0.43; P = 0.05) and PPE (r2 = 0.69; P = 0.04), supporting a compensatory mechanism resulting in normal blood pressures in both groups. Overall, these data indicate that PPE retain their ability to buffer elevated MSNA. We propose that the higher incidence of cardiovascular disease observed later in life in PPE results from this arterial stiffness, combined with the loss of protective vascular mechanisms and the "unmasking" of high MSNA.NEW & NOTEWORTHY We demonstrate that resting muscle sympathetic nerve activity is elevated in women with a recent history of preeclampsia relative to women who have recently had uncomplicated pregnancies and without a history of preeclampsia. Structural changes in the central arteries are associated with arterial stiffness following preeclampsia, independent of changes in the sympathetic nervous system. The structural changes are observed in these relatively young previously preeclamptic women, indicating elevated cardiovascular risk. Our data suggest that with aging (and the gradual loss of vascular protection for women, as established by others), this risk will become exaggerated compared with women who have had normal pregnancies.

Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor.

KEY POINTS: Polycystic ovary syndrome (PCOS) is a complex syndrome with cardiovascular risk factors, including obesity and insulin resistance. PCOS is also associated with high androgens, increases the risk of cardiovascular dysfunction in women. Due to the complexity of PCOS, had it has been challenging to isolate specific causes of the cardiovascular dysfunction. Our measure of cardiovascular dysfunction (endothelial dysfunction) was most profound in lean women with PCOS. The endothelin-1-induced vasodilation in these PCOS subject, was dependent on the ETB R but was not NO-dependent. We also demonstrated oestrogen administration improved endothelial function in lean and obese women with PCOS likely because oestrogen increased NO availability. Our studies indicate a primary role for androgens in cardiovascular dysfunction in PCOS. ABSTRACT: Endothelin-1 (ET-1) is an indicator of endothelial injury and dysfunction and is elevated in women with androgen excess polycystic ovary syndrome (AE-PCOS). The endothelin B receptor (ETB R) subtype mediates vasodilatation, but is blunted in women with PCOS. We hypothesized that androgen drives endothelial dysfunction in AE-PCOS women and oestradiol (EE) administration reverses these effects. We assessed microvascular endothelial function in women with (7 lean and 7 obese) and without AE-PCOS (controls, 6 lean, 7 obese). Only obese AE-PCOS women were insulin resistant (IR). We evaluated cutaneous vascular conductance (%CVCmax ) with laser Doppler flowmetry during low dose intradermal microdialysis ET-1 perfusions (1, 3, 4, 5 and 7 pmol) with either lactated Ringer solution alone, or with ETB R (BQ-788), or nitric oxide (NO) inhibition (l-NAME). Log[ET-1]-%maxCVC dose-response curves demonstrated reduced vasodilatory responses to ET-1 in lean AE-PCOS (logED50 , 0.59 ± 0.08) versus lean controls (logED50 , 0.49 ± 0.09, P < 0.05), but not compared to obese AE-PCOS (logED50 , 0.65 ± 0.09). ETB R inhibition decreased ET-1-induced vasodilatation in AE-PCOS women (logED50 , 0.64 ± 0. 22, P < 0.05). This was mechanistically observed at the cellular level, with ET-1-induced, DAF-FM-measurable endothelial cell NO production, which was abrogated by dihydrotestosterone in an androgen receptor-dependent manner. EE augmented the cutaneous vasodilating response to ET-1(logED50 0.29 ± 0.21, 0.47 ± 0.09, P < 0.05 for lean and obese, respectively). Androgens drive endothelial dysfunction in lean and obese AE-PCOS. We propose that the attenuated ET-1-induced vasodilatation in AE-PCOS is a consequence of androgen receptor-mediated, suppressed ETB R-stimulated NO production, and is reversed with EE.

Blunted sympathetic neurovascular transduction during normotensive pregnancy.

KEY POINTS: Normotensive pregnancy is associated with elevated sympathetic nervous system activity yet normal or reduced blood pressure. It represents a unique period of apparent healthy sympathetic hyperactivity. The present study models the blood pressure and heart rate (ECG R-R interval) responses to fluctuations in sympathetic nervous system activity aiming to understand neurocardiovascular transduction. The reported data clearly demonstrate that transduction of sympathetic nervous system signalling to systemic cardiovascular outcomes is reduced in normotensive pregnancy. These data are important for understanding how blood pressure regulation adapts during normotensive pregnancy and set the foundation for exploring similar mechanisms in hypertensive pregnancies. ABSTRACT: Previously, we described sympathetic nervous system hyperactivity yet decreased blood pressure responses to stress in normotensive pregnancy. To address the hypothesis that pregnant women have blunted neurocardiovascular transduction we assessed the relationship between spontaneous bursts of sympathetic nerve activity (SNA) and fluctuations in mean arterial blood pressure and R-R interval. Resting SNA, blood pressure and ECG were obtained in pregnant (third trimester, n = 18) and non-pregnant (n = 18) women matched for age and pre-/non-pregnant body mass index. Custom software modelled beat-by-beat pressure (photoplethysmography) and R-R interval in relation to sequences of SNA bursts and non-bursts (peroneal microneurography). Sequences were grouped by the number of bursts and non-bursts [singlets, doublets, triplets and quadruplet (four or more)] and mean blood pressure and R-R interval were tracked for 15 subsequent cardiac cycles. Similar sequences were overlaid and averaged. Peak mean pressure in relation to sequences of SNA was reduced in pregnant vs. non-pregnant women (doublets: 1.6 ± 1.1 mmHg vs. 3.6 ± 3.1 mmHg, P < 0.05; triplets: 2.4 ± 1.2 mmHg vs. 3.4 ± 2.1 mmHg, P < 0.05; quadruplets: 3.0 ± 1.0 mmHg vs. 5.5 ± 3.7 mmHg, P < 0.05). The nadir R-R interval following burst sequences was also smaller in pregnant vs. non-pregnant women (singlets: -0.01 ± 0.01 s vs. -0.04 ± 0.04 s, P < 0.05; doublets: -0.02 ± 0.03 s vs. -0.05 ± 0.04 s, P < 0.05; triplets: -0.02 ± 0.01 s vs. -0.07 ± 0.04 s, P < 0.05; quadruplets: -0.01 ± 0.01 s vs. -0.09 ± 0.09 s, P < 0.05). There were no differences between groups in the mean arterial pressure and R-R interval responses to non-burst sequences. Our data clearly indicate blunted systemic neurocardiovascular transduction during normotensive pregnancy. We propose that blunted transduction is a positive adaptation protecting pregnant women from the cardiovascular consequences of sympathetic hyperactivity.

Blood pressure predicts endothelial function and the effects of ethinyl estradiol exposure in young women.

Hypertension, obesity, and endothelial function predict cardiovascular disease in women, and these factors are interrelated. We hypothesized that hypertension and obesity are associated with endothelial dysfunction in young women and that short-term ethinyl estradiol exposure mitigates this dysfunction. We examined flow-mediated dilation (FMD) responses before and during 7 days of oral ethinyl estradiol (30 µg/day) in 19 women (25 ± 5, 18-35 yr). We divided our sample into two groups based on two criteria: blood pressure and obesity. Women were divided into normal blood pressure (NBP; mean arterial pressure range: 78-91 mmHg, n = 7) and high blood pressure (HBP; mean arterial pressure range: 95-113 mmHg, n = 9) groups. We also stratified our subjects by body composition (lean: 18-31%, n = 8; obese: 38-59%, n = 9). We evaluated brachial FMD after two distinct shear stress stimuli: occlusion alone and occlusion with ischemic handgrip exercise. Obesity was unrelated to both FMD responses. Before ethinyl estradiol administration, the HBP group had blunted ischemic exercise responses relative to the NBP group (8.0 ± 3.5 vs. 12.3 ± 3.2%, respectively, P = 0.05). However, during ethinyl estradiol administration, ischemic exercise responses increased in the HBP group (12.8 ± 6.1%, P = 0.04) but decreased in the NBP group (5.6 ± 2.4%, P = 0.01). Standard FMD did not reveal differences between groups. In summary, 1) moderate HBP predicted endothelial impairment, 2) ethinyl estradiol administration had divergent effects on FMD in women with NBP versus HBP, and 3) enhanced FMD (ischemic handgrip exercise) revealed differences in endothelial function, whereas standard FMD (occlusion alone) did not. NEW & NOTEWORTHY We are the first to show that mild hypertension is a stronger predictor of endothelial dysfunction than obesity in healthy women without overt cardiovascular dysfunction. Importantly, the standard 5-min flow-mediated vasodilation stimulus did not detect endothelial dysfunction in our healthy population; only an enhanced ischemic handgrip exercise shear stress stimulus detected endothelial impairment. Estradiol administration increased flow-mediated dilation in women with high blood pressure, so it may be a therapeutic intervention to improve endothelial function.

Activity of muscle sympathetic neurons during normotensive pregnancy.

In pathological populations, elevated sympathetic activity is associated with increased activity of individual sympathetic neurons. We used custom action potential detection software to analyze multiunit sympathetic activity in 18 normotensive pregnant women (third trimester; 33 ± 5 wk) and 19 nonpregnant women at rest and a subset (10 and 13, respectively) during a cold pressor challenge. Although the number of action potentials per burst and number of active amplitude-based "clusters" were not different between groups, the total number of sympathetic action potentials per minute was higher in pregnant women at rest. Individual clusters were active predominately once per burst, suggesting they represent single neurons. Action potentials occurred in closer succession in normotensive pregnant (interspike interval 36 ± 10 ms) versus nonpregnant women (50 ± 27 ms; P < 0.001) at rest. Pregnant women had a lower total peripheral resistance (11.7 ± 3.0 mmHg·l-1·min) than nonpregnant women (15.1 ± 2.7 mmHg·l-1·min; P < 0.001), indicating a blunted neurovascular transduction. The cold pressor reduced the number of action potentials per burst in both groups due to shortening of the R-R interval in conjunction with increased burst frequency; total neural firing per minute was unchanged. Thus elevated sympathetic activity during normotensive pregnancy is specific to increased incidence of multiunit bursts. This is likely due to decreased central gating of burst output as opposed to generalized increases in central drive. These data also reinforce the concept that pregnancy appears to be the only healthy state of chronic sympathetic hyperactivity of which we are aware.

Sympathetic neurovascular regulation during pregnancy: A longitudinal case series study.

NEW FINDINGS: What is the main observation in this case? The main observation of this case report is that during pregnancy there is a progressive sympatho-excitation in basal conditions and under stress, which is offset by a concurrent reduction in neurovascular transduction. Strong correlations between autonomic nervous system activity and sex hormones (oestrogen and progesterone), vasopressin and aldosterone were found. What insights does it reveal? Our findings suggest that hormonal surges might be associated with central sympathetic activation. ABSTRACT: The adaptations of sympathetic nerve activity (SNA) during pregnancy remain poorly understood. An increase in blood volume, cardiac output and SNA, with a concomitant drop in total peripheral resistance (TPR), suggest that during pregnancy there is a reduced transduction of SNA into TPR. Most of these findings have originated from cross-sectional studies; thus, we conducted a longitudinal assessment of SNA and TPR in two participants. Measurements were made before pregnancy (early follicular phase), on four occasions during pregnancy and at 2 months postpartum. Mean arterial pressure and cardiac output were used to calculate TPR. The SNA was measured using microneurography (peroneal nerve). There was a gestation-dependent increase in SNA burst frequency (r2  = 0.96, P = 0.009). Neurovascular transduction, however, decreased by 53% in both women. Sympathetic hyperactivity was reversed postpartum, whereas neurovascular transduction remained lower. These longitudinal data highlight the progressive sympatho-excitation of pregnancy, which is offset by a concurrent reduction in neurovascular transduction.

Muscle sympathetic nerve activity and volume-regulating factors in healthy pregnant and nonpregnant women.

Healthy, normotensive human pregnancies are associated with striking increases in both plasma volume and vascular sympathetic nerve activity (SNA). In nonpregnant humans, volume-regulatory factors including plasma osmolality, vasopressin, and the renin-angiotensin-aldosterone system have important modulatory effects on control of sympathetic outflow. We hypothesized that pregnancy would be associated with changes in the relationships between SNA (measured as muscle SNA) and volume-regulating factors, including plasma osmolality, plasma renin activity, and arginine vasopressin (AVP). We studied 46 healthy, normotensive young women (23 pregnant and 23 nonpregnant). We measured SNA, arterial pressure, plasma osmolality, plasma renin activity, AVP, and other volume-regulatory factors in resting, semirecumbent posture. Pregnant women had significantly higher resting SNA (38 ± 12 vs. 23 ± 6 bursts/min in nonpregnant women), lower osmolality, and higher plasma renin activity and aldosterone (all P < 0.05). Group mean values for AVP were not different between groups [4.64 ± 2.57 (nonpregnant) vs. 5.17 ± 2.03 (pregnant), P > 0.05]. However, regression analysis detected a significant relationship between individual values for SNA and AVP in pregnant (r = 0.71, P < 0.05) but not nonpregnant women (r = 0.04). No relationships were found for other variables. These data suggest that the link between AVP release and resting SNA becomes stronger in pregnancy, which may contribute importantly to blood pressure regulation in healthy women during pregnancy.NEW & NOTEWORTHY Sympathetic nerve activity and blood volume are both elevated during pregnancy, but blood pressure is usually normal. Here, we identified a relationship between vasopressin and sympathetic nerve activity in pregnant but not nonpregnant women. This may provide mechanistic insights into blood pressure regulation in normal pregnancy and in pregnancy-related hypertension.

Hormone phase influences sympathetic responses to high levels of lower body negative pressure in young healthy women.

We tested the hypothesis that sympathetic responses to baroreceptor unloading may be affected by circulating sex hormones. During lower body negative pressure at -30, -60, and -80 mmHg, muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure were recorded in women who were taking (n = 8) or not taking (n = 9) hormonal contraceptives. All women were tested twice, once during the low-hormone phase (i.e., the early follicular phase of the menstrual cycle and the placebo phase of hormonal contraceptive use), and again during the high-hormone phase (i.e., the midluteal phase of the menstrual cycle and active phase of contraceptive use). During baroreceptor unloading, the reductions in stroke volume and resultant increases in MSNA and total peripheral resistance were greater in high-hormone than low-hormone phases in both groups. When normalized to the fall in stroke volume, increases in MSNA were no longer different between hormone phases. While stroke volume and sympathetic responses were similar between women taking and not taking hormonal contraceptives, mean arterial pressure was maintained during baroreceptor unloading in women not taking hormonal contraceptives but not in women using hormonal contraceptives. These data suggest that differences in sympathetic activation between hormone phases, as elicited by lower body negative pressure, are the result of hormonally mediated changes in the hemodynamic consequences of negative pressure, rather than centrally driven alterations to sympathetic regulation.