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.

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.

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.

Limb-specific muscle sympathetic nerve activity responses to the cold pressor test.

Recent studies have demonstrated that muscle sympathetic nerve activity (MSNA) responses to isometric exercise differs between active and inactive limbs. Whether limb-dependent responses are characteristic of responses to the cold pressor test (CPT) remains to be established. Therefore, we tested the hypothesis that CPT-induced MSNA responses differ between affected and unaffected limbs such that MSNA in the affected lower limb is greater than MSNA responses in the contralateral lower limb and the upper limb. Integrated peroneal MSNA (microneurography) was measured in young healthy individuals (n = 10) at rest and during three separate 3-min CPTs: the microneurography foot, opposite foot, and opposite hand. Peak MSNA responses were extracted for further analysis, as well as corresponding hemodynamic outcomes including mean arterial pressure (MAP; Finometer). MSNA responses were greater when the microneurography foot was immersed in ice water than when the opposite foot was immersed (38 ± 18 vs 28 ± 16 bursts/100hb: P < 0.01). MSNA responses when the opposite hand was immersed were greater than both the microneurography foot (46 ± 22 vs 38 ± 18 bursts/100hb: P < 0.01) and opposite foot (46 ± 22 vs 28 ± 16 bursts/100hb: P ≤0.01). Likewise, MAP responses were greater during the hand CPT than the microneurography foot (99 ± 9 vs 96 ± 8 mmHg: P < 0.01) and opposite foot CPT (99 ± 9 vs 96 ± 9 mmHg: P < 0.01). These data indicate that (a) upper limbs and (b) immersed limbs elicit greater MSNA responses to the CPT than lower and/or non-immersed limbs.

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.

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.

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.

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.

The effects of sex and menstrual cycle phase on sympathetic action potential recruitment patterns during hypercapnic-hypoxic apnea.

Previously, we demonstrated that integrated muscle sympathetic nerve activity (MSNA) responses to acute chemoreflex stress were augmented during the early follicular (EF) phase of the menstrual cycle relative to both the midluteal (ML) phase and males. These differences were most pronounced in the amplitude component of MSNA, suggesting EF-driven increases in action potential (AP) recruitment in females. Therefore, we tested the hypothesis that neural recruitment, quantified as MSNA AP discharge patterns during acute chemoreflex stress, is potentiated during EF. We retrospectively analyzed MSNA data from 9 young males and 7 young females tested during the EF and ML phases at rest and during a voluntary end-inspiratory hypercapnic-hypoxic apnea. Sympathetic AP discharge patterns were analyzed using wavelet-based methodology. Apnea-driven increases in AP frequency and AP content per integrated burst were greater in EF relative to ML (APs/min: P = 0.02; APs/burst: P = 0.03) and to males (APs/min: P = 0.04; APs/burst: P = 0.02). The recruitment of new larger AP clusters was greater in EF than ML (P < 0.01) but not different from males (P = 0.50). Interestingly, we observed a positive association between the magnitude of change in the estrogen/progesterone ratio from EF to ML and the change in AP cluster recruitment, as both decreased from EF to ML (R2 = 0.82; P < 0.01). This suggests that the enhanced progesterone dominance over estrogen during ML may blunt the recruitment of new larger APs. Overall, these data indicate that both sex and the menstrual cycle impact AP recruitment patterns in a manner which may be mediated, at least in part, by gonadal hormones.

Effects of androgen excess and body mass index on endothelial function in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction; whether this is attributable to comorbid hyperandrogenism and/or obesity remains to be established. Therefore, we 1) compared endothelial function between lean and overweight/obese (OW/OB) women with and without androgen excess (AE)-PCOS and 2) examined androgens as potential modulators of endothelial function in these women. The flow-mediated dilation (FMD) test was applied in 14 women with AE-PCOS (lean: n = 7; OW/OB: n = 7) and 14 controls (CTRL; lean: n = 7, OW/OB: n = 7) at baseline (BSL) and following 7 days of ethinyl estradiol supplementation (EE; 30 µg/day) to assess the effect of a vasodilatory therapeutic on endothelial function; at each time point we assessed peak increases in diameter during reactive hyperemia (%FMD), shear rate, and low flow-mediated constriction (%LFMC). BSL %FMD was attenuated in lean AE-PCOS versus both lean CTRL (5.2 ± 1.5 vs. 10.3 ± 2.6%, P < 0.01) and OW/OB AE-PCOS (5.2 ± 1.5 vs. 6.6 ± 0.9%, P = 0.048). A negative correlation between BSL %FMD and free testosterone was observed in lean AE-PCOS only (R2 = 0.68, P = 0.02). EE increased %FMD in both OW/OB groups (CTRL: 7.6 ± 0.6 vs. 10.4 ± 2.5%, AE-PCOS: 6.6 ± 0.9 vs. 9.6 ± 1.7%, P < 0.01), had no impact on %FMD in lean AE-PCOS (5.17 ± 1.5 vs. 5.17 ± 1.1%, P = 0.99), and reduced %FMD in lean CTRL (10.3 ± 2.6 vs. 7.6 ± 1.2%, P = 0.03). Collectively, these data indicate that lean women with AE-PCOS exhibit more severe endothelial dysfunction than their OW/OB counterparts. Furthermore, endothelial dysfunction appears to be mediated by circulating androgens in lean but not in OW/OB AE-PCOS, suggesting a difference in the endothelial pathophysiology of AE-PCOS between these phenotypes.NEW & NOTEWORTHY We present evidence for marked endothelial dysfunction in lean women with androgen excess polycystic ovary syndrome (AE-PCOS) that is 1) associated with free testosterone levels, 2) impaired relative to overweight/obese women with AE-PCOS, and 3) unchanged following short-term ethinyl estradiol supplementation. These data indicate an important direct effect of androgens on the vascular system in women with AE-PCOS. Our data also suggest that the relationship between androgens and vascular health differs between phenotypes of AE-PCOS.

Effect of Exercise Training on Blood Pressure in Healthy Postmenopausal Females: A Systematic Review with Meta-analysis.

INTRODUCTION: The prevalence of hypertension is greater in postmenopausal females compared with males of similar age. Previous meta-analyses of normotensive and hypertensive adults have shown that aerobic exercise training reduces systolic blood pressure (SBP) and/or diastolic blood pressure (DBP). However, the effect of aerobic exercise training on blood pressure specifically within healthy postmenopausal females remains unclear. This systematic review with meta-analysis quantified the effect of aerobic exercise training on resting SBP and DBP in healthy postmenopausal females. METHODS: The systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines and was registered in PROSPERO (CRD42020198171). The literature search was done in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL Plus, and SPORTDiscus. Randomized controlled trials involving healthy postmenopausal females with normal or high normal blood pressure and undergoing ≥4 wk of aerobic exercise training were included. The total weighted mean change in SBP and DBP was compared between the exercise and the control interventions. A random-effects model was used to calculate the overall effect sizes of the weighted mean differences and the 95% confidence interval (CI). RESULTS: Twelve studies were included in the meta-analysis (exercise interventions: n = 357, age = 60 ± 4 yr, baseline SBP/DBP = 128 ± 13/79 ± 8 mm Hg; control interventions: n = 330, age = 60 ± 4 yr, baseline SBP/DBP = 126 ± 11/77 ± 6 mm Hg). Compared with the change observed in response to the control interventions, exercise training significantly reduced SBP (-0.43 mm Hg, 95% CI = -0.78 to -0.09, P = 0.02) and DBP (-0.39 mm Hg, 95% CI = -0.73 to -0.05, P = 0.05). CONCLUSIONS: Aerobic exercise training significantly reduces resting SBP and DBP in healthy postmenopausal females with normal or high normal blood pressure. However, this reduction is small and of uncertain clinical significance.

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.

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.

Preeclampsia is not associated with elevated muscle sympathetic reactivity.

To determine whether increased chemoreflex tonic activity is associated with augmented muscle sympathetic nervous system activity (MSNA) in women diagnosed with preeclampsia. Women with preeclampsia (n = 19; 32 ± 5 yr old, 31 ± 3 wk of gestation) were matched by age and gestational age with pregnant women (controls, n = 38, 32 ± 4 yr old, 31 ± 4 wk gestation; 2:1 ratio). MSNA (n = 9 preeclampsia) was assessed during baseline, peripheral chemoreflex deactivation (hyperoxia), and a cold pressor test (CPT). Baroreflex gain and diastolic blood pressure at which there is a 50% likelihood of MSNA occurring (T50) and plasma noradrenaline concentrations were measured. Baseline mean arterial pressure (MAP: 106 ± 11 vs. 87 ± 10 mmHg, P < 0.0001), noradrenaline concentrations (498 ± 152 pg/mL vs. 326 ± 147, P = 0.001), and T50 (79 ± 7 vs. 71 ± 9 mmHg, P = 0.02) were greater in women with preeclampsia than in controls. However, baseline MSNA (burst incidence [BI]: 41 ± 16 vs. 45 ± 13 bursts/100 hb, P = 0.4) was not different between groups. Responses to hyperoxia (ΔBI -5 ± 7 vs. -1 ± 8 bursts/100 hb, P = 0.1; ΔMAP -1 ± 3 vs. -2 ± 3 mmHg, P = 0.7) and CPT (ΔBI 15 ± 7 vs. 12 ± 11 bursts/100 hb, P = 0.6; ΔMAP 10 ± 4 vs. 12 ± 11 mmHg, P = 0.6) were not different between groups. Our findings question the assumption that increased MSNA contributes to hypertension in women with preeclampsia. The chemoreflex does not appear to contribute to an increase in MSNA in women with preeclampsia.NEW & NOTEWORTHY We wanted to determine whether increased chemoreflex tonic activity is associated with augmented muscle sympathetic nervous system activity (MSNA) in women diagnosed with preeclampsia. The chemoreflex does not contribute to increased MSNA in women with preeclampsia. Our data also challenge the belief that preeclampsia is associated with sympathetic neural hyperactivity. Thus, targeting sympathetic neural hyperactivity as therapeutic strategy is unlikely to be the most efficacious approach to treatment and management.

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.

Sympathetic nervous system activity and reactivity in women with gestational diabetes mellitus.

INTRODUCTION: Gestational diabetes mellitus (GDM) is associated with vascular dysfunction. Sympathetic nervous system activity (SNA) is an important regulator of vascular function, and is influenced by glucose and insulin. The association between GDM and SNA (re)activity is unknown. We hypothesize that women with GDM would have increased SNA during baseline and during stress. METHODS: Eighteen women with GDM and 18 normoglycemic pregnant women (controls) were recruited. Muscle SNA (MSNA; peroneal microneurography) was assessed at rest, during a cold pressor test (CPT) and during peripheral chemoreflex deactivation (hyperoxia). Spontaneous sympathetic baroreflex gain was quantified versus diastolic pressure at rest and during hyperoxia. RESULTS: Age, gestational age (third trimester) and pre-pregnancy body mass index and baseline MSNA was not different among the groups. Women with GDM had a similar increase in MSNA, but a greater pressor response to CPT compared to controls (% change in MAP 17 ± 7% vs. 9 ± 9%; p = .004). These data are consistent with a greater neurovascular transduction in GDM (% change in total peripheral resistance/% change in burst frequency [BF]: 15.9 ± 30.2 vs. -5.2 ± 16.4, p = .03). Interestingly, women with GDM had a greater reduction in MSNA during hyperoxia (% change in BF -30 ± 19% vs. -6 ± 17%; p = .01). CONCLUSION: Women diagnosed with GDM have similar basal SNA versus normoglycemic pregnant women, but greater neurovascular transduction, meaning a greater influence of the sympathetic nerve activity in these women. We also document evidence of chemoreceptor hyperactivity, which may influence SNA in women with GDM but not in controls.

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.

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.

Device-guided slow breathing reduces blood pressure and sympathetic activity in young normotensive individuals of both sexes.

Slow breathing (SLOWB) is recommended for use as an adjuvant treatment for hypertension. However, the extent to which blood pressure (BP) responses to SLOWB differ between men and women are not well-established. Therefore, we tested the hypothesis that an acute bout of SLOWB would induce larger decreases in BP in males than in females, given that males typically have higher resting BP. We also examined autonomic contributors to reduced BP during SLOWB; that is, muscle sympathetic nerve activity and spontaneous cardiovagal (sequence method) and vascular sympathetic baroreflex sensitivity. We tested normotensive females (n = 10, age: 22 ± 2 y, body mass index: 22 ± 2 kg/m2) and males (n = 12, age: 23 ± 3 y, body mass index: 26 ± 4 kg/m2). Subjects were tested at baseline and during the last 5 min of a 15-min RESPeRATE-guided SLOWB session. Overall, SLOWB reduced systolic BP by 3.2 ± 0.8 mmHg (main effect, P < 0.01). Females had lower systolic BP (main effect, P = 0.02); we observed no interaction between sex and SLOWB. SLOWB also reduced muscle sympathetic nerve activity burst incidence by -5.0 ± 1.4 bursts/100 heartbeats (main effect, P < 0.01). Although females tended to have lower burst incidence (main effect, P = 0.1), there was no interaction between sex and SLOWB. Cardiovagal baroreflex sensitivity improved during SLOWB (21.0 vs. 36.0 ms/mmHg, P = 0.03) with no effect of sex. Despite lower overall BP in females, our data support a lack of basement effect on SLOWB-induced reductions in BP, as SLOWB was equally effective in reducing BP in males and females. Our findings support the efficacy of the RESPeRATE device for reducing BP in both sexes, even in young, normotensive individuals.NEW & NOTEWORTHY We provide support for the effectiveness of device-guided slow breathing for blood pressure reduction in young normotensive women and men. Despite having lower baseline blood pressure and sympathetic nerve activity, women experienced equivalent reductions in both measures in response to RESPeRATE-guided slow breathing as men. Thus, slow breathing appears to be effective in young healthy normotensive individuals of both sexes and may be an ideal preventative therapy against future hypertension.