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.

Regulation of body temperature and blood pressure in women: Mechanisms and implications for heat illness risk.

Increasing global temperatures due to ongoing climate change phenomena have resulted in increased risk of exertional heat illness in otherwise healthy, young individuals who work or play in the heat. With increasing participation of women in athletic, military and industrial activities that involve exertion in the heat, there is a growing need to study female physiology in this context. Mechanisms controlling blood pressure and body temperature have substantial overlap in humans, largely due to autonomic mechanisms which contribute to both. Similarly, illnesses that result from excessive heat exposure can often be traced back to imbalances in one or more of these autonomic mechanisms. In recent years, there has been increased recognition of the importance of sex as a biological variable for basic and applied research in these areas. The goal of this paper is to present an update on the integrative physiology and pathophysiology of responses to heat stress in women (thermoregulation and blood pressure regulation). In this context, it is often the case that differences between sexes are presented as 'advantages' and 'disadvantages' of one sex over the other. In our opinion, this is an over-simplification of the physiology which ignores the nuances and complexities of the integrative physiology of responses to heat exposure and exercise, and their relevance for practical outcomes.

Human performance augmentation: the importance of integrative physiological quantification.

In recent years, there has been an explosion of new approaches (technological, methodological, pharmacological, etc.) designed to improve physical performance for athletes, the military and in other applications. The goal of the present discussion is to review and quantify several ways in which physiology can provide important insights about which tools may lead to improved performance (and may therefore be worth resource investment) and which tools are less likely to provide meaningful enhancement. To address these objectives, we review examples of technological solutions/approaches in terms of the magnitude of their potential (or actual) influences: transformational, moderate, ineffective or undetermined. As one example, if there were a technology which significantly increased arterial oxygen partial pressure by 10%, this would be relatively meaningless in healthy people resting at sea level, where it would have a minimal effect on arterial oxygen content. However, there might be specific situations where such an effect would be very helpful, including at high altitude or in some patient populations. We discuss the importance of quantitative evaluation of putative approaches to performance enhancement and highlight the important role of integrative physiologists in the development and critical appraisal of these approaches.

Effects of sex and ageing on the human respiratory muscle metaboreflex.

Intense inspiratory muscle work evokes a sympathetically mediated pressor reflex, termed the respiratory muscle metaboreflex, in which young females demonstrate an attenuated response relative to males. However, the effects of ageing and female sex hormones on the respiratory muscle metaboreflex are unclear. We tested the hypothesis that the pressor response to inspiratory work would be similar between older males and females, and higher relative to their younger counterparts. Healthy, normotensive young (26 ± 3 years) males (YM; n = 10) and females (YF; n = 10), as well as older (64 ± 5 years) males (OM; n = 10) and females (OF; n = 10), performed inspiratory pressure threshold loading (PTL) to task failure. Older adults had a greater mean arterial pressure (MAP) response to PTL than young (P < 0.001). YF had a lower MAP compared to YM (+10 ± 6 vs. +19 ± 15 mmHg, P = 0.026); however, there was no difference observed between OF and OM (+26 ± 11 vs. +27 ± 11 mmHg, P = 0.162). Older adults had a lower heart rate response to PTL than young (P = 0.002). There was no effect of sex between young females and males (+19 ± 9 and +27 ± 11 bpm, P = 0.186) or older females and males (+17 ± 7 and +20 ± 7 bpm, P = 0.753). We conclude the respiratory muscle metaboreflex response is heightened in older adults, and the sex effect between older males and post-menopause females is absent, suggesting an effect of circulating sex hormones. KEY POINTS: The arterial blood pressure response to the respiratory muscle metaboreflex is greater in older males and females. Compared to sex-matched young individuals, there is no sex differences in the blood pressure response between older males and post-menopause females. Our results suggest the differences between males and females in the cardiovascular response to high levels of inspiratory muscle work is abolished with reduced circulating female sex hormones.

Aging in females is associated with changes in respiratory modulation of sympathetic nerve activity and blood pressure.

Sympathetic nerve activity (SNA) is tightly coupled with the respiratory cycle. In healthy human males, respiratory modulation of SNA does not change with age. However, it is unclear how this modulation is affected by age in females. We investigated whether respiratory sympathetic modulation is altered in healthy postmenopausal (PMF) versus premenopausal female (YF), and younger male (YM) adults, and determined its relationship to resting blood pressure. Muscle SNA (MSNA; microneurography), respiration (transducer belt), ECG, and continuous blood pressure were measured in 12 YF, 13 PMF, and 12 YM healthy volunteers. Respiratory modulation of MSNA was quantified during two phases of the respiratory cycle: mid-late expiration and inspiration/postinspiration. All groups showed respiratory modulation of MSNA (P < 0.0005). There was an interaction between the respiratory phase and group for MSNA [bursts/100 heartbeats (HB) (P = 0.004) and bursts/min (P = 0.029)], with smaller reductions in MSNA during inspiration observed in PMF versus the other groups. Respiratory modulation of blood pressure was also reduced in PMF versus YF (6 [2] vs. 12 [9] mmHg, P = 0.008) and YM (13 [13] mmHg, P = 0.001, median [interquartile range]). The magnitude of respiratory sympathetic modulation was related to resting blood pressure in PMF only, such that individuals with less modulation had greater resting blood pressure. The data indicate that aging in postmenopausal females is associated with less inspiratory inhibition of MSNA. This correlated with a higher resting blood pressure in PMF only. Thus, the reduced modulation of MSNA could contribute to the age-related rise in blood pressure that occurs in females.NEW & NOTEWORTHY The current study demonstrates that respiratory modulation of sympathetic nerve activity (SNA) is reduced in healthy postmenopausal (PMF) versus premenopausal females (YF). Furthermore, respiratory sympathetic modulation was negatively related to resting blood pressure in postmenopausal females, such that blood pressure was greater in individual with less modulation. Reduced respiratory sympathetic modulation may have implications for the autonomic control of blood pressure in aging postmenopausal females, by contributing to age-related sympathetic activation and reducing acute, respiratory-linked blood pressure variation.

Body mass index, but not sex, influences exertional heat stroke risk in young healthy men and women.

Exertional heat stroke (EHS) remains a persistent threat for individuals working or playing in the heat, including athletes and military and emergency service personnel. However, influence of biological sex and/or body mass index (BMI) on the risk of EHS remain poorly understood. The purpose of this study was to retrospectively assess the influence of sex and BMI on risk of EHS in the active-duty US Army. We analyzed data from 2016 to 2021, using a matched case-control approach, where each individual with a diagnosis of EHS was matched to five controls based on calendar time, unit ID, and job category, to capture control individuals who were matched to EHS events by location, time, and activity. We used a multivariate logistic regression model mutually adjusted for sex, BMI, and age to compare 745 (n = 61 F) individuals (26 ± 7 yr) with a diagnosed EHS to 4,290 (n = 384 F) case controls (25 ± 5 yr). Group average BMI were similar: 26.6 ± 3.1 (EHS) and 26.5 ± 3.6 kg/m2 (CON). BMI was significantly (P < 0.0001) associated with higher risk of EHS with a 3% increase in risk of EHS for every unit increase in BMI. Notably, sex was not associated with any difference in risk for EHS (P = 0.54). These data suggest that young healthy people with higher BMI have significantly higher risk of EHS, but, contrary to what some have proposed, this risk was not higher in young women.

Combining hypoxia with thermal stimuli in humans: physiological responses and potential sex differences.

Increasing prevalence of native lowlanders sojourning to high altitudes (>2,500 m) for recreational, occupational, military, and competitive reasons has generated increased interest in physiological responses to multistressor environments. Exposure to hypoxia poses recognized physiological challenges that are amplified during exercise and further complicated by environments that might include combinations of heat, cold, and high altitude. There is a sparsity of data examining integrated responses in varied combinations of environmental conditions, with even less known about potential sex differences. How this translates into performance, occupational, and health outcomes requires further investigation. Acute hypoxic exposure decreases arterial oxygen saturation, resulting in a reflex hypoxic ventilatory response and sympathoexcitation causing an increase in heart rate, myocardial contractility, and arterial blood pressure, to compensate for the decreased arterial oxygen saturation. Acute altitude exposure impairs exercise performance, for example, reduced time to exhaustion and slower time trials, largely owing to impairments in pulmonary gas exchange and peripheral delivery resulting in reduced V̇o2max. This exacerbates with increasing altitude, as does the risk of developing acute mountain sickness and more serious altitude-related illnesses, but modulation of those risks with additional stressors is unclear. This review aims to summarize and evaluate current literature regarding cardiovascular, autonomic, and thermoregulatory responses to acute hypoxia, and how these may be affected by simultaneous thermal environmental challenges. There is minimal available information regarding sex as a biological variable in integrative responses to hypoxia or multistressor environments; we highlight these areas as current knowledge gaps and the need for future research.

Implications of a patent foramen ovale for environmental physiology and pathophysiology: do we know the 'hole' story?

The foramen ovale is an essential component of the fetal circulation contributing to oxygenation and carbon dioxide elimination that remains patent under certain circumstances in ∼30% of the healthy adult population, without major negative sequelae in most. Adults with a patent foramen ovale (PFO) have a greater tendency to develop symptoms of acute mountain sickness and high-altitude pulmonary oedema upon ascent to high altitude, and PFO presence is associated with worse cardiopulmonary function in chronic mountain sickness. This increase in altitude illness prevalence may be related to dysregulated cerebral blood flow associated with altered respiratory chemoreflex sensitivity; however, the mechanisms remain to be elucidated. Interestingly, men with a PFO appear to have a shift in thermoregulatory control to higher internal temperatures, both at rest and during exercise, and they have blunted thermal hyperpnoea. The teleological 'reason' for this thermoregulatory shift is unclear, but the shift of ∼0.5°C in core body temperature does not appear to be sufficient to have any significant negative consequences in terms of risk of heat illness. Further work in this area is needed, particularly in women, to evaluate mechanisms of heat storage and dissipation in these individuals compared to people without a PFO. Consequences of a PFO in SCUBA divers include a greater incidence of unprovoked decompression sickness, but whether PFO is beneficial or detrimental to breath hold diving remains unexplored. Whether PFO presence will explain interindividual variability in responses to, and consequences from, other environmental stressors such as spaceflight remain entirely unknown.

When it's time for the sex talk, words matter.

In recent years, the traditional, unspoken assumption in published biomedical research studies that the young, healthy (usually white) male is the "default human" has received increasing scrutiny and criticism. The historical underrepresentation of female participants in biomedical research has been increasingly recognized and addressed, including with the current call for papers at the American Journal of Physiology-Heart and Circulatory Physiology. Our goal in the present Perspectives is to discuss the topic of terminology (man/woman vs. male/female) for human research participants when considering sex as a biological variable. This important consideration is consistent with the importance of gender identity and related topics to psychological, emotional, and physical health. Just as pronouns are important, so is appropriate terminology when referring to human research volunteers. Despite some disagreement regarding terminology between our two groups of authors, we provide consensus recommendations. Importantly, we all agree that the most vital aspect of the present discussion is the broader focus on sex as a biological variable and appropriate inclusion of biological sex in in vitro, preclinical, and human research studies.

Influence of graded hypercapnia on endurance exercise performance in healthy humans.

Military and/or emergency services personnel may be required to perform high-intensity physical activity during exposure to elevated inspired carbon dioxide (CO2). Although many of the physiological consequences of hypercapnia are well characterized, the effects of graded increases in inspired CO2 on self-paced endurance performance have not been determined. The aim of this study was to compare the effects of 0%, 2%, and 4% inspired CO2 on 2-mile run performance, as well as physiological and perceptual responses during time trial exercise. Twelve physically active volunteers (peak oxygen uptake = 49 ± 5 mL·kg-1·min-1; 3 women) performed three experimental trials in a randomized, single-blind, crossover manner, breathing 21% oxygen with either 0%, 2%, or 4% CO2. During each trial, participants completed 10 min of walking at ∼40% peak oxygen uptake followed by a self-paced 2-mile treadmill time trial. One participant was unable to complete the 4% CO2 trial due to lightheadedness during the run. Compared with the 0% CO2 trial, run performance was 5 ± 3% and 7 ± 3% slower in the 2% and 4% CO2 trials, respectively (both P < 0.001). Run performance was significantly slower with 4% versus 2% CO2 (P = 0.046). The dose-dependent performance impairments were accompanied by stepwise increases in mean ventilation, despite significant reductions in running speed. Dyspnea and headache were significantly elevated during the 4% CO2 trial compared with both the 0% and 2% trials. Overall, our findings show that graded increases in inspired CO2 impair endurance performance in a stepwise manner in healthy humans.

Integrative cardiovascular control in women: Regulation of blood pressure, body temperature, and cerebrovascular responsiveness.

Over the past several decades, it has become increasingly clear that women have distinct cardiovascular profiles compared to men. In this review, our goal is to provide an overview of the literature regarding the influences of female sex and reproductive hormones (primarily estradiol) on mechanisms of cardiovascular control relevant to regulation of blood pressure, body temperature, and cerebral blood flow. Young women tend to have lower resting blood pressure compared with men. This sex difference is reversed at menopause, when women develop higher sympathetic nerve activity and the risk of systemic hypertension increases sharply as postmenopausal women age. Vascular responses to thermal stress, including cutaneous vasodilation and vasoconstriction, are also affected by reproductive hormones in women, where estradiol appears to promote vasodilation and heat dissipation. The influence of reproductive hormones on cerebral blood flow and sex differences in the ability of the cerebral vasculature to increase its blood flow (cerebrovascular reactivity) are relatively new areas of investigation. Sex and hormonal influences on integrative blood flow regulation have further implications during challenges to physiological homeostasis, including exercise. We propose that increasing awareness of these sex-specific mechanisms is important for optimizing health care and promotion of wellness in women across the life span.

Are there sex differences in risk for exertional heat stroke? A translational approach.

NEW FINDINGS: What is the topic of this review? Whether there are sex differences in exertional heat stroke. What advances does it highlight? This review utilizes a translational model between animal and human research to explore possible physical and physiological differences with respect to risk and treatment of exertional heat stroke. ABSTRACT: Exertional heat stroke (EHS) is a potentially fatal condition brought about by a combination of physical activity and heat stress and resulting in central nervous system dysfunction and organ damage. EHS impacts several hundred individuals each year ranging from military personnel, athletes, to occupational workers. Understanding the pathophysiology and risk factors can aid in reducing EHS across the globe. While we know there are differences between sexes in mechanisms of thermoregulation, there is currently not a clear understanding of if or how those differences impact EHS risk. The purpose of this review is to assess the current status of the literature surrounding EHS from risk factors to treatment using both animal and human models. We use a translational approach, considering both animal and human research to elucidate the possible influence of female sex hormones on temperature regulation and performance in the heat and highlight the specific areas with limited research. While more work is necessary to comprehensively understand these differences, the current research presented provides a good framework for future investigations.

Individual variability in achievement of short-term heat acclimation during a fixed intensity protocol.

INTRODUCTION: Heat acclimation (HA) occurs with ∼8-10d of repeated heat exposure; however, adaptations can occur earlier (<7d; termed short-term heat acclimation; STHA). PURPOSE: To test the hypothesis that some, but not all, young healthy men would achieve STHA after 5d of a standard HA protocol. METHODS: We conducted a novel, post-hoc analysis of data from 13 healthy men (21 ± 3 yrs; 173 ± 8 cm; 75.1 ± 12.2 kg) who participated in an 8d HA protocol (120 min treadmill walking: 5 km h-1, 2% grade; 40 °C, 40% relative humidity). Core temperature (Tc), heart rate (HR), and whole body sweating rate (SR) were compared across 1d, 5d, and 8d of HA. Criteria for HA were delta (Δ)Tc ≤ 0.9 °C and ΔHR≤33 beats·min-1. RESULTS: Group averages on 1d, 5d, and 8d of HA for end exercise Tc (38.1 ± 0.34; 37.9 ± 0.3; 37.8 ± 0.3 °C) and HR (134 ± 17; 122 ± 13; 121 ± 13 beats·min-1) were decreased by 5d (p < 0.05) and did not decrease further by 8d. ΔTc (1.1 ± 0.36; 0.95 ± 0.45; 0.95 ± 0.33 °C) and ΔHR (36 ± 18; 33 ± 17; 33 ± 15 beats·min-1) showed similar patterns (p > 0.05). At 5d, 31% (4/13) of the volunteers achieved HA; the remaining 9 volunteers had further adaptations between 5d and 8d. SR was not different across 1d, 5d, and 8d (860 ± 148; 908 ± 210; 873 ± 203 mL h-1 respectively; p > 0.05). CONCLUSION: Our results suggest that during a fixed-intensity HA protocol in young men, using criteria of changes in Tc and HR, ∼1/3 achieve STHA. Future research should evaluate potential mechanisms, and whether similar inter-individual variability occurs in women.

Neural control of cardiovascular function in black adults: implications for racial differences in autonomic regulation.

Black adults are at increased risk for developing hypertension and cardiovascular and chronic kidney disease and have greater associated morbidity/mortality than white adults who are otherwise demographically similar. Despite the key role of the autonomic nervous system in the regulation of cardiovascular function, the mechanistic contributions of sympathetic nerves to racial differences in cardiovascular dysfunction and disease remain poorly understood. In this review, we present an update and synthesis of current understanding regarding the roles of autonomic neural mechanisms in normal and pathophysiological cardiovascular control in black and white adults. At rest, many hemodynamic and autonomic variables, including blood pressure, cardiac output, and sympathetic nerve activity, are similar in healthy black and white adults. However, resting sympathetic vascular transduction and carotid baroreflex responses are altered in ways that tend to promote increased vasoconstriction and higher blood pressure, even in healthy, normotensive black adults. Acute sympathoexcitatory maneuvers, including exercise and cold pressor test, often result in augmented sympathetic and hemodynamic responses in healthy black adults. Clinically, although mechanistic evidence is scarce in this area, existing data support the idea that excessive sympathetic activation and/or transduction into peripheral vasoconstriction contribute importantly to the pathophysiology of hypertension and chronic kidney disease in black compared with white adults. Important areas for future work include more detailed study of sympathetic and hemodynamic reactivity to exercise and other stressors in male and female black adults and, particularly, sympathetic control of renal function, an important area of clinical concern in black patients.

Effects of sex and menstrual cycle on volume-regulatory responses to 24-h fluid restriction.

Reproductive hormones have significant nonreproductive physiological effects, including altering fluid regulation. Our purpose was to explore the impact of sex and menstrual cycle (MC) phase on volume-regulatory responses to 24-h fluid restriction (24-h FR). Participants (men: n = 12, 20 ± 2 yr; women: n = 10, 20 ± 1 yr) were assigned two randomized and counterbalanced fluid prescriptions [Euhy: euhydrated, urine specific gravity (USG) < 1.020; Dehy: 24-h FR, USG > 1.020]. Men completed both (MEuhy, MDehy), while women completed both in the late-follicular (days 10-13; FDehy, FEuhy) and midluteal (days 18-22; LDehy, LEuhy) phases. We measured body mass, plasma and urine osmolality (Posm, Uosm), urine specific gravity (USG), urine color (Ucol), and serum copeptin; 24-h FR yielded mild dehydration without influence of sex or MC (P > 0.05). Copeptin increased in men following Dehy (pre: 8.2 ± 5.2, post: 15.8 ± 12.6, P = 0.04) but not in women (FDehy pre: 4.3 ± 1.6, post: 10.5 ± 6.9, P = 0.06; LDehy pre: 5.6 ± 3.5, post: 10.4 ± 6.2, P = 0.16). In FDehy, Posm increased following FR (pre: 288 ± 2, post: 292 ± 1, P = 0.03) but not in men (pre: 292 ± 3, post: 293 ± 2, P = 0.46). No MC differences were observed between body mass loss, Posm, Uosm, USG, and copeptin (P > 0.05). These results suggest that volume-regulatory responses to 24-h FR were present in men but not in women, without apparent effects of the menstrual cycle.

Effect of 8 days of exercise-heat acclimation on aerobic exercise performance of men in hypobaric hypoxia.

Exercise-heat acclimation (EHA) induces adaptations that improve tolerance to heat exposure. Whether adaptations from EHA can also alter responses to hypobaric hypoxia (HH) conditions remains unclear. This study assessed whether EHA can alter time-trial performance and/or incidence of acute mountain sickness (AMS) during HH exposure. Thirteen sea-level (SL) resident men [SL peak oxygen consumption (V̇o2peak) 3.19 ± 0.43 L/min] completed steady-state exercise, followed by a 15-min cycle time trial and assessment of AMS before (HH1; 3,500 m) and after (HH2) an 8-day EHA protocol [120 min; 5 km/h; 2% incline; 40°C and 40% relative humidity (RH)]. EHA induced lower heart rate (HR) and core temperature and plasma volume expansion. Time-trial performance was not different between HH1 and HH2 after 2 h (106.3 ± 23.8 vs. 101.4 ± 23.0 kJ, P = 0.71) or 24 h (107.3 ± 23.4 vs. 106.3 ± 20.8 kJ, P > 0.9). From HH1 to HH2, HR and oxygen saturation, at the end of steady-state exercise and time-trial tests at 2 h and 24 h, were not different (P > 0.05). Three of 13 volunteers developed AMS during HH1 but not during HH2, whereas a fourth volunteer only developed AMS during HH2. Heat shock protein 70 was not different from HH1 to HH2 at SL [1.9 ± 0.7 vs. 1.8 ± 0.6 normalized integrated intensities (NII), P = 0.97] or after 23 h (1.8 ± 0.4 vs. 1.7 ± 0.5 NII, P = 0.78) at HH. Our results indicate that this EHA protocol had little to no effect-neither beneficial nor detrimental-on exercise performance in HH. EHA may reduce AMS in those who initially developed AMS; however, studies at higher elevations, having higher incidence rates, are needed to confirm our findings.

Influences of hypobaric hypoxia on skin blood flow and sweating responses during exercise in neutral and hot environments.

Exposure to hot environments augments cutaneous vasodilation and sweating during exercise compared with these responses in cooler environments. The effects of hypobaric hypoxia on these responses are less clear, as are the effects of heat and simulated altitude combined. We evaluated the individual and potential additive effects of environmental heat and hypobaric hypoxia on skin blood flow and sweating responses during exercise. Thirteen volunteers (11 M, 2 F; age 25.3 ± 6.1 yr; height 177 ± 9 cm; weight 81.2 ± 16.8 kg) completed 30 min of steady-state (SS) exercise on a cycle ergometer at 50% V̇o2peak during four separate conditions: 1) sea level thermoneutral (SLTN; 250 m, 20°C, 30-50% RH), 2) sea level hot (SLH; 250 m, 35°C, 30% RH), 3) simulated altitude thermoneutral (ATN; 3,000 m, 20°C, 30-50% RH), and 4) simulated altitude hot (AH; 3,000 m, 35°C, 30% RH). Skin blood flow and local sweating rate (LSR) were recorded on the ventral forearm. During exercise, SS cutaneous vascular conductance in AH (63 ± 31% peak) and SLH (52 ± 19% peak) were significantly higher than both SLTN (20 ± 9% peak, P < 0.001) and ATN (25 ± 12% peak, P < 0.05) but were not different from each other (P > 0.05). SS LSR was similarly increased in the hot environments but unaffected by simulated altitude. We propose that multiple antagonistic mechanisms during exposure to 3,000-m simulated altitude result in no net effect on skin blood flow or sweating responses during exercise in thermoneutral or hot environments.

Cold-induced cutaneous vasoconstriction in humans: Function, dysfunction and the distinctly counterproductive.

NEW FINDINGS: What is the topic of this review? This review presents an update and synthesis of normal mechanisms of human cutaneous vasoconstriction in response to cold stress. It then discusses conditions in which cutaneous vasoconstrictor responses are excessive or insufficient and cases in which cold-induced vasoconstrictor responses become counter to maintaining thermal and haemodynamic homeostasis. What advances does it highlight? The review highlights our current understanding of the mechanisms that mediate alterations in cold-induced cutaneous vasoconstriction in pathology and environmental extremes, which has important clinical implications for preventing cold- and cardiovascular-related deaths. ABSTRACT: In humans, cold-induced peripheral vasoconstriction is an essential element of body temperature regulation. Given that the thermoregulatory system responds rapidly to changes in skin temperature, sympathetically mediated cutaneous vasoconstriction represents a crucial 'first line of defense' against excessive reduction in body temperature. Sympathetic noradrenergic vasoconstrictor nerves cause a rapid decrease in skin blood flow, thus increasing the insulative capacity of the skin and decreasing heat loss from the body. Small changes in the activity of these nerves are also responsible for the subtle changes in skin blood flow that occur with normal daily activities or minor changes in environmental temperature. With ageing, hypertension and other conditions, the cutaneous reflex vasoconstrictor response can become excessive or insufficient. Healthy older adults have impaired reflex vasoconstriction, which may result in an impaired ability to defend body temperature in some circumstances. Hypertension is associated with augmented vasoconstriction, which could have pathological implications for left ventricular afterload in individuals already at risk for cardiovascular events. Finally, in some cases, the reflex vasoconstrictor response becomes distinctly counterproductive to its own goals of maintaining cardiovascular and thermoregulatory homeostasis. Examples include Raynaud's phenomenon, in which exaggerated vasoconstriction can produce ischaemia in the periphery, and the cutaneous vasoconstrictor response to therapeutic body cooling in severe hyperthermia, which can limit the heat exchange necessary to prevent serious heat illness.

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.

Sympathetic neural and hemodynamic responses to head-up tilt during isoosmotic and hyperosmotic hypovolemia.

We hypothesized that muscle sympathetic nerve activity (MSNA) during head-up tilt (HUT) would be augmented during exercise-induced (hyperosmotic) dehydration but not isoosmotic dehydration via an oral diuretic. We studied 26 young healthy subjects (7 female, 19 male) divided into three groups: euhydrated (EUH, n = 7), previously exercised in 40°C while maintaining hydration; dehydrated (DEH, n = 10), previously exercised in 40°C during which ~3% of body weight was lost via sweat loss; and diuretic (DIUR, n = 9), a group that did not exercise but lost ~3% of body weight via diuresis (furosemide, 80 mg by mouth). We measured MSNA, heart rate (HR), and blood pressure (BP) during supine rest and 30° and 45° HUT. Plasma volume (PV) decreased similarly in DEH (-8.5 ± 3.3%) and DIUR (-11.4 ± 5.7%) (P > 0.05). Plasma osmolality was similar between DIUR and EUH (288 ± 4 vs. 284 ± 5 mmol/kg, respectively) but was significantly higher in DEH (299 ± 5 mmol/kg) (P < 0.05). Mixed-model ANOVA was used with repeated measures on position (HUT) and between-group analysis on condition. HR and MSNA increased in all subjects during HUT (main effect of position; P < 0.05). There was also a significant main effect of group, such that MSNA and HR were higher in DEH compared with DIUR (P < 0.05). Changes in HR with HUT were larger in both hypovolemic groups compared with EUH (P < 0.05). The differential HUT response "strategies" in each group suggest a greater role for hypovolemia per se in controlling HR responses during dehydration, and a stronger role for osmolality in control of SNA.NEW & NOTEWORTHY Interactions of volume regulation with control of vascular sympathetic nerve activity (SNA) have important implications for blood pressure regulation. Here, we demonstrate that SNA and heart rate (HR) during hyperosmotic hypovolemia (exercise-induced) were augmented during supine and tilt compared with isoosmotic hypovolemia (diuretic), which primarily augmented the HR response. Our data suggest that hypovolemia per se had a larger role in controlling HR responses, whereas osmolality had a stronger role in control of SNA.