Interactions between sympathetic baroreflex sensitivity and vascular transduction in males and females

The control of muscle sympathetic nerve activity (MSNA) via the baroreflex is an important mechanism of blood pressure control. Spontaneous sympathetic baroreflex sensitivity (BRS) is a tool used to examine how well the baroreflex buffers beat-to-beat changes in arterial pressure. Due to the lack of research around the baroreflex control of MSNA, it is unknown if an individual's sympathetic BRS reflects the end organ response and thus is indicative of how effective they are at regulating their blood pressure. It was hypothesised that poor baroreflex sensitivity was compensated for by enhanced vascular transduction, and vice versa. Given that sex differences are known to exist in regulatory mechanisms involved in cardiovascular control, these interactions were explored and contrasted in young males and females. In order to further our understanding of the regulatory mechanism of the sympathetic baroreflex, MSNA, blood pressure and superficial femoral artery (SFA) blood flow were measured to i) examine the stability and repeatability of measures of spontaneous sympathetic BRS, ii) examine whether vascular transduction, quantified on a beat-to-beat basis using two different approaches, were different between males and females, iii) examine the relationship between sympathetic BRS and vascular transduction, and iv) examine sympathetic BRS and vascular transduction during physiological stressors that drive increases in MSNA. Here I present evidence of sex differences in sympathetic baroreflex function in healthy young adults. Spontaneous sympathetic BRS was moderately stable in the same recording period and also when examined on different days. Recording periods of at least 5 min should be used when quantifying BRS as shorter durations can overestimate BRS values. Using the Fairfax method, sympathetic vascular transduction was significantly lower in males when compared with females. In contrast, the Briant method did not reveal sex differences in vascular transduction between males and females. Sympathetic BRS and vascular transduction was negatively correlated under resting conditions. This means that individuals with high sympathetic BRS have less effective vascular transduction during spontaneous changes in blood pressure. However, this was only apparent in young males; there was no relationship observed in females. Furthermore, resting MSNA did not predict sympathetic BRS or vascular transduction in either males or females. Finally, vascular transduction was significantly greater in males when quantified as the relationship between MSNA and leg vascular conductance during isometric handgrip and the cold pressor test. Sympathetic BRS was not different between males and females during the cold pressor test but was reset to a higher blood pressure range. Collectively, the studies conducted in this thesis provide insight into the dynamic nature of the baroreflex control of arterial pressure at rest, and during increases in muscle vasoconstrictor drive. Whilst this thesis provides evidence of sex differences in sympathetic BRS and vascular transduction, it also highlights the differences between the various approaches available for quantifying vascular transduction. The method chosen can have a profound effect on the findings regarding sex differences and the interaction vascular transduction has with sympathetic BRS

Sympathetic and hemodynamic responses to exercise in heart failure with preserved ejection fraction

Excessive sympathetic activity during exercise causes heightened peripheral vasoconstriction, which can reduce oxygen delivery to active muscles, resulting in exercise intolerance. Although both patients suffering from heart failure with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively) exhibit reduced exercise capacity, accumulating evidence suggests that the underlying pathophysiology may be different between these two conditions. Unlike HFrEF, which is characterized by cardiac dysfunction with lower peak oxygen uptake, exercise intolerance in HFpEF appears to be predominantly attributed to peripheral limitations involving inadequate vasoconstriction rather than cardiac limitations. However, the relationship between systemic hemodynamics and the sympathetic neural response during exercise in HFpEF is less clear. This mini review summarizes the current knowledge on the sympathetic (i.e., muscle sympathetic nerve activity, plasma norepinephrine concentration) and hemodynamic (i.e., blood pressure, limb blood flow) responses to dynamic and static exercise in HFpEF compared to HFrEF, as well as non-HF controls. We also discuss the potential of a relationship between sympathetic over-activation and vasoconstriction leading to exercise intolerance in HFpEF. The limited body of literature indicates that higher peripheral vascular resistance, perhaps secondary to excessive sympathetically mediated vasoconstrictor discharge compared to non-HF and HFrEF, drives exercise in HFpEF. Excessive vasoconstriction also may primarily account for over elevations in blood pressure and concomitant limitations in skeletal muscle blood flow during dynamic exercise, resulting in exercise intolerance. Conversely, during static exercise, HFpEF exhibit relatively normal sympathetic neural reactivity compared to non-HF, suggesting that other mechanisms beyond sympathetic vasoconstriction dictate exercise intolerance in HFpEF

Sex differences in vascular transduction of sympathetic nerve activity

Purpose: Sympathetic vasoconstriction plays a major role in the beat-to-beat control of blood pressure. To be effective and thus avoid dangerously high or low blood pressures, this mechanism relies upon transduction of sympathetic nerve activity at the level of the vasculature. However, recent evidence suggests that considerable variability exists in beat-to-beat vascular transduction, particularly between the sexes. Methods: We reviewed the methods available for quantifying beat-to-beat transduction of muscle sympathetic nerve activity (MSNA) and explored the recent evidence for sex differences in vascular transduction. We paid specific attention to relationships between vascular transduction and factors such as resting levels of sympathetic nerve activity and baroreflex sensitivity. Results: There are two dominant methods now available for the quantification of beat-to-beat transduction of muscle sympathetic nerve activity at rest. Whilst there is some evidence to suggest that young females exhibit lower levels of vascular transduction, results vary depending on the method used and the direction of change in MSNA. Evidence suggests that compensatory relationships may exist between key components of neurovascular control, such as vascular transduction and resting levels of MSNA. Also consistent is the presence of such relationships in young males but not young females. Conclusion: The lack of significant relationships in young females may reflect the influence of vasodilator mechanisms that counteract sympathetic vasoconstriction. The assessment of vascular transduction following MSNA bursts and non-bursts in males and females, both young and older, may help to gain a mechanistic understanding of the prevalence of hypotensive and hypertensive disorders across the lifespan

Sympathetic baroreflex sensitivity is inversely related to vascular transduction in men but not women

Sympathetic baroreflex sensitivity (BRS) is a measure of how effectively the baroreflex buffers beat-to-beat changes in blood pressure through the modulation of muscle sympathetic nerve activity (MSNA). However, current methods of assessment do not take into account the transduction of sympathetic nerve activity at the level of the vasculature, which is known to vary between individuals. In this study we tested the hypothesis that there is an inverse relationship between sympathetic BRS and vascular transduction. In 38 (18 men) healthy adults, continuous measurements of blood pressure, MSNA and superficial femoral artery diameter and blood flow (Doppler ultrasound) were recorded during 10 min of rest. Spontaneous sympathetic BRS was quantified as the relationship between diastolic pressure and MSNA burst incidence. Vascular transduction was quantified by plotting the changes in leg vascular conductance for 10 cardiac cycles following each burst of MSNA, and taking the nadir. In men, sympathetic BRS was inversely related to vascular transduction (r= -0.49; P = 0.04). However, this relationship was not present in women (r= -0.17; P = 0.47). To conclude, an interaction exists between sympathetic BRS and vascular transduction in healthy men, such that men with high sympathetic BRS have low vascular transduction and vice versa. This may be to ensure that blood pressure is regulated effectively, although further research is needed to explore what mechanisms are involved and examine why this relationship was not apparent in women

The Stability and Repeatability of Spontaneous Sympathetic Baroreflex Sensitivity in Healthy Young Individuals

Spontaneous sympathetic baroreflex sensitivity (BRS) is a valuable tool for assessing how well the baroreflex buffers beat-to-beat changes in blood pressure. However, there has yet to be a study involving appropriate statistical tests to examine the stability of sympathetic BRS within an experimental session and the repeatability between separate sessions. The aim of this study was to use intra-class correlations, ordinary least products regression, and Bland–Altman analyses to examine the stability and repeatability of spontaneous sympathetic BRS assessment. In addition, the influence of recording duration on values of BRS was assessed. In eighty-four healthy young individuals (49 males, 35 females), continuous measurements of blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) were recorded for 10 min. In a subgroup of 13 participants (11 male, 2 female) the measurements were repeated on a separate day. Sympathetic BRS was quantified using MSNA burst incidence (BRS inc) and total MSNA (BRS total) for the first 5-min period, the second 5-min period, and a 2-min segment taken from the second 5-min period. Intra-class correlation coefficients indicated moderate stability in sympathetic BRS inc and BRS total between the first and second 5-min periods in males (BRS inc r = 0.63, BRS total r = 0.78) and females (BRS inc r = 0.61, BRS total r = 0.47) with no proportional bias, but with fixed bias for BRS inc in females. When comparing the first 5-min with the 2-min period (n = 76), the intra-class correlation coefficient indicated poor to moderate repeatability in sympathetic BRS inc and BRS total for males (BRS inc r = −0.01, BRS total r = 0.70) and females (BRS inc r = 0.46, BRS total r = 0.39). However, Bland–Altman analysis revealed a fixed bias for BRS total in males and proportional bias for BRS total in females, with lower BRS values for 5-min recordings. In the subgroup, intra-class correlations indicated moderate repeatability for measures of BRS inc (9 male, 2 female, r = 0.63) and BRS total (6 male, 2 female, r = 0.68) assessed using 5-min periods recorded on separate days. However, Bland–Altman analysis indicated proportional bias for BRS inc and fixed bias for BRS total. In conclusion, measures of spontaneous sympathetic BRS are moderately stable and repeatable within and between testing sessions in healthy young adults, provided that the same length of recording is used when making comparisons

Baroreflex modulation of muscle sympathetic nerve activity at rest does not differ between morning and afternoon

The incidence of cardiovascular events is significantly higher in the morning than other times of day. This has previously been associated with poor blood pressure control via the cardiac baroreflex. However, it is not known whether diurnal variation exists in vascular sympathetic baroreflex function, in which blood pressure is regulated via muscle sympathetic nerve activity (MSNA). The aim of this study was to compare vascular sympathetic baroreflex sensitivity (BRS) in the same participants between the morning and afternoon. In 10 participants (mean age 22 ± 2.9 yrs), continuous measurements of blood pressure, heart rate and MSNA were made during 10 minutes of rest in the morning (between 9:00 and 10:00am) and afternoon (between 2:00 and 3:00pm). Spontaneous vascular sympathetic BRS was quantified by plotting MSNA burst incidence against diastolic pressure (vascular sympathetic BRSinc), and by plotting total MSNA against diastolic pressure (vascular sympathetic BRStotal). Significant vascular sympathetic BRSinc and vascular sympathetic BRStotal slopes were obtained for 10 participants at both times of day. There was no significant difference in vascular sympathetic BRSinc between morning (-2.2 ± 0.6 %bursts/mmHg) and afternoon (-2.5 ± 0.2 %bursts/mmHg; P=0.68) sessions. Similarly, vascular sympathetic BRStotal did not differ significantly between the morning (-3.0 ± 0.5 AU/beat/mmHg) and afternoon (-2.9 ± 0.4 AU/beat/mmHg; P=0.89). It is concluded that in healthy, young individuals baroreflex modulation of MSNA at rest does not differ between the morning and afternoon. The results indicate that recording MSNA at different times of the day is a valid means of assessing sympathetic function

Blood pressure reactivity at onset of mental stress determines sympathetic vascular response in young adults

We have previously shown in young males that the rate of rise in blood pressure (BP) at the onset of mental stress determines whether or not muscle sympathetic nerve activity (MSNA) has a role in driving the pressor response. The aim of this study was to investigate these interactions in young females. BP and MSNA were recorded continuously in 19 females and 21 males during 2‐min mental stressors (mental arithmetic and Stroop test). Physical stressor tasks (cold pressor, handgrip exercise, postexercise ischemia) were also performed. During the first minute of mental arithmetic, the rate of rise in mean arterial pressure (MAP) was significantly greater in negative responders (mean decrease in MSNA) compared with positive responders (mean increase in MSNA) in both males (1.9 ± 0.7 vs. 0.7 ± 0.3 mmHg/sec) and females (1.0 ± 0.3 vs. 0.5 ± 0.2 mmHg/sec). For the Stroop test, there was no significant difference in the rate of the rise in BP between positive and negative responders (P > 0.05). However, peak changes in MAP were significantly greater in negative responders compared with positive responders in both males (22 ± 6 vs. 13 ± 3 mmHg) and females (12 ± 2 vs. 6 ± 1 mmHg). Sympathetic baroreflex sensitivity was greater in negative responders and may contribute to the fall in MSNA experienced by these individuals during mental stress. During physical stressors there were consistent increases in BP and MSNA in males and females. The findings suggest that, in both males and females, BP reactivity at the onset of mental stress dictates whether or not there is an increase or decrease in MSNA

Rate of rise in diastolic blood pressure influences vascular sympathetic response to mental stress

Research indicates that individuals may experience a rise (positive responders) or fall (negative responders) in muscle sympathetic nerve activity (MSNA) during mental stress. The aim was to examine the early blood pressure response to stress in positive and negative responders and thus its influence on the direction of change in MSNA. Blood pressure and MSNA were recorded continuously in 21 healthy young males during 2 min mental stressors (mental arithmetic, Stroop test) and physical stressors (cold pressor, handgrip exercise, post-exercise ischaemia). Participants were classified as negative or positive responders according to the direction of the mean change in MSNA during the stressor tasks. The peak changes, time of peak and rate of changes in blood pressure were compared between groups. During mental arithmetic negative responders experienced a significantly greater rate of rise in diastolic blood pressure in the first minute of the task (1.3 ± 0.5 mmHg s−1) compared with positive responders (0.4 ± 0.1 mmHg s−1; P = 0.03). Similar results were found for the Stroop test. Physical tasks elicited robust parallel increases in blood pressure and MSNA across participants. It is concluded that negative MSNA responders to mental stress exhibit a more rapid rise in diastolic pressure at the onset of the stressor, suggesting a baroreflex-mediated suppression of MSNA. In positive responders there is a more sluggish rise in blood pressure during mental stress, which appears to be MSNA-driven. This study suggests that whether MSNA has a role in the pressor response is dependent upon the reactivity of blood pressure early in the task

Muscle sympathetic nerve activity peaks in the first trimester in healthy pregnancy : a longitudinal case study

Objective and methods Muscle sympathetic nerve activity and baroreflex sensitivity were examined at rest before, during (weeks 6, 11, 17, 22, 25, 33 and 36) and after a normotensive pregnancy. Results Muscle sympathetic nerve activity is elevated during pregnancy with a large peak in the first trimester (∆17 bursts/min) and a secondary peak in the third trimester (∆11 bursts/min). Cardiac baroreflex sensitivity peaked in the first trimester (10 vs. 6 ms/mmHg pre-pregnancy), whereas sympathetic baroreflex sensitivity was greater throughout. Interpretation The increase in sympathetic outflow early in pregnancy cannot be explained by a reduction in baroreflex sensitivity, while the secondary increase in burst frequency in the third trimester may, in part, be explained by the elevated heart rate

Magnitude of the Morning Surge in Blood Pressure is Associated with Sympathetic but not Cardiac Baroreflex Sensitivity

The ability of the arterial baroreflex to regulate blood pressure may influence the magnitude of the morning surge in blood pressure. The aim was to investigate the relationships between sympathetic and cardiac baroreflex sensitivity (BRS) and the morning surge. Twenty-four hour ambulatory blood pressure was recorded in 14 young individuals. The morning surge was defined via the pre-awakening method, which is calculated as the difference between mean blood pressure values two hours before and two hours after rising from sleep. The mean systolic morning surge, diastolic morning surge and morning surge in mean arterial pressures were 15 ± 2 mmHg, 13 ± 1 mmHg and 11 ± 1 mmHg respectively. During the laboratory protocol, continuous measurements of blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) were made over a 10-min period of rest. Sympathetic BRS was quantified by plotting MSNA burst incidence against diastolic pressure (sympathetic BRSinc), and by plotting total MSNA against diastolic pressure (sympathetic BRStotal). Cardiac BRS was quantified using the sequence method. The mean values for sympathetic BRSinc, sympathetic BRStotal and cardiac BRS were -1.26 ± 0.26 bursts/100hb/mmHg, -1.60 ± 0.37 AU/beat/mmHg and 13.1 ± 1.5 ms/mmHg respectively. Significant relationships were identified between sympathetic BRSinc and the diastolic morning surge (r =0.62, p =0.02) and the morning surge in mean arterial pressure (r =0.57, p =0.03). Low sympathetic BRS was associated with a larger morning surge in mean arterial and diastolic blood pressure. Trends for relationships were identified between sympathetic BRStotal and the diastolic morning surge (r =0.52, p =0.066) and the morning surge in mean arterial pressure (r =0.48, p =0.095) but these did not reach significance. There were no significant relationships between cardiac BRS and the morning surge. These findings indicate that the ability of the baroreflex to buffer increases in blood pressure via reflexive changes in MSNA may play a role in determining the magnitude of the morning surge in blood pressure