Bursting our understanding of baroreflex control in older adults: Sex differences in the neurovascular mechanisms regulating blood pressure

The arterial baroreflex is a vital homeostatic mechanism involved in regulating blood pressure (BP). When disequilibrium is detected, stretch-sensitive baroreceptors provide afferent feedback to stabilise BP through modulating heart rate and muscle sympathetic nervous activity (MSNA). The magnitude of the sympathetic response to changes in BP is termed the BP buffering capacity and is measured as baroreflex sensitivity (BRS). With age, this buffering capacity deteriorates, and risks of hypertension and cardiovascular disease concomitantly increase. Nevertheless, this age-related deterioration is complex and multifactorial. Subpopulations of baroreceptor afferents range in sensitivity and display divergent excitation thresholds to different BP stimuli. Therefore, baroreflex-mediated sympathetic responses are thought to be independently modulated and vary with age. Furthermore, distinct sex differences appear to exist in the neurovascular mechanisms that regulate BP in older adults. Okada et al. (2011) reported increased arterial stiffness and lower BRS, using burst occurrence, in older women compared with older men. This increased arterial stiffness was inversely correlated with BRS across both sexes, suggesting that with age increased arterial stiffness impairs the pressure-sensing ability of the baroreceptors. Nonetheless, integrated sympathetic BRS has been described as comparable between older men and women (Studinger et al. 2009). This discrepancy may be explained by the difference in the mean age of participants in these two studies. However, this finding also hints at the possibility of compensatory neural modules which recoup the impaired response of MSNA burst occurrence in women. Two neural modules have been suggested to regulate the occurrence and area of MSNA bursts separately (Kienbaum et al. 2001). Therefore, it is possible that when burst occurrence regulation is impaired, burst area regulation becomes the dominant BP buffering system. However, until recently, research into these compensatory mechanisms has been lacking. In a recent issue of the Journal of Physiology, Okada et al. (2020) investigated sex differences in the mechanisms regulating resting BP in older adults. In 61 healthy males and females (68 ± 7 years), peroneal MSNA was assessed via microneurography during supine rest. The distributions of MSNA burst area and intervals were evaluated and BRS was analysed using burst occurrence and area simultaneously. These values were then compared with changes in arterial stiffness and BP. Carotid β-stiffness was derived using B-mode ultrasonography, whilst BP was assessed using finger photoplethysmography and electrosphygmomanometry. Additionally, heart rate and cardiac output were measured using electrocardiography and the modified acetylene rebreathing technique. The researchers hypothesised that the ratio of variation in MSNA burst area to burst occurrence would be greater in older women than in older men. They also postulated that increased arterial stiffness would correlate with BRS calculated using burst area in an opposite direction to BRS calculated using burst occurrence. Overall, Okada et al. (2020) found that BP variability was similar among older men and women. However, the mechanisms regulating this variability were different. Women demonstrated increased arterial stiffness compared with men and a lower range of MSNA burst intervals. The distribution of burst area was comparable across the sexes, but the ratio in variation of burst area to burst occurrence was larger in women. These results suggested that MSNA burst occurrence in women was impaired and that it was compensated for by increased regulation of burst area. These findings were subsequently confirmed by an analysis of BRS. When assessed using burst occurrence, BRS overall was lower in women but it decreased equally with arterial stiffness in both sexes. Meanwhile, BRS assessed using burst area was only lower in women after adjusting for arterial stiffness, and it increased in women but not in men as arterial stiffness increased. These results indicate that MSNA burst size becomes more adaptable to changes in BP in women to compensate for the impaired regulation of burst occurrence. This compensatory mechanism is adequate enough that BP is regulated to the same extent in older women as it is in older men. Okada et al. (2020) present a well-executed study with robust methodologies, enabling the sex differences in the baroreflex control of BP in older adults to be explored. The study was the first to compare BRS using burst occurrence and area simultaneously. Therefore, it contributes novel findings which advance the current field of arterial baroreflex research. The results support the concept of two distinct neural mechanisms underpinning the regulation of MSNA burst occurrence and burst area separately, thus highlighting the importance of evaluating both in clinical and research settings. Additionally, the findings help resolve discrepancies in previous literature where BRS was assessed using either burst occurrence or burst area separately (Studinger et al. 2009; Okada et al. 2011). Nevertheless, pioneering work like this often raises a plethora of questions and challenges, and these novel findings merit further discussion with regard to: sex differences in the prevalence of hypertension, the mechanisms responsible for detecting impaired burst occurrence, age differences in burst area regulation and the clinical implications. Although some useful insights into the sex differences in BP regulation in older adults can be gained from this study, a conundrum that pertains is why hypertension is more prevalent in elderly women than elderly men. Okada and colleagues demonstrated that there are compensatory neural mechanisms which allow older women to regulate BP to the same extent as men. Yet, large epidemiological studies show that hypertension is more prevalent in older women than older men and that there are even forms of hypertension which occur exclusively in women. If burst area regulation becomes the dominant BP buffering system when burst occurrence regulation is impaired, then prevalence levels should be equivalent among both sexes. However, evidence suggests that this is not the case. This study alone cannot fully explain the sex differences in the prevalence of hypertension, and thus further understanding is needed into the mechanisms regulating BP in older adults. Specifically, one mechanism that remains unclear is how burst area becomes the dominant BP buffering system when burst occurrence regulation is impaired. In humans, carotid resectioning induces a rise in MSNA and BP. This rise in sympathetic activity returns to baseline even with consistently low levels of BRS (Timmers et al. 2003). The ability of MSNA and BP to return to baseline without increasing the BRS suggests that the baroreflex is not the only mechanism involved. It is likely that there are other receptors and factors involved which detect the impaired MSNA burst occurrence response and subsequently activate the system responsible for regulating burst area. This pathway needs to be further explored to help explain why hypertension is more prevalent in older women. Particularly, biochemical analyses are needed to identify the factors and signalling molecules that comprise these responses and to examine how these molecules interact with the baroreflex response. Moreover, it remains poorly understood how burst area is regulated. Okada et al. (2020) offer some enlightenment on this. They demonstrated that burst interval affects burst area less than burst occurrence. This suggests that the timing of baroreceptor input may regulate burst occurrence, whilst the strength of input may regulate burst area. However, in younger cohorts, increases in baroreceptor loading appear to have stronger effects on burst occurrence than burst area. This suggests that the regulation of burst area and occurrence varies across age groups. The complex interactions between age, sex and the regulation of MSNA bursts need to be examined further by future research. Direct comparisons of older and younger populations may therefore be useful to fully understand the mechanisms regulating MSNA burst area and occurrence in older adults. Finally, it would be of great value to observe how MSNA burst occurrence and area regulation differ in hypertensive and non-hypertensive populations. This would provide greater insights into the neural mechanisms regulating BP in older adults and help to explain why hypertension is more prevalent in older women than men. Okada et al.’s research offers some insights into these sex differences but further research in clinical populations may be needed to fully understand the mechanisms involved. This research would hopefully lead to more targeted treatments for hypertension and its related cardiovascular morbidities. It is also important to note that Okada et al. (2020) acknowledged two limitations of their study. They did not observe aortic stiffness and the entire baroreflex stimulus–response curve was not determined. Therefore, future research improving on these limitations would be useful to corroborate their findings. In summary, Okada et al. (2020) have presented a respectable study which explored the sex differences in the baroreflex control of BP in older adults. The findings support previous ideas of a compensatory mechanism in older women when baroreceptor functioning is impaired due to increased arterial stiffness. It is noteworthy that this is the first study to compare MSNA burst area and burst occurrence regulation in older adults. Studies like this which reveal the intricacies of the sympathetic nervous system have important clinical and research implications which will improve the treatment of hypertension and cardiovascular disease. Further research using different cohorts is needed to fully understand the interactions between age, sex and baroreflex control. None. Sole author. None.