The carotid baroreflex: The ultimate haemodynamic factor limiting aerobic capacity?

One of the simpler and more relevant axioms in medical physiology reads as follows: the more oxygen (O2) an individual can consume per unit of time and body mass, the fitter he or she is. Maximal O2 consumption ( V ̇ O 2 max V̇_O₂max ), elicited by incremental exercise, is essentially determined by the capacity of the circulatory system to deliver O2 to active skeletal muscle fibres (Lundby et al., 2017). Because of the wide-ranging and large dose of stimuli required to enhance the main function of the circulatory system, as well as the ensuing capacity to burn calories with ease, a high V ̇ O 2 max V̇_O₂max entails strong protection against cardiovascular, metabolic and neoplastic diseases, among others (Imboden et al., 2018). The question presents itself: what can we do to increase V ̇ O 2 max V̇_O₂max ? The ubiquitous presence of negative feedback mechanisms in the circulatory system entails an intriguing possibility. The delivery of arterial blood, and thereby O2, to dilated vascular beds might not be maximized, but limited to a certain degree by a mechanism amenable to modification. Herein, we integrate sound yet seemingly scattered pieces of evidence leading to a testable and clinically relevant hypothesis. The rise of arterial pressure during exercise is restrained by negative feedback from carotid baroreceptors. The intravenous infusion of a blood volume expander in moderately fit individuals positioned in a hydrostatically stable cycle ergometer (limiting the leaking of plasma out of the circulation) enhances Q during exercise, conforming to the Law of the Heart (Guo et al., 2024). However, a marked decrement (−10%) in V ̇ O 2 max V̇_O₂max ensues, despite blood volume being precisely augmented to the hypervolemic level typically elicited by endurance training interventions (+10% over baseline) (Guo et al., 2024). In parallel, blood volume expansion decreases SVR and systemic O2 extraction during exercise (Guo et al., 2024). The increase in Q and decrease in SVR induced by blood volume expansion are inversely proportional to each other, thereby mean and systolic arterial pressure are unaltered (Guo et al., 2024). Exercise arterial pressure is thus subjected to the stringent homeostatic regulation among systemic haemodynamic variables, at the cost of inefficient blood flow distribution and O2 delivery, resulting in suboptimal O2 extraction. The regulation of the circulatory system partly restricts the increase in arterial pressure during exercise via the carotid baroreflex. Q and SVR, the two systemic components for which the product explains arterial pressure, determine blood flow to active muscle fibres. Therefore, in the healthy circulatory system, the larger the exercise-induced increase in arterial pressure (Q × SVR), the greater the effective O2 delivery and V ̇ O 2 max V̇_O₂max – provided that functional sympatholysis in active muscle, which contributes to optimize blood flow distribution, is not impaired (Heinonen et al., 2013). Accordingly, the Q × SVR product constitutes a physiological ceiling limiting V ̇ O 2 max V̇_O₂max , such that the increase in one factor (Q or SVR) elicits a proportional decrease in the other factor. To break that ceiling, long-term endurance training is needed to enhance exercise arterial pressure, underlain by simultaneously increases in Q and SVR, compared to pre-training values. Therefore, endurance training must modify the intrinsic mechanisms of the carotid baroreflex and/or its main moderating factors: central command and exercise pressor reflex. The forthright possibility emerges to modulate carotid sinus afferent signals in humans non-invasively (e.g. with external restriction of carotid sinus distension during exercise) in order to magnify O2 delivery to vasodilated beds in active muscles, leading to increased V ̇ O 2 max V̇_O₂max . A novel mechanism for V ̇ O 2 max V̇_O₂max improvement, which can be triggered via specific endurance training programs, will facilitate the effectiveness of lifestyle interventions in the general population, notably in individuals whose pathophysiology impedes the enhancement of the Frank–Starling mechanism (e.g. congestive heart failure patients). In this regard, supine endurance training markedly increases V ̇ O 2 max V̇_O₂max via alternative mechanisms to the classic hypervolemic-related adaptations (Ray & Cureton, 1991), with the latter being restricted to a large fraction of cardiometabolic patients (Montero et al., 2019). Supine endurance training does not elicit hypervolemia and plausibly entails carotid baroreflex modifications of greater magnitude than upright endurance training (Ray & Cureton, 1991). In other respects, multiple therapeutic targets related to the carotid baroreflex remain to be assessed in patients presenting with unexplained low arterial pressure response to exercise (Hedman et al., 2021). Underpinning the current hypothesis is the fact that low, but not high, arterial blood pressure during exercise is associated with increased mortality (Hedman et al., 2021). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. D.M. was responsible for the conception or design of the work; drafting the work or revising it critically for important intellectual content; and final approval of the version to be published, D.M. agrees to be accountable for all aspects of the work. This work was funded by the Research Grants Council of Hong Kong – ECS (106210224 to DM) and SF (104006024 to DM).