Highs and lows of sympathetic neurocardiovascular transduction: influence of altitude acclimatization and adaptation

Abstract

High-altitude (>2500m) exposure results in increased muscle sympathetic nervous activity (MSNA) in acclimatizing lowlanders. However, little is known about how altitude affects MSNA in indigenous high-altitude populations. Additionally, the relationship between MSNA and blood pressure regulation (i.e., neurovascular transduction) at high-altitude is unclear. We sought to determine 1) how high-altitude effects neuro-cardiovascular transduction and 2) whether differences exist in neuro-cardiovascular transduction between low and high-altitude populations. Measurements of MSNA (microneurography), mean arterial blood pressure (MAP; finger photoplethysmography), and heart rate (electrocardiogram) were collected in: I) lowlanders (n=14) at low (344m) and high-altitude (5050m), II) Sherpa highlanders (n=8; 5050m), and III) Andean (with and without excessive erythrocytosis) highlanders (n=15; 4300m). Cardiovascular responses to MSNA burst sequences (i.e. singlet, couplet, triplet, and quadruplets) were quantified using custom software (coded in MATLAB, v2015b). Slopes were generated for each individual based on peak responses and normalized total MSNA. High altitude reduced neuro-cardiovascular transduction in lowlanders (MAP slope: high-altitude, 0.0075±0.0060 vs low-altitude, 0.0134±0.080; p=0.03). Transduction was elevated in Sherpa (MAP slope, 0.012±0.007) compared to Andeans (0.003±0.002; p=0.001). MAP transduction was not statistically different between acclimatizing lowlanders and Sherpa (MAP slope, p=0.08) or Andeans (MAP slope, p=0.07). When accounting for resting MSNA (ANCOVA), transduction was inversely related to basal MSNA (bursts/min) independent of population (RRI, r= 0.578 p<0.001; MAP, r= -0.627 p<0.0001). Our results demonstrate transduction is blunted in individuals with higher basal MSNA, suggesting blunted neuro-cardiovascular transduction is a physiological adaptation to elevated MSNA rather than an effect or adaptation specific to chronic hypoxic exposure.

A sympathetic view of blood pressure control at high altitude: new insights from microneurographic studies

“…Augmented MSNA counteracts vasodilatory mechanisms during systemic hypoxia (Weisbrod et al., 2001) and may offset blunted neurovascular transduction (i.e., vasoconstrictor response to a burst of MSNA). Indeed, Berthelsen et al., (2020) reported a blunted pressor response following a burst of MSNA in lowlanders at HA, compared to LA. Moreover, Sherpa exhibit a greater pressor response to a burst of MSNA at HA, whereas Andeans exhibit a smaller pressor response compared to both lowlanders and Sherpa at HA.…”

Signal-averaged resting sympathetic transduction of blood pressure: is it time to account for prevailing muscle sympathetic burst frequency?

“…regional vascular conductance). In particular, a number of recent studies have employed signal-averaging methods (4)(5)(6)(7)(8)(9)(10)(11), whereby the effects of each MSNA burst (or non-burst cardiac cycles) on hemodynamic variables (e.g. blood pressure [BP]) are tracked for 10-15 subsequent cardiac cycles (termed resting sympathetic transduction of BP).…”

“…A second observation used to establish the biological validity of the signal-averaging method is the effects of within-subject MSNA firing pattern or burst amplitude (both of which shown to increase neurotransmitter release (14)) on the magnitude and kinetics of sympathetic transduction of BP, respectively (16,17). These responses can be incorporated by quantifying the slope of regression between the increases in BP across MSNA burst amplitudes quartiles and burst firing patterns (termed sympathetic transduction slope) (7).…”

“…This is an important consideration given that 1) current analyses of sympathetic transduction of BP and the sympathetic transduction slope fail to integrate the prevailing level of resting MSNA, and 2) the majority of evidence has observed a negative association between the neural stimulus and transduction response, such that sympathetic transduction of BP and the sympathetic transduction slope are lower in individuals with high resting MSNA burst frequency (4, 6-8, 11, 12). The majority of work has ascribed this negative relationship as a compensatory change to help maintain normal BP (4,(6)(7)(8)11). However, high resting MSNA burst frequency has also been described as a limitation towards quantifying resting sympathetic transduction of BP (12, 21) and thought to prevent its use in individuals with high resting MSNA (3,21,22).…”

“…High MSNA burst frequency can result in greater temporal dependency amongst burst-triggering events which may disproportionally lower resting sympathetic transduction and explain the heteroscedasticity observed along the regression line between sympathetic transduction of BP and resting MSNA (4). This might suggest that general linear models previously utilized to account for differences in resting sympathetic outflow (7,23) may not be entirely valid.…”