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.

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The relationship between sympathetic nerve activity and the vasculature has been of great interest due to its potential role in various cardiovascular-related disease. This relationship, termed "sympathetic transduction", has been quantified using several different laboratory and analytical techniques. The most common method is to assess the association between relative changes in muscle sympathetic nerve activity, measured via microneurography, and physiological outcomes (e.g., blood pressure, total peripheral resistance, and blood flow etc.) in response to a sympathetic stressor (e.g. exercise, cold stress, orthostatic stress). This approach, however, comes with its own caveats. For instance, elevations in blood pressure and heart rate during a sympathetic stressor can have an independent impact on muscle sympathetic nerve activity. Another assessment of sympathetic transduction was developed by Wallin and Nerhed in 1982, where alterations in blood pressure and heart rate were assessed immediately following bursts of muscle sympathetic nerve activity at rest. This approach has since been characterized and further innovated by others, including the breakdown of consecutive burst sequences (e.g., singlet, doublet, triplet, and quadruplet), and burst height (quartile analysis) on specific vascular outcomes (e.g., blood pressure, blood flow, vascular resistance). The purpose of this review is to provide an overview of the literature that has assessed sympathetic transduction using microneurography and various sympathetic stressors (static sympathetic transduction) and using the same or similar approach established by Wallin and Nerhed at rest (dynamic neurovascular transduction). Herein, we discuss the overlapping literature between these two methodologies and highlight the key physiological questions that remain.

Purpose Autonomic control of the heart is balanced by sympathetic and parasympathetic inputs. Excitation of both sympathetic and parasympathetic systems occurs concurrently during certain perturbations such as hypoxia, which stimulate carotid chemoreflex to drive ventilation. It is well established that the chemoreflex becomes sensitized throughout hypoxic exposure; however, whether progressive sensitization alters cardiac autonomic activity remains unknown. We sought to determine the duration of hypoxic exposure at high altitude necessary to unmask cardiac arrhythmias during instances of voluntary apnea. Methods Measurements of steady-state chemoreflex drive (SS-CD), continuous electrocardiogram (ECG) and SpO 2 (pulse oximetry) were collected in 22 participants on 1 day at low altitude (1045 m) and over eight consecutive days at high-altitude (3800 m). SS-CD was quantified as ventilation (L/min) over stimulus index (P ET CO 2 /SpO 2 ). Results Bradycardia during apnea was greater at high altitude compared to low altitude for all days (p < 0.001). Cardiac arrhythmias occurred during apnea each day but became most prevalent (> 50%) following Day 5 at high altitude. Changes in saturation during apnea and apnea duration did not affect the magnitude of bradycardia during apnea (ANCOVA; saturation, p = 0.15 and apnea duration, p = 0.988). Interestingly, the magnitude of bradycardia was correlated with the incidence of arrhythmia per day (r = 0.8; p = 0.004). Conclusion Our findings suggest that persistent hypoxia gradually increases vagal tone with time, indicated by augmented bradycardia during apnea and progressively increased the incidence of arrhythmia at high altitude.

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Apnea (breath-holding) elicits co-activation of sympathetic and parasympathetic nervous systems, affecting cardiac control. In situations of autonomic co-activation (e.g., cold water immersion), cardiac arrhythmias are observed during apnea. Chronic endurance training reduces resting heart rate in part via elevation in parasympathetic tone, and has been identified as a risk factor for development of arrhythmias. However, few studies have investigated autonomic control of the heart in trained athletes during stress. Therefore, we determined whether heightened vagal tone resulting from endurance training promotes a higher incidence of arrhythmia during apnea. We assessed the heart rate, rhythm (ECG lead II), and cardiac inotropic (speckle-tracking echocardiography) response to apnea in 10 endurance trained and 7 untrained participants. Participants performed an apnea at rest and following sympathetic activation using post-exercise circulatory occlusion (PECO). All apneas were performed prior to (CON) and following vagal block using glycopyrrolate (GLY). Trained participants had lower heart rates at rest (p=0.03) and during apneas (p=0.009) under CON. At rest, 3 trained participants exhibited instances of junctional rhythm and 4 trained participants developed ectopy during CON apneas, whereas 3 untrained participants developed ectopic beats only with concurrent sympathetic activation (PECO). Following GLY, no arrhythmias were noted in either group. Vagal block also revealed increased cardiac chronotropy (heart rate) and inotropy (strain rate) during apnea, demonstrating a greater sympathetic influence in the absence of parasympathetic drive. Our results highlight that endurance athletes may be more susceptible to ectopy via elevated vagal tone, whereas untrained participants may only develop ectopy through autonomic conflict.