The extremely high-altitude environment, marked by sparse oxygen and reduced partial pressure of oxygen, often leads to a range of discomforts, such as headaches, reduced appetite, and breathing difficulties among those from lower altitudes living in these regions, potentially triggering various systemic diseases (Hackett and Roach, 2001; Naeije, 2010; Swenson, 2013). It is widely recognized that high-altitude environments impact the function of the autonomic nervous system (ANS) (Billman, 2011), and the ANS plays a significant role in the regulation of cardiovascular functions (Malpas, 2010; Esler, 2000). Monitoring ANS alterations can aid in the early detection of diseases related to high altitudes, leading to the implementation of effective preventative measures. Previous research has indicated that a rapid ascent to a high-altitude area of 3180 m results in a suppression of autonomic nervous activity, with a relative dominance of sympathetic nerve activity (Chen et al., 2008). Lundby et al. have observed that both individuals from plains and native highlanders consistently exhibit increased sympathetic nervous system activity in high-altitude environments (Lundby et al., 2018). However, the patterns of ANS changes in ultra-high plateau environments are not yet fully understood and warrant further research.

The time intervals between successive heartbeats in a healthy heart are subject to continuous fluctuation; these variations are indicative of Heart rate variability (HRV) (Shaffer and Ginsberg, 2017). Importantly, the activity of the ANS is a crucial factor in regulating HRV. In recent years, following the standardization of quantitative indicators for HRV by the “European Society of Cardiology and the North American Society of Pacing and Electrophysiology”, an increasing number of scholars have been utilizing HRV as a means to detect and evaluate the functional activity of the ANS in humans (Author anonymous, 1996; Zaza and Lombardi, 2001). As a non-invasive method, the convenience and reliability of HRV enable doctors to assess the function of the ANS more rapidly and economically, particularly in high-altitude environments where experimental instruments and equipment are lacking. Dhar and colleagues conducted a cross-sectional analysis on the autonomic nervous activity of subjects from plains at altitudes >3500m, finding that altitude significantly affects the HRV and ANS function balance in people from plains (Dhar et al., 2018). However, research is notably scarce on the ultra-high plateau environment, particularly above 5000 m, and the impact of such extreme altitudes on HRV in young healthy populations demands urgent exploration.

This study aims to conduct a cross-sectional investigation through a substantial research cohort on the patterns of HRV in young individuals who have stayed long-term in the ultra-high plateau environment, in order to reveal the characteristics of changes in autonomic nervous function, cardiac and sleep aspects. We hypothesize that prolonged exposure to ultra-high plateau environments may reduce heart rate variability, leading to decreased vagal tone, increased sympathetic tone, and impaired sleep quality in this population.

Studies indicate that ascending to high-altitude areas can lead to significant changes in HRVdue to disturbances in the ANS functions (Calbet, 2003; Hainsworth and Drinkhill, 2007). However, the specific changes and characteristics that occur in the youth population from plains who have long resided in ultra-high plateau environments (altitude >5000 m) remain unclear. In this study, we conducted a cross-sectional comparison of HRV and ANS functions in the young population on a diurnal and nocturnal level, and delved deeper into the variations in △HRV. The findings reveal that the ultra-high plateau environment significantly reduces the overall HRV in young healthy individuals. This is characterized by a notable decrease in vagal nerve tension accompanied by a significant increase in sympathetic nerve tension, and these changes do not vary with the day-night cycle. Importantly, the diurnal and nocturnal trends in HRV and ANS functions show consistency between the plain and ultra-high plateau environments. Further analysis of △HRV suggests that prolonged residence in ultra-high plateau environments significantly impairs the diurnal and nocturnal regulatory ability of the ANS in young healthy populations, indicated by a reduced recovery ability of vagal nerve activity and a continuous increase in sympathetic nerve tension. Additionally, the study also demonstrates that prolonged residence in ultra-high plateau environments significantly reduces cardiac reserve capacity and sleep quality in young healthy populations.

The ANS plays a crucial role in regulating the oscillatory behavior of the cardiovascular system. Analyzing time-domain, frequency-domain, and nonlinear characteristics of HRV provides a non-invasive assessment of sympathetic and vagal nerve activities. Extended monitoring duration helps observe the diurnal balance changes of ANS. In HRV analysis, SDNN, TINN, and TP indicate the overall level of HRV. RMSSD, NN50, pNN50, HF, HF norm, and SD1 effectively represent vagal nerve excitability, while LF/HF and SD1/SD2 indicate the balance of ANS activity (Armstrong et al., 2022). LF was once considered a crucial index in HRV to reflect the functional state of the sympathetic nervous system. However, with advancing research, LF is no longer deemed a valid marker of autonomic activity alone, as it is also influenced by baroreceptor activity (Goldstein et al., 2011). Additionally, nonlinear indicators such as ApEn and SampEn are used to measure the regularity and complexity of HRV time series, with lower values indicating greater uniformity in adjacent beat intervals and less fluctuation between heartbeats. The HRV analysis in this study was conducted over a 24-hour period, thus providing a more accurate assessment of long-term ANS function.

In this study, significant reductions were observed in SDNN, TINN, and TP in the ultra-high plateau group compared to the plain group, indicating a substantial decrease in overall HRV in the ultra-high plateau environment. The parasympathetic markers (RMSSD, HF, and SD1) showed a decrease, whereas the sympathetic marker (LF norm) increased. Trends in LF/HF and SD1/SD2 ratios, as indicated in Table 2, reveal a shift towards increased sympathetic nervous activity within the ANS due to prolonged ultra-high plateau exposure. Previous research indicates that rapid ascent to high altitudes causes a decrease in LF and HF power and an increase in the LF/HF ratio (Saito et al., 2005; Cornolo et al., 1985; Kanai et al., 2001). Huang et al. (2010) found that the R-R intervals, LF, and HF power significantly decreased in plains-dwelling subjects within 5 days of trekking up to an altitude of 3440m, compared to sea level. Other research noted declines in SDNN, TP, and HF norm, along with an increase in LF norm and LF/HF ratio, in subjects ascending rapidly to 3180 m (Chen et al., 2008). Similarly, Dhar et al. (2018) reported that prolonged stay at altitudes >3500 m significantly reduced overall HRV indices (SDNN, TINN, and TP) and parasympathetic nervous tension indicators (RMSSD, NN50, pNN50, HF, HF norm, SD1) in lowlanders, while sympathetic nervous tension indicators (LF norm) and the LF/HF ratio significantly increased. It is evident that both rapid ascent and prolonged stay in high-altitude areas lead to significant changes in HRV indices. In this study, the trend of HRV changes in the ultra-high plateau group (see Table 2) is consistent with the results of the aforementioned studies, indicating that even after a 12-month stay, the hypoxic environment of the ultra-high plateau region continues to impact the ANS function of individuals from the plains. It is commonly believed that acute hypoxia leads to enhanced sympathetic nerve activity, primarily due to the activation of carotid bodies and chemoreceptors in the brainstem (Marshall, 1994; Solomon, 2000). Calbet et al. demonstrated significant activation of the sympathetic nervous system under chronic hypoxia by examining the systemic epinephrine and norepinephrine overflow in lowlanders exposed to an altitude of 5260 m for 9 weeks (Calbet, 2003). Recently, Siebenmann et al. conducted a pharmacological blockade experiment at 3454 m and discovered that a reduction in cardiac vagal nerve activity is the primary mechanism for the heart rate increase related to 2 weeks of hypoxia (Siebenmann et al., 2017). The current study’s findings point towards ongoing sympathetic nerve tension activation and a simultaneous decrease in vagal nerve tension, as reflected by HRV indices. The specific factors contributing to the reduced function of the vagal nerve remain to be elucidated. Persistent hypoxia is a significant factor in the development of pulmonary arterial hypertension due to long-term exposure to high altitudes (Penaloza and Arias-Stella, 2007). Reductions in SDNN, LF, LF/HF, and VLF, as observed by Tsai et al. in patients with pulmonary arterial hypertension (Tsai et al., 2019), were also evident in the ultra-high plateau group. These reductions may be early indicators of cardio-pulmonary diseases associated with continuous exposure to an extreme high-altitude environment.

Previous study highlights that HRV in healthy individuals, influenced by diurnal rhythmicity, reflects circadian shifts in ANS function, typically showing greater sympathetic nerve activity during the day and heightened vagal nerve tension at night (Sammito et al., 2016). Nevertheless, the changes in HRV diurnal rhythms within ultra-high plateau environments are still not well-defined. To address this question, the current study segmented data from both ultra-high plateau and plain groups into daytime and nighttime periods for comparative analysis (refer to Table 3). The findings indicate that, when comparing the ultra-high plateau group with the plain group during corresponding day and night periods, the trends in HRV indices were generally in line with the overall 24-h variation observed. Notably, the analysis of day and night periods within the same group reveals that both groups exhibited increased HRV at night, suggesting reduced sympathetic and enhanced vagal nerve activity. The aforementioned findings indicate that although the ultra-high plateau environment significantly influences human HRV during both day and night periods, it does not change the natural diurnal rhythm trend. Furthermore, the △HRV values were used to analyse and compare the diurnal variation amplitudes between the two groups. This study found that compared with the plain group, the ultra-high plateau group showed a significant increase in △LF and △LF/HF, and a significant decrease in △HF and △S. HF is widely used to characterize vagal nerve tension, and the results of this study show that the △HF value in the ultra-high plateau group was significantly lower than that in the plain group. This may suggest that the ultra-high plateau environment reduces the normal diurnal recovery ability of vagal nerve tension. In recent years, the significance of LF in indicating baroreflex sensitivity has garnered attention (Goldstein et al., 2011). Research by Sleight et al. (1995) indicates that carotid sinus stimulation induced by neck suction can increase LF in individuals with normal baroreflexes, whereas no increase in LF is observed in individuals with impaired baroreflexes. In this study, the significant increase in △LF in the ultra-high plateau group compared to the plain group may suggest that the ultra-high plateau environment excessively activates the body’s baroreceptors during the day-night transition, potentially leading to increased blood pressure. A clinical randomized trial has shown that 24-hour ambulatory blood pressure continuously rises with increasing altitude and decreases after lowering the altitude (Parati et al., 2014). Moreover, the increase in △LF and decrease in △HF observed in the ultra-high plateau group in this study led to an increased △LF/HF ratio. This can be explained from a mathematical logic perspective and also reflects changes in the balance of the ANS, namely, prolonged residence in the ultra-high plateau increases the inclination of ANS balance towards sympathetic nervous activity.

This study’s heart rate analysis indicates that both the mean and minimum heart rates in the ultra-high plateau group were significantly higher than those in the plain group. It has been reported that acute hypoxia can cause an increase in resting heart rate, which is associated with sympathetic nervous activation and a decline in parasympathetic nerve function (Koller et al., 1988). However, despite the gradual restoration of blood oxygen content with prolonged hypoxia and adaptation to the environment, the resting heart rate remains elevated (Naeije, 2010). Siebenmann et al. highlighted that the sustained elevation in heart rate during chronic hypoxia primarily stems from a persistent decrease in parasympathetic activity rather than continuous sympathetic stimulation (Siebenmann et al., 2017). This is consistent with our analysis of the overall 24-hour ANS function changes, showing a significant decline in vagal nerve tension accompanied by a significant increase in sympathetic nerve tension. Furthermore, the study observed a notably lower maximum heart rate in the ultra-high plateau group (see Table 5), echoing findings from ascents to extreme altitudes (Reeves et al., 1985). Chronic hypoxia leads to increased adrenaline spillover in healthy individuals (Calbet, 2003), resulting in continuous sympathetic nervous activation. Studies have shown that prolonged exposure to hypoxic conditions downregulates the density of cardiovascular adrenergic receptors (Kacimi et al., 1985a; Voelkel et al., 1981) and increases the expression of M2 muscarinic receptors (Kacimi et al., 1985b). This combined modulation of cardiac receptors could be one of the reasons for the decrease in maximum heart rate. Additionally, Richalet et al. have suggested that the ANS automatically regulates cardiovascular oxygen supply through this mechanism to prevent myocardial ischemia and potential hazardous events (Richalet and Hermand, 2022). Nonetheless, the increase in average and minimum heart rates caused by prolonged residence in the ultra-high plateau suggests a decline in cardiac reserve capacity and an increase in cardiac workload.

Recently, with in-depth research on HRV and its relationship with the ANS, scholars have linked HRV to sleep conditions, attempting to characterize sleep features through changes in HRV metrics (Cabiddu et al., 2012). In this study, we also attempted to analyze the sleep conditions of the healthy young population residing in the ultra-high plateau using HRV data. Findings indicate that, relative to the plain dwelling cohort, the ultra-high plateau residents exhibited increased awakenings, higher apnea-hypopnea index (AHI), and diminished sleep efficiency and quality. Such phenomena are prevalent in groups ascending to high-altitude locales (Weil, 2004), signifying potential sleep disturbances. In the high-altitude hypoxic environment, the gradual decrease in nighttime oxygen saturation and frequent occurrences of obstructive events caused by central sleep apneas lead to an increase in AHI and are somewhat related to the increased number of awakenings (Nussbaumer-Ochsner et al., 2010). Nevertheless, given that HRV analysis alone lacks the precision for definitive sleep condition assessment, these findings might only partly reflect the sleep dynamics of individuals in the ultra-high plateau.

Although HRV is an important indicator for assessing ANS function and is widely used to evaluate individual health status, it is influenced by multiple factors that cannot be ignored. Studies have shown that time-domain HRV measures, such as SDNN, SDANN, and the SDNN index, are not only higher in males but also gradually decline with age (Bonnemeier et al., 2003), whereas RMSSD and pNN50 exhibit a U-shaped pattern with increasing age (Almeida-Santos et al., 2016). A meta-analysis on sex differences in HRV indicated that females tend to exhibit a relative vagal dominance, while males show a relative sympathetic dominance (Koenig and Thayer, 2016). In this study, the age range of the included participants were within the young adult population. Therefore, the variations in HRV under ultra-high plateau conditions in other age groups remain to be further explored. Regarding sex differences, the study primarily included male participants, which may have influenced the final observations of sympathetic nervous activity indicators. Furthermore, whether male sympathetic nervous activity is more sensitive to altitude increases than that of females requires further investigation and validation in future research. In this study, there was an inter-group difference in BMI, but all participants were within a normal BMI range, with no instances of overweight or obesity. Although no correlation between HRV and BMI was found in a study with a sample of 653 individuals without heart disease (Antelmi et al., 2004), the relationship between BMI and HRV in ultra-high plateau environments still requires further investigation. Autonomic dysfunction is linked to various pathophysiological conditions, including hypertension (Lucini et al., 2014; Huikuri et al., 1996), diabetes mellitus (Gerritsen et al., 2001), and others. The Framingham Heart Study demonstrated that lower HRV is associated with an increased risk of hypertension in men with normal blood pressure (Singh et al., 1998). Similarly, the Atherosclerosis Risk in Communities (ARIC) study revealed that during a 9-year follow-up, participants in the lowest RMSSD quartile had a 1.36-fold higher risk of developing hypertension compared to those in the highest quartile (Schroeder et al., 2003). A study by Mori et al. indicated that a decrease in HRV is associated with an increase in blood pressure, significantly affecting diastolic blood pressure levels in both genders (Mori et al., 2014). A meta-analysis highlighted that type 2 diabetes mellitus is associated with an overall reduction in HRV, with both sympathetic and parasympathetic nervous tone diminished in patients with type 2 diabetes mellitus (Benichou et al., 2018). In our study, participants from the ultra-high plateau group exhibited lower overall HRV, elevated sympathetic nerve tone, and reduced parasympathetic nerve tone compared to those from plain areas. This suggests that individuals from plain areas living in ultra-high plateau environments for prolonged periods may have an increased risk of developing hypertension and diabetes. The relationship between ultra-high plateau environments and the body’s pathophysiological state, as well as the associated increased disease risk, warrants further research.

In summary, prolonged residence in the ultra-high plateau environment will significantly decrease HRV in the healthy young population, with ANS showing reduced vagal activity accompanied by sustained increase in sympathetic activity; more importantly, although prolonged residence in the ultra-high plateau does not change the intrinsic circadian rhythm trend of the young healthy population, it reduces their vagal recovery ability during the circadian cycle and causes an imbalance in the ANS towards increased sympathetic activity. Additionally, the ultra-high plateau environment not only reduces the cardiac reserve function of the healthy young population but also decreases their sleep quality. HRV, as a convenient and non-invasive index, can provide accurate guidance on the health status of people residing in high-altitude areas, thus effectively preventing the occurrence of high-altitude risks. Of course, the variations in HRV in various diseases, especially the characteristics in high-altitude illnesses, still need to be further explored.

In summary, our study found that prolonged residence in the ultra-high plateau reduces HRV, cardiac reserve capacity, and sleep quality in healthy young adults, diminishes the diurnal recovery capacity of the vagal nerve, and leads to a shift in ANS balance towards reduced vagal activity and enhanced sympathetic activity.

The limitations of this study are as follows: 1) The subjects were primarily male, which may lead to a gender bias in the data; 2) Polysomnography (PSG) is the gold standard for assessing sleep phases, and the subjects did not undergo PSG measurements; 3) The subject group did not undergo a comprehensive assessment of physiological indicators. In future experiments, we will address these shortcomings by including gender, PSG, and physiological parameters in our research plan to fully assess the role of HRV.