Effects of long-term very high-altitude exposure on cardiopulmonary function of healthy adults in plain areas

Abstract

Due to the unique plateau climate, such as low atmospheric pressure, hypoxia, cold, and dryness, people in plain areas will have a series of physiological and pathological changes after entering the plateau. This observational study was designed to assess the effects of long-term very high-altitude (HA) exposure on the cardiopulmonary function of healthy adults in plain areas through cardiopulmonary exercise testing (CPET). We tracked and observed 45 healthy adult men or women from the plain area (Beijing, with an altitude of approximately 40 m). They worked and lived in very HA areas (Lhasa, with an altitude of approximately 3,700 m) for 5 months before returning to plain areas. Participants completed health checkups, including basic physiological indexes, static pulmonary function tests, and CPET at baseline and after very HA exposure. The resulting data showed that after long-term very HA exposure, multiple CPET indicators significantly decreased (p < 0.05), including peak oxygen uptake, anaerobic threshold, peak work rate, oxygen uptake/work rate, peak oxygen uptake/heart rate, oxygen uptake efficiency slope, peak minute ventilation, peak end-expiratory carbon dioxide partial pressure, and peak cardiac output. The minute ventilation/carbon dioxide production slope was significantly higher than that before very HA exposure (p = 0.004). There were no significant changes in static pulmonary function (p > 0.05). In conclusion, long-term very HA exposure can lead to varying degrees of negative effects on cardiopulmonary function (including respiratory, circulatory, and metabolic function decline) in healthy adults in plain areas. The abnormality of related functional indicators may indicate that the body’s adaptive compensatory mechanism to the high altitude hypobaric hypoxia environment is decompensated. It is suggested that it is necessary to implement individualized cardiopulmonary rehabilitation training as soon as possible after long-term very HA exposure to mitigate functional decline in individuals.

Introduction

Compared with the plain area, the plateau not only has high altitude and complex and changeable terrain but also has the characteristics of low atmospheric pressure, hypoxia, cold, strong wind, dryness, intense radiation, and significant temperature differences, among which low atmospheric pressure and hypoxia have a significant impact on the human body¹. A previous study showed that at altitudes higher than 2,500 m, the sigmoidal shape of the blood oxygen saturation curve is no longer enough to protect against systemic hypoxia²and saturation drops to 95% at 2,000 m and down to 84% at 5,000 meters³. This unique environment will cause pathological and physiological changes in the heart and lung vessels. At the same time, people exposed to high-altitude (HA) for a long time may also suffer from severe high-altitude disease, chronic heart disease, high-altitude heart injury (such as myocardial hypertrophy, heart failure, etc.), high-altitude pulmonary hypertension, and high-altitude hypertension, which significantly reduce their cardiopulmonary function and exercise endurance^4,5.

With the development of medical technology and the continuous improvement of people’s attention, high-altitude medicine has made great progress. At the same time, the research on the effects of a high-altitude hypobaric hypoxia environment on the body is also increasing^6,7. The cardiopulmonary function is directly related to the integrated function of numerous systems, and it is thus considered a reflection of total body health⁸. Although many studies have shown that a high-altitude hypoxia environment has a negative impact on cardiopulmonary function^{9, 10–11} studies using cardiopulmonary exercise testing (CPET) to assess the effects of very HA exposure on the cardiopulmonary function of healthy adults in plain areas are rare. CPET is an objective, quantitative, and non-invasive cardiopulmonary function assessment method that integrates and analyzes the continuous dynamic changes of respiratory, circulatory, blood, metabolic, and other system functions during exercise¹². It is the gold standard for evaluating cardiopulmonary metabolic function and the best way to evaluate aerobic exercise. As a result, this article aims to quantitatively assess the effects of long-term very HA exposure on the cardiopulmonary function of healthy adults in plain areas through CPET and to provide prevention and treatment recommendations to promote socio-economic development in high-altitude areas.

According to this information, we hypothesize that a 5-month exposure to very HA will reduce the cardiopulmonary function of healthy adults in plain areas. This study intends to quantitatively evaluate this hypothesis through CPET and static pulmonary function tests, with the aim of providing scientific recommendations for the prevention and management of relevant health issues during the socioeconomic development of high-altitude regions.

Materials and methods

Study design and participants

The study was observational and used a one-group pre- and post-test research design. We tracked and observed 45 healthy adult men or women from the plain area. In mid-July 2022, participants took a train from the plain area (Beijing, with an altitude of approximately 40 m, atmospheric pressure of about 100 kPa, and partial pressure of oxygen of about 158 mmHg) to very HA areas (Lhasa, with an altitude of approximately 3700 m, atmospheric pressure of about 65.2 kPa, and partial pressure of oxygen of about 100 mmHg). Participants worked and lived in very HA areas for five months, then returned to the plain area by train in mid-December 2022. All the participants voluntarily went to the very HA areas from the plain areas to carry out support work. They were all white-collar workers who did not do much physical labour, such as doctors, teachers, and managers. Additionally, their work and daily activity levels in very HA areas were not significantly different from those in plain areas.

Participants were required to complete a health checkup before going to very HA areas and after returning to plain areas. After completing the two examinations, we conducted a statistical analysis of the participants’ health checkup data. We have excluded participants with respiratory diseases, cardiovascular diseases, hematological diseases, musculoskeletal and joint diseases, neurological diseases, liver or kidney dysfunction, and an inability to perform CPET due to low physical fitness. We also excluded people with a history of HA exposure above 3,500 m in the past six months and those with missing health checkup data. Protocols used in this study were in accordance with International Ethical Guidelines (according to the Helsinki Declaration) and approved by the Ethics Committee of Beijing Xiaotangshan Hospital (Approval No. 2024–09). We carried out all methods in accordance with relevant guidelines and regulations. Informed consent was obtained from all participants and their legal guardians.

Data collection

The general information of the participants was collected through a face-to-face questionnaire interview, including age, gender, educational level, and health status. The health checkup data mainly include height, weight, body mass index (BMI), waist circumference (WC), hip circumference (HC), heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), oxygen saturation (SpO₂), static pulmonary function, and respiratory, circulatory, and metabolic indexes measured by CPET. The whole test was carried out in strict accordance with the operating procedures and precautions to ensure the safety and accuracy of the test.

Measurement of the basic physiological indexes

Weight and height were measured using a calibrated electronic scale while the participants were shoeless and wearing light clothing. BMI (kg/m²) was calculated as weight (kg) divided by height squared (m²). WC was taken midway between the lowest rib margin and the highest iliac crest at the end of expiration, and the maximum circumference around the buttocks while wearing thin clothing was taken as HC. SBP and DBP in the right arm of seated participants were measured using an Omron electronic sphygmomanometer (Omron Healthcare Co. Ltd., Kyoto, Japan), and HR and SpO₂ were determined using a finger pulse oximeter (Lepu Medical Technology Co., Ltd., Beijing, China). The mean of two measurements separated by a 5-minute interval was taken as a valid determination of SBP, DBP, HR, and SpO₂.

Methods of CPET and static pulmonary function tests

We used the Quark PFT Ergo cardiopulmonary function testing system (including static pulmonary function) produced by COSMED, Italy, to perform CPET and static pulmonary function tests on participants. Participants tried to avoid alcohol, tea, or caffeinated beverages for three days before the test. Before the test, the tester must ask the participants to sign an informed consent form, which includes informing them of the purpose, implementation process, and precautions of CPET and reminding them of the potential discomfort and risks related to exercise. Before the test, the instrument’s gas, capacity, and flow rate were calibrated. Then, the participants completed the static pulmonary function assessment according to the instructions.

The test method of forced vital capacity (FVC) and forced expiratory volume in one second (FEV1): Participants first breathed calmly for 4–5 times and then quickly inhaled until they could no longer inhale, then immediately exhaled for 6 s to expel the air from the lungs as much as possible. The test method of maximum ventilation volume (MVV): Participants breathed calmly for 4–5 times, waited for the baseline of expiratory volume to be stable, and then breathed rapidly and deeply for 12 s with the deepest breathing amplitude and the maximum breathing speed to simulate the breathing state during strenuous exercise.

After a 3-minute rest, the testers transferred the participants safely to the power bicycle, adjusted the height suitable for pedalling, connected the 12-lead electrocardiogram, and wore the cuff for automatic blood pressure detection and the mask for respiratory gas analysis. The tester set the power increment rate of the power bicycle according to the participant’s age, gender, and estimated functional status so that they could reach the symptom-limiting maximum extreme exercise within 6 to 10 min. During the whole exercise process, the testers should closely monitor the status of the participants¹³.

CPET indexes and static pulmonary function indexes

The CPET indexes include peak oxygen uptake (VO_2peak), anaerobic threshold (AT), peak work rate (WR_peak), oxygen uptake/work rate (ΔVO₂/ΔWR), peak oxygen uptake/heart rate (VO_2peak/HR), minute ventilation/carbon dioxide production slope (VE/VCO₂ slope), oxygen uptake efficiency slope (OUES), peak minute ventilation (VE_peak), end-tidal carbon dioxide partial pressure at peak (PetCO_2peak), and peak cardiac output (CO_peak). The static pulmonary function indexes include FVC, FVC percent predicted (FVC% pred), FEV1, FEV1% predicted (FEV1% pred), FEV1/FVC, and MVV.

The changes in indexes in different functional stages during CPET

We recorded and collated VO₂, HR, VO_2peak/HR, minute ventilation (VE), tidal volume (VT), and respiratory rate (RR) in the resting stage, warmup stage, AT stage, peak stage, and 2-minute recovery of CPET. These measurements represent the body’s respiratory, circulatory, and metabolic functions.

Data analysis

SPSS 27.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. The quantitative data was represented as mean ± standard deviation (SD), and the qualitative data was represented as count or frequency. We used a paired-sample t-test to assess within-group changes in respiratory, circulatory, and metabolic measures between baseline (T0) and after five months (T1). The GraphPad Prism 10.1.2 (Inc., La Jolla, CA, USA) was used to draw the graph. P < 0.05 is a significant value, indicating a statistically significant difference.

Results

Baseline characteristics and changes in basic physiological indexes of participants

A total of 45 participants completed the very HA exposure with complete data before and after exposure. The participants included 39 males and 6 females, with an age of (41.18 ± 4.80, 33–52) years and a height of (1.71 ± 0.06, 1.56–1.86) m. After long-term very HA exposure, the participant’s weight, BMI, WC, HC, and HR did not change significantly (p > 0.05). SBP and DBP increased significantly (p = 0.001), and SpO₂ decreased significantly (p < 0.001) compared with those before exposure. The baseline characteristics and changes in the basic physiological indexes of the participants are summarized in Table 1.

Table 1. Baseline characteristics and changes in basic physiological indexes of participants (N = 45).

Variable	Baseline (T0)	5 months (T1)	T0 − T1	p-value
	Mean ± SD	Mean ± SD	Mean Change (95% CI)
Age (years)	41.18 ± 4.80	–	–	–
Male (n, %)	39, 86.67%	–	–	–
Height (m)	1.71 ± 0.06	–	–	–
Weight (kg)	75.34 ± 3.40	75.78 ± 11.55	− 0.44 (− 1.50; 0.62)	0.409
BMI (kg/m2)	25.71 ± 3.40	25.81 ± 3.27	− 0.10 (− 0.55; 0.35)	0.653
WC (cm)	85.69 ± 8.98	86.40 ± 8.66	− 0.71 (− 1.95; 0.53)	0.255
HC (cm)	97.87 ± 6.78	98.47 ± 6.09	− 0.60 (− 1.61; 0.41)	0.238
HR (bpm)	86.91 ± 14.95	83.11 ± 14.06	3.80 (− 0.26; 7.86)	0.066
SBP (mmHg)	116.33 ± 15.59	125.16 ± 13.21	− 8.82 (− 13.85; −3.79)	0.001
DBP (mmHg)	75.29 ± 11.04	80.69 ± 12.42	− 5.40 (− 8.48; −2.32)	0.001
SpO2 (%)	97.31 ± 0.87	96.47 ± 1.20	0.84 (0.41; 1.27)	< 0.001

Data are presented as n, mean ± SD, or n (%). BMI, body mass index; WC, waist circumference; HC, hip circumference; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; SpO₂, oxygen saturation.

Comparison of CPET indexes before and after long-term very HA exposure

After long-term very HA exposure, the CPET indexes of 45 participants were significantly lower than those before exposure, including VO_2peak (p < 0.001), AT (p < 0.001), WR_peak (p < 0.001), ΔVO₂/ΔWR (p = 0.008), VO_2peak/HR (p < 0.001), OUES (p < 0.001), VE_peak (p < 0.001), PetCO_2peak (p = 0.001), and CO_peak (p < 0.001). The VE/VCO₂ slope was significantly higher than before very HA exposure (p = 0.004) (Table 2). VO_2peak decreased in 43 participants and increased in 2 participants. AT decreased in 41 participants and increased in 4 participants. The WR_peak of all 45 participants decreased.

ΔVO₂/ΔWR decreased in 31 participants and increased in 14 participants. VO_2peak/HR decreased in 38 participants and increased in 7 participants. The VE/VCO₂ slope of 15 participants decreased, and that of 30 increased. The OUES of 40 participants decreased, and that of 5 participants increased. VE_peak decreased in 34 participants and increased in 11 participants. PetCO_2peak decreased in 32 of 45 participants and increased in 13 participants. The CO_peak of 42 participants decreased, and 3 increased (Fig. 1). The changes in CPET indexes of each participant before and after long-term very HA exposure are shown in Fig. 2.

Table 2. Comparison of CPET indexes before and after long-term very HA exposure.

Variable	Baseline (T0)	5 months (T1)	T0 − T1	p-value
	Mean ± SD	Mean ± SD	Mean Change (95% CI)
VO2peak (mL/min/kg)	29.46 ± 6.95	23.33 ± 4.71	6.13 (4.83; 7.43)	< 0.001
AT (mL/min/kg)	16.03 ± 3.40	12.29 ± 2.32	3.74 (2.88; 4.60)	< 0.001
WRpeak (W)	208.96 ± 39.63	163.11 ± 34.15	45.84 (39.01; 52.68)	< 0.001
ΔVO2/ΔWR (mL/min/Watt)	8.49 ± 1.26	8.04 ± 0.88	0.49 (0.12; 0.77)	0.008
VO2peak/HR (mL/beat)	13.94 ± 3.19	12.02 ± 2.44	1.93 (1.35; 2.50)	< 0.001
VE/VCO2 slope	25.62 ± 3.71	27.57 ± 4.19	−1.94 (− 3.23; −0.66)	0.004
OUES (mL/min/L/min)	2603.98 ± 585.36	2167.53 ± 505.26	436.44 (327.74; 545.15)	< 0.001
VEpeak (L/min)	71.15 ± 15.54	60.51 ± 15.66	10.64 (4.94; 16.34)	< 0.001
PetCO2peak (mmHg)	41.36 ± 5.77	38.62 ± 5.10	2.73 (1.11; 4.36)	0.001
COpeak (L/min)	14.49 ± 3.18	11.63 ± 2.43	2.86 (2.27; 3.45)	< 0.001

VO_2peak, peak oxygen uptake; AT, anaerobic threshold; WR_peak, peak work rate; ΔVO₂/ΔWR, oxygen uptake/work rate; VO_2peak/HR, peak oxygen uptake/heart rate; VE/VCO₂ slope, minute ventilation/carbon dioxide production slope; OUES, oxygen uptake efficiency slope; VE_peak, peak minute ventilation; PetCO_2peak, end-tidal carbon dioxide partial pressure at peak; CO_peak, peak cardiac output.

[See PDF for image]

Fig. 1

Changes in CPET indexes before and after long-term very HA exposure. VO_2peak, peak oxygen uptake; AT, anaerobic threshold; WR_peak, peak work rate; ΔVO₂/ΔWR, oxygen uptake/work rate; VO_2peak/HR, peak oxygen uptake/heart rate; VE/VCO₂ slope, minute ventilation/carbon dioxide production slope; OUES, oxygen uptake efficiency slope; VE_peak, peak minute ventilation; PetCO_2peak, end-tidal carbon dioxide partial pressure at peak; CO_peak, peak cardiac output.

[See PDF for image]

Fig. 2

Changes in CPET indexes of each participant before and after long-term very HA exposure. VO_2peak, peak oxygen uptake; AT, anaerobic threshold; WR_peak, peak work rate; ΔVO₂/ΔWR, oxygen uptake/work rate; VO_2peak/HR, peak oxygen uptake/heart rate; VE/VCO₂ slope, minute ventilation/carbon dioxide production slope; OUES, oxygen uptake efficiency slope; VE_peak, peak minute ventilation; PetCO_2peak, end-tidal carbon dioxide partial pressure at peak; CO_peak, peak cardiac output; “+”, improvement; “−”, deterioration.

Comparison of indexes in different functional stages during CPET before and after long-term very HA exposure

The VO₂ and VE in the AT, peak, and recovery stages of CPET decreased significantly after long-term very HA exposure (p < 0.001), while the rest did not change significantly (p > 0.05). VT and HR in the warmup, AT, peak, and recovery stages of CPET were significantly decreased after long-term very HA exposure (p < 0.05) but did not change significantly in the resting stage (p > 0.05). VO₂/HR in the AT, peak, and recovery stages of CPET decreased significantly after long-term very HA exposure (p < 0.05), while there was no significant change in the rest (p > 0.05). During CPET, RR at different functional stages did not change significantly compared to before very HA exposure (p > 0.05) (Table 3; Fig. 3).

Comparison of static pulmonary function indexes before and after long-term very HA exposure

After long-term very HA exposure, participants’ FVC, FVC% pred, FEV1, and FEV1% pred decreased slightly, while FEV1/FVC and MVV increased slightly. However, all static pulmonary function indexes did not change significantly compared with those before very HA exposure (p > 0.05) (Table 4).

Table 3. Comparison of indexes in different functional stages during CPET before and after long-term very HA exposure.

Variable	CPET stages	Baseline (T0)	5 months (T1)	T0 − T1	p-value
		Mean ± SD	Mean ± SD	Mean change (95% CI)
VO2 (mL/min/kg)	Rest	5.69 ± 1.02	5.49 ± 0.93	0.20 (− 0.12; 0.52)	0.214
	Warmup	8.95 ± 1.45	8.52 ± 1.28	0.44 (− 0.02; 0.89)	0.059
	AT	16.03 ± 3.40	12.29 ± 2.32	3.74 (2.88; 4.60)	< 0.001
	Peak	29.46 ± 6.95	23.33 ± 4.71	6.13 (4.83; 7.43)	< 0.001
	Rec	11.30 ± 2.27	8.99 ± 1.99	2.31 (1.71; 2.91)	< 0.001
HR (bmp)	Rest	86.91 ± 14.95	83.11 ± 14.06	3.80 (− 0.26; 7.86)	0.066
	Warmup	95.93 ± 14.73	90.69 ± 14.06	5.24 (1.16; 9.33)	0.013
	AT	113.33 ± 15.70	101.27 ± 12.36	12.07 (7.99; 16.14)	< 0.001
	Peak	160.11 ± 16.94	145.20 ± 16.49	14.91 (11.03; 18.79)	< 0.001
	Rec	125.18 ± 19.30	112.22 ± 17.04	12.96 (8.60; 17.31)	< 0.001
VO2/HR (mL/beat)	Rest	4.83 ± 1.31	4.99 ± 1.16	− 0.17 (− 0.48; 0.14)	0.286
	Warmup	6.92 ± 1.65	7.21 ± 1.75	− 0.29 (− 0.81; 0.22)	0.260
	AT	10.71 ± 2.74	9.21 ± 2.13	1.50 (0.96; 2.04)	< 0.001
	Peak	13.94 ± 3.19	12.02 ± 2.44	1.93 (1.35; 2.50)	< 0.001
	Rec	6.74 ± 1.52	6.11 ± 1.50	0.62 (0.23; 1.02)	0.003
VE (L/min)	Rest	12.69 ± 3.10	12.04 ± 2.79	0.66 (− 0.01; 1.33)	0.055
	Warmup	18.51 ± 3.34	17.74 ± 3.00	0.77 (− 0.02; 1.55)	0.056
	AT	26.68 ± 5.22	22.38 ± 4.15	4.30 (2.88; 5.73)	< 0.001
	Peak	71.15 ± 15.54	60.51 ± 15.66	10.64 (4.94; 16.34)	< 0.001
	Rec	39.08 ± 9.89	32.14 ± 9.46	6.94 (4.53; 9.35)	< 0.001
VT (L)	Rest	0.76 ± 0.20	0.71 ± 0.20	0.05 (–0.01; 0.10)	0.077
	Warmup	0.93 ± 0.18	0.88 ± 0.16	0.05 (0.01; 0.10)	0.033
	AT	1.24 ± 0.40	1.03 ± 0.34	0.20 (0.13; 0.28)	< 0.001
	Peak	2.04 ± 0.49	1.81 ± 0.45	0.23 (0.08; 0.37)	0.003
	Rec	1.53 ± 0.39	1.33 ± 0.40	0.20 (0.10; 0.30)	< 0.001
RR (br/min)	Rest	17.74 ± 3.79	18.00 ± 3.78	− 0.26 (− 1.15; 0.63)	0.557
	Warmup	20.95 ± 3.32	20.89 ± 2.97	0.06 (− 0.70; 0.82)	0.875
	AT	22.59 ± 4.51	23.21 ± 4.03	− 0.62 (− 1.96; 0.72)	0.354
	Peak	35.96 ± 7.84	34.48 ± 7.14	1.48 (− 1.08; 4.04)	0.249
	Rec	25.79 ± 5.69	24.12 ± 6.31	1.68 (− 0.66; 4.01)	0.156

VO₂, oxygen uptake; HR, heart rate; VO₂/HR, oxygen uptake/heart rate; VE, minute ventilation; VT, tidal volume; RR, respiratory rate; rest, resting stage; Warmup, warmup stage; AT, anaerobic threshold stage; Peak, peak stage; Rec, recovery stage.

[See PDF for image]

Fig. 3

Changes in indexes in different functional stages during CPET before and after long-term very HA exposure. VO₂, oxygen uptake; HR, heart rate; VO₂/HR, oxygen uptake/heart rate; VE, minute ventilation; VT, tidal volume; RR, respiratory rate; Rest, resting stage; Warmup, warmup stage; AT, anaerobic threshold stage; Peak, peak stage; Rec, recovery stage; *, p < 0.05; **, p < 0.01; ***, p < 0.001.

Table 4. Comparison of static pulmonary function indexes before and after long-term very HA exposure.

Variable	Baseline (T0)	5 months (T1)	T0 − T1	p-value
	Mean ± SD	Mean ± SD	Mean Change (95% CI)
FVC	4.64 ± 0.82	4.49 ± 0.83	0.15 (− 0.07; 0.37)	0.172
FVC% pred	107.69 ± 15.62	104.22 ± 15.42	3.47 (− 1.84; 8.77)	0.195
FEV1	3.64 ± 0.58	3.58 ± 0.60	0.06 (− 0.08; 0.20)	0.387
FEV1% pred	101.31 ± 12.40	100.16 ± 12.85	1.16 (− 2.83; 5.14)	0.562
FEV1/FVC (%)	78.82 ± 5.61	80.07 ± 5.29	−1.25 (− 2.74; 0.24)	0.098
MVV (L/min)	135.42 ± 30.05	138.13 ± 24.16	−2.71 (− 10.17; 4.75)	0.468

FVC, forced vital capacity; FVC% pred, forced vital capacity percent predicted; FEV1, forced expiratory volume in one second; FEV1% pred, forced expiratory volume in one second percent predicted; FEV1/FVC, forced expiratory volume in one second/forced vital capacity; MVV, maximal voluntary ventilation.

Discussion

With the development of the economy and the continuous expansion of industries in high-altitude areas, the number of people who go to work and live in high-altitude areas is increasing yearly. The people in the plain area are vulnerable to the influence of the hypobaric hypoxia environment when they arrive at the plateau. Therefore, it is essential to explore the effects of long-term very HA exposure on the cardiopulmonary function of healthy adults in plain areas. In this study, we observed the changes in each index of CPET of healthy adults in plain areas before and after very HA exposure, analyzed the respiratory system, circulatory system, and overall metabolic function of the body, and explored the relevant mechanisms from the perspective of holistic integration physiology.

AT, defined as the VO₂ at anaerobic metabolism onset during submaximal exercise¹⁴ accurately assesses the individual’s aerobic capacity and cardiopulmonary function¹⁵. VO_2peak represents the highest achieved VO₂ during maximal exercise, and it can comprehensively evaluate subjects’ overall function, including their maximum aerobic metabolic capacity and heart, lung, and skeletal muscle capacity¹⁶. Both AT and VO_2peak were significantly reduced following long-term very HA exposure (p < 0.001). The possible reasons are: (1) Hypobaric hypoxia stimulation can cause vascular remodelling of pulmonary arterioles¹⁷which leads to increased pulmonary vascular resistance and thus causes pulmonary hypertension¹⁸. Long-term pulmonary hypertension eventually leads to increased right ventricular afterload and right ventricular hypertrophy¹⁹. (2) Hypoxia-inducible factors (HIFs) can stimulate the synthesis and secretion of erythropoietin (EPO) in the hypoxia environment, increasing the number of red blood cells and hemoglobin concentration²⁰ which promotes the transport of oxygen. However, excessive red blood cells will increase blood viscosity²¹ thereby increasing microcirculation resistance²². In summary, persistent pulmonary hypertension combined with increased blood viscosity will further aggravate the right heart load, which causes great pressure on the cardiopulmonary system.

When the function of the circulatory system decreases, ΔVO₂/ΔWR will decrease significantly due to the decrease in the ability of muscle to uptake oxygen or the decrease of the degree of O₂ delivery to the exercise muscle tissue²³. This study showed that ΔVO₂/ΔWR decreased significantly after very HA exposure (p = 0.008). This indicates that long-term very HA exposure will have a certain negative impact on the human circulatory system. VO₂/HR is a good index for evaluating the heart’s blood-pumping function²⁴. After long-term very HA exposure, the VO₂/HR in the AT, peak, and recovery stages of CPET decreased significantly compared to before exposure. In addition, CO_peak decreased significantly after long-term very HA exposure (p < 0.001), which is similar to the results of Wagner et al.²⁵. The main reason is that the body’s long-term structural adaptation to the high-altitude hypobaric hypoxia environment causes myocardial hypertrophy and myocardial fibrosis, which leads to the decline of myocardial contractility and overall cardiac function^26,27.

After very HA exposure, the VE/VCO₂ slope increased significantly (p = 0.004), and PetCO₂ decreased significantly (p = 0.001), suggesting lung perfusion reduction, dead space growth, and ventilation efficiency decreased^28,29. OUES is an objective, reproducible measure of cardiopulmonary reserve that does not require a maximal exercise effort^30,31. We found that OUES decreased significantly after long-term very HA exposure (p < 0.001), which may be due to the increase of pulmonary artery pressure after long-term very HA exposure, resulting in the increase of physiological dead space³²which in turn affected the VE-VO₂ relation and reduced OUES³⁰. In the high-altitude hypobaric hypoxia environment, increased pulmonary artery pressure will cause alveolar hyperosmolality and lead to alveolar edema⁶. This resulted in decreased lung compliance, affecting VT³³which is consistent with our findings. There was no significant change in static pulmonary function indexes before and after very HA exposure (p > 0.05). Combined with a previous study³⁴we believe that the difference in the effects of a high-altitude hypobaric hypoxia environment on static pulmonary function may be due to the lack of classification of compensation and decompensation.

The finding that long-term very HA exposure reduces cardiorespiratory function in healthy adults in plain areas appears paradoxical, given studies showing residents at a certain altitude exhibit lower cardiovascular disease morbidity and mortality^35,36 and hypoxic exercise benefits endurance athletes^37,38. This phenomenon is explained scientifically by two critical factors: (1) Optimal Altitude: Beneficial compensatory mechanisms and adaptive changes occur primarily at suitable altitudes³⁹. At very high altitudes (3000–4000 m or higher), severe hypoxia dominates, increasing altitude sickness risk⁴⁰. (2) Exposure Duration: Tissue cell autophagy can promote cell survival after short-term exposure to hypoxia, while tissue cell autophagy will induce cell apoptosis damage after long-term exposure to severe hypoxia^41,42.

In summary, how to effectively change the effects of long-term very HA exposure on the body is an urgent problem that needs to be solved. The following are our countermeasures and suggestions based on the results of this study and relevant research literature: Firstly, before entering the plateau, health screening and pre-adaptation to the plateau environment should be carried out to reduce the probability and severity of altitude illnesses⁴³. Secondly, correct understanding of altitude illnesses and maintaining a positive and optimistic attitude⁴⁴. Thirdly, endurance adaptability training should be carried out before entering the plateau. After entering the plateau, scientific low-intensity and medium-intensity physical exercise should be carried out to speed up the body’s adaptation to the plateau environment⁴⁵. Fourthly, adhere to a reasonable diet, eat more fruits and vegetables rich in vitamins C and E, and reduce the intake of oil, salt, sugar, and alcohol. Fifthly, oxygen should be inhaled intermittently according to physical condition⁴⁶. Finally, rational use of drugs to prevent and treat altitude illnesses⁴⁷.

Several shortcomings of this study need to be acknowledged: Firstly, the sample size of our analysis is relatively small, which may affect the universality of our research results. In the future, we will strive to increase the sample size, expand the population, and study people of different ages, occupations, health conditions, and education levels to expand the practical application of our results. Secondly, this study lacked information on individual risk factors, such as smoking and drinking habits, which may affect the results. Thirdly, the participants in this study only represent healthy adults from plain regions of China. Due to differences in genetic backgrounds and physiological adaptability among various ethnic groups (such as Caucasians, Africans, and Oceanians), the results of this study should not be extrapolated to populations in other plain regions. Finally, due to the requirement of adhering to participants’ informed consent principles, this study did not perform any invasive assessments (such as red blood cell count, hematocrit, or other invasive procedures). Future research will incorporate more comprehensive physiological monitoring to further investigate the underlying mechanisms of reduced cardiopulmonary function following very HA exposure.

Conclusions

The study findings indicated that long-term very HA exposure could lead to the decline of respiratory, circulatory, and metabolic functions of healthy adults in plain areas, which means that their cardiopulmonary function has been affected to varying degrees and suggests that rehabilitation training should be implemented as soon as possible after long-term very HA exposure to improve the overall cardiopulmonary function.

Acknowledgements

The authors thank all the individuals who participated in this study.

Author contributions

C.W.: Writing—original draft. L.Z.: Writing—original draft. Z.L.: Methodology. Z.C.: Data curation. Y.L.: Data curation. Y.F.: Methodology. A.X.: Validation. J.Q.: Validation. R.Z.: Validation. L.W.: Project administration, Supervision. L.G.: Project administration, Supervision. C.W. and L.Z. contributed equally to this work. All authors read and approved the manuscript.

Funding

The authors received no funding for this work.

Data availability

The data associated with the paper are not publicly available but are available from the corresponding author on reasonable request.

Declarations

Competing interests

The authors declare no competing interests.

Ethical approval

to conduct the study was obtained from the Ethics Committee of Beijing Xiaotangshan Hospital (Approval No. 2024-09) in accordance with the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all participants and their legal guardians.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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