Recent advances in predicting acute mountain sickness using physiological and genetic markers

Understanding the Pathophysiology of High-Altitude Illnesses

Plateau environments, defined as geographical regions with elevations surpassing 2,500 m, present extreme conditions of low oxygen, low pressure, low temperature, dry air, and strong ultraviolet radiation, which have a significant impact on the human cardiovascular system, respiratory system, metabolic system, and immune system. Especially due to hypoxia, the heart is one of the most metabolically active organs in the body, and myocardial metabolism is highly sensitive to ischemia and hypoxia. Prolonged and severe ischemia and hypoxia can directly lead to myocardial damage or even necrosis, endangering life (Maggiorini et al., 1990).

Inhabiting, working, or traveling in such high-altitude settings increases the likelihood of individuals experiencing a range of pathophysiological responses related to altitude adaptation, with Acute Mountain Sickness (AMS) being one of the most prevalent. AMS arises from an inappropriate response to hypoxic conditions, characterized predominantly by persistent headaches and often accompanied by non-specific symptoms like nausea, vomiting, general fatigue, loss of appetite, and sleep disturbances (Hackett et al., 1976). Severe cases can progress to life-threatening High Altitude Pulmonary Edema (HAPE) and/or High Altitude Cerebral Edema (HACE).

High altitude illnesses are characterized by:

1. Rapid onset: Symptoms can emerge within 24-48 hours upon reaching high altitude, as the body requires time to adapt to the hypoxic environment.

2. Broad susceptibility: Not restricted by factors like gender, age, or physical condition, as even healthy individuals may develop illness.

3. Reversibility: Most symptoms resolve when altitude is reduced or appropriate treatment is given.

4. Significant individual variation: Substantial differences in the ability to adapt to high altitude environments among different individuals.

Understanding and appreciating these characteristics are crucial for timely, accurate, and targeted prevention and intervention of high altitude illnesses.

Strategies for Preventing High-Altitude Illnesses

To ensure the safety and health of individuals entering high altitude areas, effective control measures can include hypoxic preconditioning training, scientifically sound climbing plans, gradual ascending speeds, and pharmacological prophylaxis, among others (Chen et al., 2023; Toussaint et al., 2021).

Hypoxic preconditioning training involves exposure to low oxygen for a certain amount of time and intensity before hypoxic stress to generate endogenous protection and enhance the body’s tolerance to hypoxic hypoxia later on (Wang et al., 2021). This can promote various adaptive changes in the body, including:

• Increasing erythrocyte production
• Promoting blood vessel dilation and new blood vessel formation
• Optimizing metabolic mode
• Enhancing antioxidant and anti-inflammatory functions
• Adjusting gene expression
• Helping the central nervous system adapt to low oxygen

Through these mechanisms, hypoxia pre-adaptation training can help the human body adapt to the low oxygen environment at high altitude in advance to a certain extent, reduce or avoid the occurrence of mountain diseases and related complications, and provide an effective prevention strategy for people entering high altitude areas. However, such training should be conducted under professional guidance to ensure safety and effectiveness (Girard et al., 2020).

Pathophysiological Mechanisms of High-Altitude Illnesses

The development and progression of high altitude illnesses are closely linked to the body’s adaptive responses to hypoxic environments at high altitudes, involving a series of complex pathophysiological changes, as shown in Figure 1.

Figure 1 Pathophysiological mechanisms in high altitude illnesses (By figdraw).

At high altitudes, with decreasing atmospheric pressure, the partial pressure of oxygen reduces correspondingly, which lessens the oxygen diffusion gradient across the alveolar-capillary interface, leading to a significant decrease in the amount of oxygen carried by the blood (lowering oxygen saturation). Insufficient oxygen supply constitutes the core pathophysiological basis for high altitude illnesses.

Hypoxia-inducible factors (HIFs), particularly the HIF-1α subunit, play a pivotal role here. Under low oxygen conditions, HIF-1α stabilizes and activates, regulating the expression of thousands of genes including glycolytic enzymes, Vascular Endothelial Growth Factor (VEGF), and Erythropoietin (EPO) (Dzhalilova and Makarova, 2020). Additionally, molecules like Heat Shock Protein 70 (HSP70) and Nitric Oxide (NO) also participate in modulating an individual’s tolerance to hypoxia, as shown in Figure 2.

Figure 2 Oxygen supply and demand balance mechanism in plateau environment (By figdraw).

In response to the hypoxic challenge at high altitude, the body initiates several adaptive physiological responses:

Respiratory System: By increasing respiratory rate and depth to enhance oxygen uptake and carbon dioxide elimination.

Cardiovascular System: Within days of initial exposure to hypoxia, autonomic nervous system adjustments result in increased heart rate and cardiac output, optimizing oxygen delivery to tissues throughout the body, thus protecting the heart from excessive workload due to increased metabolic demands.

Blood System: Under the stimulation of chronic hypoxia, the expression of hypoxia inducible factors is activated, thereby stimulating the kidneys and liver to secrete a large amount of EPO (Du and Bai, 2015). EPO activates JAK2 and STAT-5 related signaling pathways by binding to EPO receptors in hematopoietic organs, further upregulating the expression of membrane proteins and hemoglobin, thereby inducing massive proliferation of red blood cells and increasing the number of red blood cells in the bloodstream. This can improve tissue oxygen supply to a limited extent, making the body less prone to pathological changes.

As hypoxia worsens, EPO regulation becomes dysregulated, stimulating the proliferation of immature red blood cells at different stages of bone marrow development, and changing the size and shape of red blood cells to meet physiological needs, expanding the contact surface with oxygen, effectively improving tissue hypoxia. But when severe hypoxia occurs, the number of red blood cells increases, and the compensatory significance of the above changes into harmful effects, causing an increase in blood viscosity, a decrease in cell deformability, and difficulty for cells to pass through microvessels, further leading to tissue hypoxia, a vicious cycle, and ultimately the occurrence of HAPC.

Renal System: During acute hypoxia, activation of the adrenergic system leads to tachycardia; meanwhile, hypoxia-induced pulmonary vasoconstriction raises pulmonary artery pressure, and the kidneys respond by secreting erythropoietin to stimulate erythropoiesis in bone marrow, further augmenting red blood cell numbers (Richalet et al., 2023).

Due to the increased number of red blood cells and heightened hemoglobin concentrations, blood viscosity significantly rises under high-altitude conditions, presenting as increased resistance to blood flow, exacerbating the heart’s workload, and potentially affecting microcirculation and overall circulatory efficiency (Semenza, 1994; Savioli et al., 2022).

Long-term or severe hypoxia can trigger various tissue damages and pathological processes:

Cellular Oxidative Stress: Cellular oxidative stress is a pathophysiological state in which the balance between intracellular oxidation and antioxidant action is upset in favor of the oxidative process, resulting in the abnormal accumulation of reactive oxygen species (ROS) such as superoxide anions (O2⁻), hydrogen peroxide (H₂O₂), hydroxyl radicals (OH⁻), etc. This process not only affects normal cell metabolism, but also directly or indirectly damages biological macromolecules, including proteins, lipids, nucleic acids, etc., thus interfering with many aspects of cell signaling, energy production, gene expression, and cell cycle regulation (Tan et al., 2018).

Under low oxygen conditions, the oxygen supply to cells is limited, and the function of the electron transport chain of the mitochondria may be impaired, leading to electron leakage and promoting ROS production. At the same time, low oxygen can also affect the antioxidant defense system, such as reducing the activity of enzymes like superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), making it more difficult for cells to clear ROS, thus exacerbating oxidative stress (Zaarour et al., 2023).

Inflammatory Response: Hypoxia, a lack of oxygen supply, is one of the key factors that triggers the inflammatory response. Under hypoxia, cells induce the release of pro-inflammatory mediators through a variety of pathways, including but not limited to tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and vasoactive mediators such as histamine and bradykinin (Malkov et al., 2021). The release of proinflammatory mediators initiates a cascade of reactions that includes vascular response, leukocyte mobilization, cytokine storm, and tissue repair and remodeling.

Tissue Edema: Examples include high altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE), which are severe complications of high altitude illnesses. These occur mainly due to circulatory disturbances, increased capillary leakage, and fluid accumulation (Scoggin et al., 1977; Dehnert et al., 2005).

Severe cases of high altitude illness can lead to potentially fatal complications:

High Altitude Pulmonary Edema (HAPE): HAPE is non-cardiogenic pulmonary edema caused by acute severe hypoxia, which leads to pulmonary vein vasoconstriction, causing a sharp increase in pulmonary arterial pressure, local hyperperfusion, increased pulmonary blood flow, and imbalanced ventilation blood flow ratio. In addition, fluid leaks into the pulmonary interstitium and alveoli through pulmonary capillaries, hindering normal gas exchange (Choudhary et al., 2022).

High Altitude Cerebral Edema (HACE): HACE is considered the final stage of acute high-altitude reaction. In addition to worsening symptoms such as headache, dizziness, and vomiting, ataxia, mental confusion, varying degrees of consciousness disorders, fever, and in severe cases, brain herniation can occur, endangering life (Li et al., 2023).

A deep understanding of these pathophysiological mechanisms is essential for guiding the formulation of prevention strategies, early diagnosis, and effective treatment of high-altitude illnesses, both theoretically and practically.

Cohort Studies: Uncovering Incidence Patterns and Risk Factors

Cohort studies, due to their exceptional ability to unravel complex interplays between compounded exposures such as high-altitude environments, lifestyle habits, and genetic components with health outcomes, have been universally recognized as a preeminent research approach in exploring etiological mechanisms and formulating strategies for disease prevention and management (Li and Lyu, 2015).

Within the realm of high altitude illness research, the creation and meticulous examination of long-term, prospective cohorts among populations chronically exposed to high altitudes allow scientists to meticulously discern the fundamental patterns of disease manifestation and progression, along with related risk factors. The data harvested from these studies act as a pivotal resource and groundwork for developing predictive models.

Key Aspects of Cohort Studies on High-Altitude Illnesses

1. Study Subjects and Scope: Cohort studies on high altitude illness populations encompass a diverse range of groups, including permanent residents living in high-altitude regions like the Tibetan Plateau, workers frequently traveling between low and high altitudes, professional and amateur athletes participating in mountaineering expeditions, and tourists visiting high-altitude destinations. The diversity of study subjects helps to comprehensively understand the differences in adaptability and susceptibility among various populations to high-altitude environments.

2. Incidence and Severity Research: Several cohort studies show that the incidence of high altitude illnesses (such as Acute Mountain Sickness, Chronic Mountain Sickness, High Altitude Pulmonary Edema, and High Altitude Cerebral Edema) increases with rising altitude and exhibits significant individual variability (Hackett et al., 1976; Gongga et al., 2014; Wang et al., 2014). Through longitudinal follow-ups of large samples, research teams have quantified changes in the frequency and severity of high altitude illnesses at different altitudes, providing key data for risk prediction models.

3. Exploration of Influencing Factors: Researchers have thoroughly investigated and statistically analyzed a variety of potential factors affecting the occurrence and progression of high altitude illnesses. These factors include modifiable habits such as lifestyle, physical fitness, and nutritional status, as well as non-modifiable biological traits like genetic background, age, and gender. For instance, certain gene polymorphisms have been associated with an individual’s capacity to adapt to hypoxic high-altitude environments, thereby influencing their risk for high altitude illnesses (Zhao et al., 2023).

4. Evaluation of Prevention and Intervention Measures: Based on cohort data, scientists assess various methods for preventing and treating high altitude illnesses, such as drug prophylaxis (e.g., acetazolamide and dexamethasone use), stepwise acclimatization training, physiological and psychological conditioning, and rational dietary supplementation strategies. The research findings provide a scientific basis for developing targeted and effective health protection plans for high-altitude settings.

Cohort studies on high altitude illness populations play a vital role in etiological and epidemiological research, continually enriching and deepening our understanding of physiological and pathological changes in humans under high-altitude conditions. They significantly propel the development of high-altitude medicine and are of great importance for ensuring the health of people living in high-altitude regions and improving work efficiency in these areas.

High-Altitude Illness Cohort Studies in China

In China, cohort studies have made significant progress in different geographical regions across the country, as shown in Table 2.

Table 2 Status of cohort studies in China.

For instance, the “Southwest Region Natural Population Cohort Study” project, led by Professor Xiaosong Li from the West China School of Public Health/West China Hospital Fourth Affiliated Hospital, has made outstanding contributions to establishing a natural population cohort with unique environmental features, ethnic diversity, and disease distribution characteristics in the Southwest region. Since its inception in 2017, the “Southwest Cohort” has successfully completed baseline surveys and a follow-up visit with an impressive 93% retention rate, collecting biological samples from 112,000 individuals. It has also established baseline databases, follow-up databases, and a biobank covering the natural populations across five provinces and cities in the Southwest region, marking a major breakthrough in large-scale natural population cohort research in multi-ethnic areas of Southwest China.

In the field of high-altitude illness research in China, Professor Shurong Han’s team from Shandong University conducted a retrospective cohort study focusing on maintenance workers of the Qinghai-Tibet Railway. This study enrolled 286 individuals working at high altitudes and through long-term follow-up and testing, found that over 60% of the study subjects showed cardiac abnormalities after working at high altitude, primarily manifested as right heart enlargement and left ventricular diastolic dysfunction.

Another cohort study was carried out by the research team led by Dr. Renzheng Chen from the Second Affiliated Hospital of the Third Military Medical University (now Army Medical University), PLA Cardiovascular Disease Institute (Chen et al., 2021). They found that patients with Acute Mountain Sickness (AMS) had lower LA PP and Ea values, indicating a significant association between these baseline indicators of LA vascular relaxation and the occurrence of AMS.

Professor Leping Zhang’s research group from Xinqiao Hospital, Army Medical University, employed a high-altitude field-based cohort study method to analyze the physiological changes in 83 young Chinese male subjects following acute exposure to high altitude (Zhang et al., 2019). The study reported that after acute high-altitude exposure, participants’ SAS (Social Support Rating Scale) scores, FSAS (Flight Anxiety Scale) scores, and heart rates significantly increased, suggesting that these factors may be critical indicators for predicting AMS symptoms at higher altitudes.

These cohort studies provide robust data support for constructing and refining predictive models for high-altitude illnesses, uncovering key risk factors and informing the development of targeted prevention and intervention strategies.

Predictive Indicators and Model Development for AMS

In the construction of predictive models for assessing an individual’s susceptibility to Acute Mountain Sickness (AMS), it is imperative to systematically integrate a multitude of indicator parameters and employ classical statistical frameworks alongside cutting-edge artificial intelligence techniques, such as machine learning algorithms and deep learning architectures, to forge