European Journal of Cardiovascular Medicine

High-altitude environments, characterized by decreased atmospheric pressure and reduced oxygen availability, present significant physiological challenges to the human body. One of the most profound adaptations occurs in the cardiopulmonary system, where hypobaric hypoxia induces changes in pulmonary vascular resistance, right ventricular function, and systemic haemodynamics [1]. Long-term exposure to high altitudes—defined as elevations typically above 2,500 meters—results in a range of compensatory mechanisms, some of which can lead to maladaptive consequences over time.

Among the most critical effects is hypoxia-induced pulmonary vasoconstriction, which increases pulmonary artery pressure and may lead to pulmonary hypertension in susceptible individuals [1][2]. These vascular changes are not only of academic interest but have direct clinical implications, particularly for individuals residing at high altitudes or those suffering from pre-existing cardiopulmonary conditions. Research involving human and animal models has revealed that long-term high-altitude exposure influences the renin-angiotensin system, autonomic balance, and vascular remodeling, collectively altering blood pressure regulation and cardiac workload [3].

The haemodynamic implications of high-altitude hypoxia extend beyond the pulmonary circuit. For instance, elevated altitude has been shown to modify systemic vascular resistance and cerebral blood flow dynamics, thereby impacting cerebral perfusion and overall cardiovascular homeostasis [4]. These adaptations are often subtle in healthy individuals but can become pronounced in pathological conditions, such as pulmonary arterial hypertension and congenital heart disease. Vallecilla et al. used hemodynamic modelling to explore the impact of high altitude on individuals with Glenn circulation physiology, showing that altitude-related increases in pulmonary vascular resistance could significantly disrupt circulatory efficiency [2].

Furthermore, recent interventional studies have explored the effects of altitude exposure on exercise performance in patients with pulmonary arterial hypertension (PAH), emphasizing the compounded risks and necessary precautions in such populations [5]. High altitude can also influence pharmacokinetics and systemic drug metabolism, complicating the management of chronic conditions in high-altitude residents [6].

This study aims to investigate the long-term effects of high-altitude exposure on pulmonary vascular physiology and systemic haemodynamics through a comparative approach. By integrating clinical observations and physiological measurements, the study seeks to delineate the adaptive versus pathological changes induced by sustained hypoxic exposure, thereby contributing to the optimization of clinical strategies for individuals living or traveling at high altitudes.

Aims and Objectives

The present study aimed to investigate the long-term physiological effects of high-altitude exposure on pulmonary vascular function and systemic haemodynamics. Specifically, the study sought:

1. To evaluate changes in pulmonary arterial pressure and vascular resistance in individuals exposed to high altitudes over a prolonged period.
2. To assess alterations in systemic haemodynamic parameters, including mean arterial pressure, heart rate, and systemic vascular resistance.
3. To determine correlations between duration of exposure and the degree of physiological adaptation or dysfunction.
4. To compare these parameters between high-altitude residents and lowland controls using standardized noninvasive and minimally invasive methods.

Study Design and Setting

This was a prospective, observational, comparative study conducted over a 12-month period, from January 2023 to December 2023, at SMS Medical College, Jaipur, India. The study adhered to the ethical principles outlined in the Declaration of Helsinki and received institutional ethics committee approval prior to initiation.

Participants

A total of 100 adult participants were enrolled and stratified into two groups:

·         Group A (High-altitude residents): 50 individuals who had been living continuously at elevations above 2,500 meters for ≥12 months.

·         Group B (Lowland controls): 50 age- and sex-matched individuals residing at altitudes <500 meters with no prior history of high-altitude exposure.

Inclusion criteria were age 18–50 years, normal baseline cardiopulmonary function (as per echocardiography and spirometry), and willingness to provide informed consent. Exclusion criteria included history of cardiovascular or pulmonary disease, pregnancy, current smoking, and use of medications affecting vascular tone.

Data Collection and Parameters

Participants underwent standardized assessments of pulmonary and systemic haemodynamics, including:

·         Pulmonary parameters: Right ventricular systolic pressure (RVSP), pulmonary artery systolic pressure (PASP), and estimated pulmonary vascular resistance (PVR) measured via Doppler echocardiography.

·         Systemic parameters: Heart rate (HR), systolic and diastolic blood pressure (SBP/DBP), and mean arterial pressure (MAP), obtained through automated sphygmomanometry and validated wearable monitors.

·         Biochemical markers: Serum hemoglobin, hematocrit, arterial blood gases, and biomarkers of hypoxia (e.g., erythropoietin, NT-proBNP).

Measurements were taken at baseline and during mild exertion (submaximal treadmill testing) to assess dynamic haemodynamic changes.

Statistical Analysis

Continuous variables were expressed as means ± standard deviations and compared using independent t-tests or Mann–Whitney U tests, as appropriate. Categorical data were analyzed using chi-square tests. Correlation analyses (Pearson or Spearman) were performed to examine relationships between altitude exposure duration and haemodynamic indices. A two-tailed p-value <0.05 was considered statistically significant. All analyses were conducted using SPSS version 26.0.

Section 1: Baseline Characteristics

A total of 100 participants were enrolled in the study, with 50 individuals in each group. The mean age in the high-altitude group was 33.2 ± 5.6 years, compared to 34.6 ± 5.2 years in the lowland control group. Males constituted a higher proportion in the high-altitude group (64.0%) than in the lowland group (46.0%). The mean duration of high-altitude exposure in Group A was 65.4 ± 29.8 months, while Group B participants had no prior high-altitude exposure.

Table 1. Baseline Characteristics of Participants

Section 2: Pulmonary Haemodynamics

Pulmonary haemodynamic parameters were significantly elevated in the high-altitude group compared to the lowland controls. The mean right ventricular systolic pressure (RVSP) was 34.8 ± 6.7 mmHg in the high-altitude group versus 25.2 ± 5.3 mmHg in the lowland group. Similarly, the pulmonary artery systolic pressure (PASP) averaged 39.9 ± 6.5 mmHg in the high-altitude group, compared to 30.4 ± 5.8 mmHg in controls. Pulmonary vascular resistance (PVR) was also higher among high-altitude residents (2.48 ± 0.54 Wood units) relative to lowlanders (1.60 ± 0.38 Wood units). These findings are consistent with hypoxia-induced pulmonary vasoconstriction observed in chronic altitude exposure.

Table 2. Pulmonary Haemodynamic Parameters

Section 3: Systemic Haemodynamics

Systemic haemodynamic profiles between the two groups showed modest differences. The mean heart rate was similar across groups—77.2 ± 8.2 bpm in the high-altitude group and 76.7 ± 8.0 bpm in the lowland group. Systolic blood pressure was slightly elevated in high-altitude participants (127.4 ± 9.7 mmHg) compared to lowland controls (122.9 ± 11.1 mmHg), whereas diastolic pressure values were comparable between the two cohorts. Mean arterial pressure (MAP) followed a similar trend, averaging 95.7 ± 5.6 mmHg in high-altitude dwellers versus 94.5 ± 5.7 mmHg in lowlanders. These subtle variations suggest partial systemic vascular adaptation to long-term high-altitude exposure, but without significant hypertensive response.

Table 3. Systemic Haemodynamic Parameters

Section 4: Biochemical and Gas Exchange Parameters

Significant differences in biochemical and gas exchange parameters were observed between high-altitude residents and lowland controls. Mean hemoglobin concentration and hematocrit were markedly higher in the high-altitude group (16.8 ± 1.3 g/dL and 50.4 ± 3.9%, respectively), compared to lowlanders (13.8 ± 1.0 g/dL and 41.4 ± 3.1%). PaO₂ was substantially reduced in high-altitude individuals (59.4 ± 4.8 mmHg) versus controls (84.7 ± 5.8 mmHg), reflecting the hypoxic environment. In response, erythropoietin levels were more than doubled in the high-altitude group (39.2 ± 9.5 mIU/mL vs. 15.3 ± 5.0 mIU/mL). NT-proBNP levels showed no significant intergroup difference, suggesting preserved cardiac function in both populations. These findings highlight systemic physiological adaptations to chronic hypoxia.

Table 4. Biochemical and Gas Exchange Parameters

Section 5: Correlation Analyses

To evaluate the influence of exposure duration on physiological adaptation, Pearson correlation analyses were conducted within the high-altitude group. Weak correlations were observed between duration of residence and haemodynamic or biochemical indices. Specifically, duration showed a minimal positive correlation with hemoglobin (r = 0.12), and a slight negative correlation with erythropoietin (r = -0.12), suggesting a potential decrease in hypoxic stimulus over time. Pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) showed negligible associations with exposure duration (r = -0.03 and r = -0.02, respectively), indicating relative stability of these measures irrespective of duration.

Section 6: Summary of Statistical Significance

Statistical comparisons between the high-altitude and lowland groups revealed significant differences in key haemodynamic and biochemical parameters. Pulmonary measures including RVSP (t = 8.75, p < 0.001), PASP (t = 8.92, p < 0.001), and PVR (t = 10.09, p < 0.001) were all markedly elevated in the high-altitude group, reflecting pulmonary vascular remodeling secondary to chronic hypoxia. Systolic blood pressure was modestly but significantly higher in high-altitude participants (t = 2.16, p = 0.034), while no significant differences were observed in heart rate (p = 0.758), suggesting stable systemic autonomic regulation. These findings support the hypothesis that long-term high-altitude exposure primarily affects pulmonary vasculature more than systemic circulation.

Table 5. Summary of Statistical Comparisons

This comparative study provides important insights into the impact of long-term high-altitude exposure on pulmonary vascular physiology and systemic haemodynamics. Our findings reveal that chronic exposure to high altitudes is associated with significant pulmonary vascular remodeling, mild systemic haemodynamic shifts, and clear haematological adaptations.

Pulmonary Vascular Changes

One of the principal findings was the elevation of pulmonary pressures and resistance in high-altitude residents. Right ventricular systolic pressure (RVSP) and pulmonary artery systolic pressure (PASP) were significantly higher in the high-altitude group (34.8 ± 6.7 mmHg and 39.9 ± 6.5 mmHg, respectively) compared to lowland controls (25.2 ± 5.3 mmHg and 30.4 ± 5.8 mmHg), with t-statistics of 8.75 and 8.92 respectively (p < 0.001 for both). These results align with the well-documented physiological response to chronic hypoxia, which promotes hypoxic pulmonary vasoconstriction and eventual vascular remodeling. Our data are consistent with the findings of studies investigating pulmonary physiology under chronic stress environments, such as in interstitial lung disease, where elevated PASP and reduced vascular compliance are similarly observed (7).

Pulmonary vascular resistance (PVR) was also significantly elevated in the high-altitude group (2.48 ± 0.54 Wood units) vs. lowlanders (1.60 ± 0.38), with a t-statistic of 10.09 (p < 0.001). These haemodynamic alterations suggest progressive but compensatory changes rather than maladaptive failure, particularly in the absence of elevated NT-proBNP, indicating no overt right ventricular strain.

Systemic Haemodynamic Stability

Despite the marked pulmonary effects, systemic haemodynamics showed relatively minor differences. Mean arterial pressure (MAP) was slightly higher in the high-altitude group (95.7 ± 5.6 mmHg) than in lowland controls (94.5 ± 5.7 mmHg), but this was not statistically significant (t = 1.10, p = 0.274). Systolic blood pressure, however, was modestly elevated (127.4 ± 9.7 mmHg vs. 122.9 ± 11.1 mmHg, t = 2.16, p = 0.0336), suggesting subtle systemic vascular adaptation. These findings echo those reported in patients undergoing intermittent hypoxia therapy, where MAP tends to remain stable while systemic vascular tone adjusts gradually to the hypoxic stimulus (12). The absence of tachycardia and unchanged heart rate between groups (p = 0.758) further suggests autonomic compensation, in line with preserved baroreflex sensitivity noted in long-term altitude exposure studies and autonomic physiology assessments (14).

Haematological and Gas Exchange Adaptations

As expected, our study demonstrated significant haematological adaptation. Hemoglobin levels in high-altitude residents were 16.8 ± 1.3 g/dL versus 13.8 ± 1.0 g/dL in controls (t = 11.51, p < 0.001), while hematocrit followed a similar trend (50.4 ± 3.9% vs. 41.4 ± 3.1%, t = 12.18, p < 0.001). These changes reflect compensatory erythropoiesis driven by chronic hypoxia. The high erythropoietin levels (39.2 ± 9.5 mIU/mL) in altitude dwellers vs. 15.3 ± 5.0 mIU/mL in controls (t = 14.88, p < 0.001) confirm this pathway. Our findings mirror those seen in translational models of hypoxia-induced erythropoiesis and cardiopulmonary conditioning, where long-term hypoxia elevates erythropoietin secretion and improves oxygen delivery (8, 13). Moreover, arterial blood gas analysis showed a clear decline in PaO₂ in high-altitude residents (59.4 ± 4.8 mmHg) compared to controls (84.7 ± 5.8 mmHg), with a t-statistic of -23.29 (p < 0.001). This hypoxemia serves as the primary stimulus for the erythropoietic response, reinforcing the physiological narrative. The finding is well-aligned with studies on cerebral and systemic oxygenation under stress, such as in stroke recovery (9) or chronic fatigue syndrome (11), where chronic low PaO₂ is associated with compensatory biochemical cascades.

Correlation and Exposure Duration

Despite the observed physiological differences, duration of altitude exposure was only weakly correlated with most parameters. PASP and PVR showed minimal associations with exposure duration (r = –0.03 and –0.02, respectively), while erythropoietin showed a slight inverse trend (r = –0.12), suggesting some degree of adaptation and possible downregulation over time. This supports prior findings in longitudinal physiology trials, such as those exploring arterial stiffness and vascular remodeling in long-term hypertension (10). The mild positive correlation between duration and hemoglobin (r = 0.12) is congruent with data from chronic exposure studies in cardiovascular physiology (15).

Clinical Relevance and Implications

This study reinforces that long-term high-altitude residence leads to predictable pulmonary and hematologic adaptation without systemic haemodynamic instability or overt cardiovascular compromise. It suggests that humans living chronically above 2,500 meters can maintain systemic homeostasis despite ongoing hypoxic stress. These insights could inform safety guidelines for residents, military personnel, and high-altitude athletes. Moreover, lessons from natural adaptation may translate into therapeutic strategies, as highlighted in recent work on novel cardiometabolic therapies and their vascular effects (15).

Limitations

This study has several limitations. First, although group matching was done by age and sex, unmeasured confounding factors such as genetic adaptation, nutritional status, or microenvironmental differences could influence outcomes. Second, noninvasive assessments (e.g., echocardiographic estimates of PVR) may have limited precision compared to invasive gold standards. Finally, the cross-sectional design precludes causal inference regarding the time course of adaptation.

Long-term residence at high altitude is associated with significant pulmonary vascular remodeling and haematological adaptation, while systemic haemodynamic stability is largely preserved. Elevated PASP and PVR in high-altitude dwellers highlight the enduring impact of chronic hypoxia, yet the absence of significant NT-proBNP elevation or systemic hypertension suggests effective compensatory mechanisms. These findings enhance our understanding of physiological resilience in hypoxic environments and may inform future studies on altitude medicine, cardiovascular adaptation, and translational therapeutics.

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