This prospective study was embedded in a randomized controlled trial investigating the effect of 3 weeks of asthma rehabilitation at a high altitude (Saxer et al., 2019). We conducted three sequential measurements of PAP and cardiac function by echocardiography and lung sonography in patients with asthma. The first measurement was made at a low altitude baseline in Bishkek (Kyrgyzstan, altitude 760 m), and the second was made the day after arrival at the Too Ashu high-altitude clinic (Kyrgyzstan, altitude 3,100 m) by minibus (acute exposure), and the last was made after 17 nights at 3100 m (subacute hypoxia).

The patients participated in a rehabilitation program during the high-altitude stay, including patient education, endurance training, muscle strength training, breathing exercises, and guided walks. A detailed description of the intervention can be found in the previous publication (Saxer et al., 2019).

The study was performed between June and July 2016 and was approved by the Ethics Committee of the National Center of Cardiology and Internal Medicine, Bishkek, Kyrgyzstan (No. 01-8/151). All patients provided written informed consent.

Resting transthoracic echocardiography was conducted by three experienced cardiac sonographers (P.B., M.L., and S.U.). The images were obtained with a CX 50 Ultrasound System (Philips^®, Bothell, United States of America), using a 5 to 1 MHz sector array transducer, and analyzed after the examination on the same system by the same physicians. A standard echocardiographic investigation was performed according to guidelines (Quiñones et al., 2002; Rudski et al., 2010; Lang et al., 2015).

The tricuspid regurgitation pressure gradient (TRPG) was derived from the maximal tricuspid regurgitation jet velocity (TRVmax) using the modified Bernoulli equation. The systolic PAP (sPAP) was calculated by adding the maximal TRPG to the right atrial pressure (RAP), which was rated as 3, 8, or 15 mmHg, depending on the diameter and collapsibility of the inferior vena cava (Rudski et al., 2010; Lichtblau et al., 2019). The mean PAP (mPAP) was estimated by the equation mPAP = sPAP * 0.61 + 2 (Chemla et al., 2004).

The left ventricular systolic function was assessed by the ejection fraction (EF) according to the modified Simpson’s rule. Stroke volume (SV) was calculated using the velocity time integral and the diameter of the left ventricular outflow tract (LVOT). Cardiac output (CO) was derived by multiplying the SV by the heart rate (HR). Stroke volume index (SVI) and cardiac index (CI) were obtained by dividing SV and CO by the body surface area (BSA). The assessment of the right ventricular function included the following parameters: tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (TASV), RV end-diastolic area (RV-EDA), RV end-systolic area (RV-ESA), right ventricular fractional area change (RV-FAC), diastolic right and left ventricular internal diameters and their ratios (RVIDd/LVIDd) from an apical four-chamber view, and right atrial end-systolic area (RA-ESA). The total pulmonary resistance was calculated with mPAP/CO, the right ventricular arterial coupling was calculated with TAPSE/sPAP (Tello et al., 2019), the pulmonary arterial wedge pressure (PAWP) was calculated with the formula (PAWP = 1.24 × (E/e’) + 1.9) (Nagueh et al., 2016), and the pulmonary vascular resistance (PVR) was calculated as with PVR = (mPAP − PAWP)/CO.

After the echocardiographic examination, all patients were assessed for EVLW by looking for the number of B-lines in a supine position with the same ultrasound machine and transducer described previously (Lichtblau et al., 2021a). A B-line is defined as an echogenic linear signal with a narrow origin from the pleural line that crosses the image parallel to the sector arrays. These B-lines, observed at 28 different intercostal sites (on the left hemithorax from the second to the fourth and on the right from the second to the fifth intercostal spaces in the parasternal, midclavicular, anterior axillary, and midaxillary lines), were totaled (Picano et al., 2006).

In addition, systemic blood pressure (BP), heart rate (HR) and pulse oximetry (SpO₂) spirometry, and a 6-min walk test (6 MWT) were obtained in the same time frame (Saxer et al., 2019).

Patients performed a comprehensive 3-week, in-patient rehabilitation program at a high altitude that was described previously (Saxer et al., 2019).

The analyses included all available measurements at different time points. The analysis was performed per protocol. Missing data were not imputed.

Data are presented as mean and ± SD. EVLW (B-lines) and echocardiographic and physiological parameters were analyzed in linear mixed models with different time points (baseline, acute, and subacute hypoxia as fixed effects and subjects as random intercept). The average marginal effects (mean difference) induced by time were extracted from these regression models and expressed as mean change with 95% confidence intervals. Model assumptions were tested by visual inspection of the homogeneity and normality of the residuals and the random effects (Kentucky–Ascombe and Q–Q plots). A p-value threshold of <0.05 or a confidence interval not including zero was considered to be statistically significant. All statistical analyses were performed using R Studio (version 1.0.153, R Studio Inc., San Francisco, United States).

As expected, SpO₂ decreased from 95% to 89% upon acute exposure to the high altitude and slightly rose during subacute exposure but remained decreased compared to the low altitude. Mean systemic blood pressure did not change with acute or subacute exposure to the high altitude. Previous studies have shown that blood pressure tends to be elevated only in the first 10–24 h and then normalizes over the next days at a moderate altitude (∼2500 m), but several weeks of acclimatization are needed to normalize the blood pressure at higher altitudes (Calbet et al., 2003; Parati et al., 2014; Sagoo et al., 2017).

In contrast to most reports, resting HR was only slightly but not significantly increased during acute exposure to the high altitude. This may be due to increased HR at the low altitude due to sympathetic activity caused by inhaled sympathomimetic bronchodilators with no further changes at the high altitude under maintained therapy (Huez et al., 2009; Gaur et al., 2021). As in other studies of acclimatization to high altitudes, the HR further increased after 17 nights at high altitude (Huez et al., 2009; Gaur et al., 2021). The acute effect of high altitudes on PAP and PVR due to hypoxic pulmonary vasoconstriction is well known (Grünig et al., 2000; Maggiorini and Leon-Velarde, 2003; Grunig et al., 2009) and is usually reversible after descent (Hilty et al., 2016). As previously described in healthy subjects and patients with lung diseases, PAP rose upon acute exposure to the high altitude in our asthma patients (Lichtblau et al., 2019; Lichtblau et al., 2021b; Schneider et al., 2022). However, sPAP remained below what would be considered pathological. At the end of the 3-week rehabilitation program, the PAP was still higher than at the low altitude, which is consistent with other reports (Lichtblau et al., 2021a; Gaur et al., 2021).

The stroke volume index was reduced in the acute and subacute phases at high compared to the low altitude, whereas the cardiac index remained stable due to the increase in the heart rate during the subacute phase.

In contrast to our study, Huez et al. (2009) showed a higher cardiac output in lowlanders during acute exposure and after acclimatization. They showed adaptive changes in the diastolic function of both ventricles; however, pulmonary vascular resistance was not directly calculated but was stated as being only moderately increased.

Gaur et al. (2021) studied young, healthy male Kyrgyz and Indian residents during a comparable length of stay at a higher altitude (4100 m). They showed comparable changes for HR, stroke volume, PAP, and PVR as shown in the investigated asthma cohort and thus may indicate that the presently investigated patients with mostly mild asthma could stay at a high altitude without exaggerated changes in pulmonary or systemic hemodynamics. The acute effect of high altitudes on PAP and PVR due to hypoxic pulmonary vasoconstriction is well known (Grünig et al., 2000; Maggiorini and Leon-Velarde, 2003; Grunig et al., 2009) and is reversible after descent (Hilty et al., 2016). In contrast to our study, the cardiac index increased at high altitude, probably due to a higher increase in heart rate. An increase in cardiac output during acute exposure was also found in patients with other obstructive lung diseases such as chronic obstructive pulmonary disease (Lichtblau et al., 2023).

In non-acclimatized Chinese Han lowlanders, Liu et al. (2022) showed that subacute exposure led to an enlargement of the right ventricle and a decrease of the diastolic right ventricular function, whereas the systolic function only decreased after long-term exposure to high altitudes (working at high altitudes for more than two decades). In our study, only the right ventricular end-systolic area was significantly enlarged at acute and subacute measurements at high altitude. Right ventricular systolic function was preserved; TAPSE did not significantly change during the high-altitude stay; FAC decreased slightly and was significantly lower in the subacute phase. We do not have a certain explanation for these changes; however, baseline examinations were performed during the summer at Bishkek with temperatures ranging around 45°C, and participants might have been dehydrated during the assessment leading to reduced intravascular and intracardiac fluid volumes, whereas the temperatures were significantly colder at the higher altitude. However, all values measured at high altitude were still within the normal range, and changes were slight and in accordance with those expected in healthy subjects (Gaur et al., 2021).

A study from Turkey focused on the long-term effect of migrating to higher altitudes in lowlanders. That study performed echocardiography within 48 h and 6 months after arrival at a moderate altitude (1890 m) but did not take baseline measurements at the low altitude. In contrast to the Chinese study, the Turkish study showed that RV diastolic function is altered upon long-term exposure to moderate altitudes, whereas systolic function was preserved (Arisoy et al., 2016).

B-lines can be used to measure extravascular lung water. High-altitude exposure can lead to acute mountain sickness and HAPE (Fagenholz et al., 2007). The increase in EVLW might be explained initially by elevated hydrostatic pressure that causes capillary leakage followed by extravasation of large-molecular-weight proteins and erythrocytes in the interstitial space, creating an increased osmotic gradient. This can then lead to pulmonary edema (Bartsch et al., 2005). The participants of this study did not show any clinical symptoms or signs of HAPE. Studies have shown that HAPE usually develops after 2–5 days upon exposure to high altitudes (Maggiorini, 2006). Similar to the study of Lichtblau et al. (2021a) that assessed healthy subjects at a low (720 m) and a high altitude (5050 m) in Chile, we have shown in this study that upon acute exposure to a high altitude, the number of B-lines initially increased and then decreased upon acclimatization. Our study showed acclimatization in terms of B-lines and also a moderate recovery of SpO₂. This is consistent with compensatory mechanisms that assure adequate homeostasis of lung water during prolonged exposure to hypobaric hypoxia.