HAPE-susceptible Subjects Research Articles

Susceptibility to high-altitude pulmonary edema is associated with increased pulmonary arterial stiffness during exercise.

High-altitude pulmonary edema (HAPE), a reversible form of capillary leak, is a common consequence of rapid ascension to high altitude and a major cause of death related to high-altitude exposure. Individuals with a prior history of HAPE are more susceptible to future episodes, but the underlying risk factors remain uncertain. Previous studies have shown that HAPE-susceptible subjects have an exaggerated pulmonary vasoreactivity to acute hypoxia, but incomplete data are available regarding their vascular response to exercise. To examine this, seven HAPE-susceptible subjects and nine control subjects (HAPE-resistant) were studied at rest and during incremental exercise at sea level and at 3,810 m altitude. Studies were conducted in both normoxic (inspired Po2 = 148 Torr) and hypoxic (inspired Po2 = 91 Torr) conditions at each location. Here, we report an expanded analysis of previously published data, including a distensible vessel model that showed that HAPE-susceptible subjects had significantly reduced small distal artery distensibility at sea level compared with HAPE-resistant control subjects [0.011 ± 0.001 vs. 0.021 ± 0.002 mmHg-1; P < 0.001). Moreover, HAPE-susceptible subjects demonstrated constant distensibility over all conditions, suggesting that distal arteries are maximally distended at rest. Consistent with having increased distal artery stiffness, HAPE-susceptible subjects had greater increases in pulmonary artery pulse pressure with exercise, which suggests increased proximal artery stiffness. In summary, HAPE-susceptible subjects have exercise-induced increases in proximal artery stiffness and baseline increases in distal artery stiffness, suggesting increased pulsatile load on the right ventricle.NEW & NOTEWORTHY In comparison to subjects who appear resistant to high-altitude pulmonary edema, those previously symptomatic show greater increases in large and small artery stiffness in response to exercise. These differences in arterial stiffness may be a risk factor for the development of high-altitude pulmonary edema or evidence that consequences of high-altitude pulmonary edema are long-lasting after return to sea level.

Subclinical pulmonary dysfunction contributes to high altitude pulmonary edema susceptibility in healthy non-mountaineers

HAPE susceptible (HAPE-S, had HAPE episode in past) subjects may have subclinical cardio-pulmonary dysfunction. We compared the results of pulmonary function tests in 25 healthy HAPE-S non-mountaineers and 19 matched HAPE resistant (HAPE-R, no HAPE episode in past). Acute normobaric hypoxia (FIo2 0.12) was administered at sea level to confirm hypoxia intolerance in HAPE-S. Unlike HAPE-R, HAPE-S subjects had elevated baseline and post-hypoxia systolic pulmonary arterial pressures (20.9 ± 3 vs 27.3 ± 5 mm Hg during normoxia and 26.2 ± 6 vs 45.44 ± 10 mm Hg during hypoxia, HAPE-R vs HAPE-S). Forced vital capacity (FVC) and single breath alveolar volume (SBVA) were significantly lower in HAPE-S compared to HAPE-R (FVC: 4.33 ± 0.5 vs 4.6 ± 0.4; SBVA: 5.17 ± 1 vs 5.6 ± 1 Lt; HAPE-S vs HAPE-R). Two subgroups with abnormal pulmonary function could be identified within HAPE-S; HAPE-S1 (n = 4) showed DLCO>140% of predicted, suggestive of asthma and HAPE-S2 (n = 12) showed restrictive pattern. Each of these patterns have previously been linked to early small airway disease and may additionally represent a lower cross-sectional area of the pulmonary vascular bed, related to lower lung volumes. HAPE susceptibility in healthy non-mountaineers may be related to sub-clinical pulmonary pathology that limits compensatory rise in ventilation and pulmonary circulation during hypoxic stress.

Susceptibility to high-altitude pulmonary edema is associated with a more uniform distribution of regional specific ventilation.

High-altitude pulmonary edema (HAPE) is a potentially fatal condition affecting high-altitude sojourners. The biggest predictor of HAPE development is a history of prior HAPE. Magnetic resonance imaging (MRI) shows that HAPE-susceptible (with a history of HAPE), but not HAPE-resistant (with a history of repeated ascents without illness) individuals develop greater heterogeneity of regional pulmonary perfusion breathing hypoxic gas (O2 = 12.5%), consistent with uneven hypoxic pulmonary vasoconstriction (HPV). Why HPV is uneven in HAPE-susceptible individuals is unknown but may arise from regionally heterogeneous ventilation resulting in an uneven stimulus to HPV. We tested the hypothesis that ventilation is more heterogeneous in HAPE-susceptible subjects (n = 6) compared with HAPE-resistant controls (n = 7). MRI specific ventilation imaging (SVI) was used to measure regional specific ventilation and the relative dispersion (SD/mean) of SVI used to quantify baseline heterogeneity. Ventilation heterogeneity from conductive and respiratory airways was measured in normoxia and hypoxia (O2 = 12.5%) using multiple-breath washout and heterogeneity quantified from the indexes Scond and Sacin, respectively. Contrary to our hypothesis, HAPE-susceptible subjects had significantly lower relative dispersion of specific ventilation than the HAPE-resistant controls [susceptible = 1.33 ± 0.67 (SD), resistant = 2.36 ± 0.98, P = 0.05], and Sacin tended to be more uniform (susceptible = 0.085 ± 0.009, resistant = 0.113 ± 0.030, P = 0.07). Scond was not significantly different between groups (susceptible = 0.019 ± 0.007, resistant = 0.020 ± 0.004, P = 0.67). Sacin and Scond did not change significantly in hypoxia (P = 0.56 and 0.19, respectively). In conclusion, ventilation heterogeneity does not change with short-term hypoxia irrespective of HAPE susceptibility, and lesser rather than greater ventilation heterogeneity is observed in HAPE-susceptible subjects. This suggests that the basis for uneven HPV in HAPE involves vascular phenomena.NEW & NOTEWORTHY Uneven hypoxic pulmonary vasoconstriction (HPV) is thought to incite high-altitude pulmonary edema (HAPE). We evaluated whether greater heterogeneity of ventilation is also a feature of HAPE-susceptible subjects compared with HAPE-resistant subjects. Contrary to our hypothesis, ventilation heterogeneity was less in HAPE-susceptible subjects and unaffected by hypoxia, suggesting a vascular basis for uneven HPV.

Raised HIF1α during normoxia in high altitude pulmonary edema susceptible non-mountaineers.

High altitude pulmonary edema (HAPE) susceptibility is associated with EGLN1 polymorphisms, we hypothesized that HAPE-susceptible (HAPE-S, had HAPE episode in past) subjects may exhibit abnormal HIF1α levels in normoxic conditions. We measured HIF1α levels in HAPE-S and HAPE resistant (HAPE-R, no HAPE episode) individuals with similar pulmonary functions. Hemodynamic responses were also measured before and after normobaric hypoxia (Fi02 = 0.12 for 30 min duration at sea level) in both groups. . HIF1α was higher in HAPE-S (320.3 ± 267.5 vs 58.75 ± 33.88 pg/ml, P < 0.05) than HAPE-R, at baseline, despite no significant difference in baseline oxygen saturations (97.7 ± 1.7% and 98.8 ± 0.7). As expected, HAPE-S showed an exaggerated increase in pulmonary artery pressure (27.9 ± 6 vs 19.3 ± 3.7 mm Hg, P < 0.05) and a fall in peripheral oxygen saturation (66.9 ± 11.7 vs 78.7 ± 3.8%, P < 0.05), when exposed to hypoxia. HIF1α levels at baseline could accurately classify members of the two groups (AUC = 0.87). In a subset of the groups where hemoglobin fractions were additionally measured to understand the cause of elevated hypoxic response at baseline, two of four HAPE-S subjects showed reduced HbA. In conclusion, HIF 1 α levels during normoxia may represent an important marker for determination of HAPE susceptibility.

Elevated pulmonary artery pressure and brain natriuretic peptide in high altitude pulmonary edema susceptible non-mountaineers.

Exaggerated pulmonary pressor response to hypoxia is a pathgonomic feature observed in high altitude pulmonary edema (HAPE) susceptible mountaineers. It was investigated whether measurement of basal pulmonary artery pressure (Ppa) and brain natriuretic peptide (BNP) could improve identification of HAPE susceptible subjects in a non-mountaineer population. We studied BNP levels, baseline hemodynamics and the response to hypoxia (FIo2 = 0.12 for 30 min duration at sea level) in 11 HAPE resistant (no past history of HAPE, Control) and 11 HAPE susceptible (past history of HAPE, HAPE-S) subjects. Baseline Ppa (19.31 ± 3.63 vs 15.68 ± 2.79 mm Hg, p < 0.05) and plasma BNP levels (52.39 ± 32.9 vs 15.05 ± 9.6 pg/ml, p < 0.05) were high and stroke volume was less (p < 0.05) in HAPE-S subjects compared to control. Acute hypoxia produced an exaggerated increase in heart rate (p < 0.05), mean arterial pressure (p < 0.05) and Ppa (28.2 ± 5.8 vs 19.33 ± 3.74 mm Hg, p < 0.05) and fall in peripheral oxygen saturation (p < 0.05) in HAPE-S compared to control. Receiver operating characteristic (ROC) curves showed that Ppa response to acute hypoxia was the best variable to identify HAPE susceptibility (AUC 0.92) but BNP levels provided comparable information (AUC 0.85). BNP levels are easy to determine and may represent an important marker for the determination of HAPE susceptibility.

Hypoxia-Induced Inflammatory Chemokines in Subjects with a History of High-Altitude Pulmonary Edema.

High altitude hypoxia is known to induce an inflammatory response in immune cells. Hypoxia induced inflammatory chemokines may contribute to the development of high altitude pulmonary edema (HAPE) by causing damage to the lung endothelial cells and thereby capillary leakage. In the present study, we were interested to know whether chronic inflammation may contribute to HAPE susceptibility. We examined the serum levels of macrophage inflammatory protein-1α (MIP-1α), monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 in group (1) HAPE Susceptible subjects(n=20) who had past history of HAPE and group (2) Control (n=18) consist of subjects who had stayed at high altitude for 2years without any history of HAPE. The data obtained confirmed that circulating MCP-1, MIP-1α were significantly upregulated in HAPE-S individuals as compared to the controls suggestive of chronic inflammation. However, it is not certain whether chronic inflammation is cause or consequence of previous episode of HAPE. The moderate systemic increase of these inflammatory markers may reflect considerable local inflammation. The existence of enhanced level of inflammatory chemokines found in this study support the hypothesis that subjects with past history of HAPE have higher baseline chronic inflammation which may contribute to HAPE susceptibility.

Echocardiographic Assessment of Cardiac Performance in Response to High Altitude and Development of Subclinical Pulmonary Edema in Healthy Climbers

BackgroundData regarding the effect of high altitude on heart function are sparse and conflicting. We aimed to assess the right and left ventricular responses to altitude-induced hypoxia and the occurrence of subclinical pulmonary edema. MethodsEchocardiography was performed according to protocol on 14 subjects participating in an expedition in Nepal, at 3 altitude levels: Montreal (30 m), Namche Bazaar (3450 m), and Chukkung (4730 m). Systematic lung ultrasound was performed to detect ultrasound lung comets. ResultsPulmonary artery systolic pressure increased in all subjects between Montreal and Chukkung (mean 27.4 ± 5.4 mm Hg vs 39.3 ± 7.7 mm Hg; P < 0.001). Right ventricular (RV) myocardial performance index (MPI) increased significantly (0.32 ± 0.08 at 30 m vs 0.41 ± 0.10 at 4730 m; P = 0.046). A trend toward deteriorated RV free wall longitudinal strain was observed between Montreal and Chukkung (−25.9 [5.3%] vs −21.9 [6.4%]; P = 0.092). The left ventricular early diastolic inflow velocity/atrial mitral inflow velocity and early diastolic inflow velocity/mean of the maximal early diastolic mitral annulus tissue doppler velocities ratios remained unchanged. At 4730 m, ultrasound lung comets were seen in all subjects except 1. None had clinical criteria for high-altitude pulmonary edema (HAPE). All altered parameters normalized after return to sea level. ConclusionSubclinical HAPE is frequent in healthy lowlander climbers. This is the first study to document a trend towards decreased RV free wall strain and MPI increment at high altitude. Whether rising RV MPI is a physiologic adaptive mechanism to hypoxia or a pathologic response identifying HAPE-susceptible subjects needs further study.

241 Echocardiographic Assessment of Myocardial Performance in Response to High Altitude and Development of Subclinical Pulmonary Edema in Healthy Climbers

Despite a known association with increased pulmonary artery pressure (PAP), the pathophysiology of high-altitude pulmonary edema (HAPE) remains incompletely understood. Data regarding the impact of high altitude on left and right heart functions are sparse and conflicting. No single parameter has been validated to predict the development of HAPE among recreational climbers. We aimed to assess, by echocardiography, the right and left ventricular responses to high-altitude-induced hypoxia and to detect the occurrence of subclinical pulmonary edema. This observational study included 14 healthy subjects (8 men ; ages 27-65 years old) participating in a trekking expedition in the Everest Valley, Nepal. Echocardiography, using a portable unltrasound system (Vivid I, GE Healthcare), including the assessment of right ventricular performance parameters, was performed in Montréal (30 meters above sea level), Namche Bazar, Nepal (3450m) and Chhukkung (4730m). Lung ultrasound was performed to detect the appearance of ultrasound lung comets (ULCs) suggestive of subclinical pulmonary edema, quantified by a previously validated ULC score integrating the extent and severity of lung comets. Symptoms of high altitude sickness were assessed via the validated Lake Louise Questionnaire (LLQ). At high altitude, ULCs were seen in all except one of the subjects, with ULC scores ranging from 0 to 18 at 4730m (Fig. 1). None of the subjects had clinical criteria for HAPE. Systolic PAP increased in all subjects between Montréal and Chhukkung (mean PAP 27.4 +/− 5.4 mmHg vs. 39.3 +/− 7.7 mmHg respectively; p<0.001). Right ventricular myocardial performance index (MPI; Tei index), assessed by the pulsed-wave doppler method, increased with rising altitude (0.32 +/− 0.08 at 30m vs. 0.41 +/− 0.10 at 4730m; p=0.046). The right ventricular parameters S' and Tricuspid Annular Plane Systolic Excursion (TAPSE) remained unchanged, as did the left ventricular E/A ratio suggesting no significant change in left ventricular diastolic function. Heart rate and cardiac output increased in every subject at high altitude. No correlation could be drawn between PAP increment and MPI, MPI and ULC score, and MPI and LLQ score. Subclinical high-altitude pulmonary edema is frequent in healthy climbers living at low altitude. Right ventricular MPI increases at high altitude, and does not seem to be correlated to the magnitude of PAP increment. Whether rising MPI is a physiologic adaptive mechanism to high-altitude hypoxia or a pathologic response identifying HAPE-susceptible subjects needs to be further determined.

Bosentan Effects in Hypoxic Pulmonary Vasoconstriction: Preliminary Study in Subjects with or without High Altitude Pulmonary Edema‐History

Hypoxia-induced pulmonary vasoconstriction in patients with a medical history of high-altitude pulmonary edema (HAPE) may involve activation of the endothelin-1 (ET-1) pathway. We, therefore, compared the effect of the ETA/ETB receptor antagonist, bosentan, on pulmonary artery systolic pressure (PASP) in healthy subjects with (HS: HAPE subjects, n=5) or without a HAPE-history (CS: Control subjects, n=10). A double-blind, placebo-controlled, randomized, crossover design was performed in order to study the effects on PASP of a single oral dose of bosentan (250 mg) after 90 min exposure to normobaric hypoxia (FiO2 =0.12). In normoxia, PASP, evaluated by echocardiography, was 23.4±2.7 mmHg in CS and 28±5.8 mmHg in HS (NS). During the placebo period, hypoxia induced a significant decrease in SaO2, PaO2 and PCO2 and increase in pH in both CS and HS. Pulmonary arterial systolic pressure was also significantly increased (+8.5±5.0 mmHg in CS; +13.4±3.1 mmHg in HS) and reached significantly higher levels in HS than in CS (P=0.02). Bosentan significantly but similarly blunted the hypoxia-induced increase in PASP in both CS (Bosentan: 27.0±3.3 mmHg; placebo: 32.1±3.5 mmHg; P<0.01) and HS (Bosentan: 35.0±2.9 mmHg; placebo: 41.4±7.6 mmHg; P<0.05), (CS 5.2±5.3 vs. HS -6.4±5.2 mmHg, NS). Bosentan did not have a major effect on the hypoxia-induced changes in blood gas, or on cardiac output (CO) and systemic blood pressure (SBP), which were not modified by hypoxia. Plasma ET-1 in hypoxia during the bosentan period was 2.8 times higher than during for both CS and HS. A single oral dose of bosentan similarly blunted the hypoxia-induced increase in PASP both in healthy and HAPE-susceptible subjects, without altering CO or SBP.

Pulmonary arterial systolic pressure and susceptibility to high altitude pulmonary edema

There is evidence that pulmonary arterial hypertension plays a major role in the occurrence of high altitude pulmonary edema (HAPE). We tested the hypothesis that the pulmonary arterial systolic pressure response to a challenge associated with hypoxia and mild exercise may be considered a predictive factor of HAPE. Pulmonary arterial systolic pressure was measured by Doppler echocardiography in 8 HAPE susceptible (HAPE-S) subjects and 8 HAPE resistant mountaineers (HAPE-R) during a hypoxic exercise challenge established by the French Association for Sport Medicine (Richalet's test). Pulmonary arterial systolic pressure during hypoxic exercise allowed a significant discrimination between the groups, although an overlap of values was observed. When expressed as individual variations from baseline to hypoxic exercise level however, we found a highly significant difference. No overlap was observed between HAPE-R (range: 6.7-18.5 mmHg) and HAPE-S (range: 19.2-30.4 mmHg) groups, with a cut-off value at 19 mmHg. Plasma Vascular Endothelial growth factor (VEGF) and malondialdehyde (MDA) increased in response to hypoxic exercise only in HAPE-S group. Individual increases in pulmonary arterial systolic pressure during hypoxic exercise from basal resting normoxic values seem relevant to estimate HAPE susceptibility when measured during the Richalet's test.

Myocardial Performance Index in Subjects Susceptible to High-Altitude Pulmonary Edema

A recent study concerning high-altitude pulmonary edema (HAPE), a non-cardiogenic pulmonary edema, suggested that it is initially a hydrostatic-type pulmonary edema. We suspect that some extent of cardiac insufficiency may likely relate to the mechanism of the development of this disease. By Doppler echocardiography, the Tei index (a new quantitative index proposed for the evaluation of global myocardial performance) and the systolic pulmonary artery pressure (sPAP) were measured before and after 30 minutes of hypoxic breathing. Eleven HAPE-susceptible subjects (HAPE-s) and nine HAPE-resistant subjects (HAPE-r). The results of Tei index indicated an enhanced left myocardial performance but an impaired right performance in HAPE-s during hypoxic breathing. The sPAP of HAPE-s was significantly increased after hypoxic breathing, which was not correlated with the heart functions such as right ventricular (RV) Tei index, cardiac index (CI), percent ejection fraction (EF%) and percent fractional shortening (FS%) under hypoxic condition. Comparatively, the HAPE-r subjects did not show such significant changes of Tei index after hypoxic breathing. The results suggested that a paradoxical myocardial performance, in a format of an augmented left ventricular (LV) in contrast to an attenuated RV, was observed in the HAPE-s exposed to acute hypoxia. The responses of the left and right myocardial performances to hypoxia may be involved in the pathogenesis of HAPE.

High-altitude pulmonary hypertension is associated with a free radical-mediated reduction in pulmonary nitric oxide bioavailability

High altitude (HA)-induced pulmonary hypertension may be due to a free radical-mediated reduction in pulmonary nitric oxide (NO) bioavailability. We hypothesised that the increase in pulmonary artery systolic pressure (PASP) at HA would be associated with a net transpulmonary output of free radicals and corresponding loss of bioactive NO metabolites. Twenty-six mountaineers provided central venous and radial arterial samples at low altitude (LA) and following active ascent to 4559 m (HA). PASP was determined by Doppler echocardiography, pulmonary blood flow by inert gas re-breathing, and vasoactive exchange via the Fick principle. Acute mountain sickness (AMS) and high-altitude pulmonary oedema (HAPE) were diagnosed using clinical questionnaires and chest radiography. Electron paramagnetic resonance spectroscopy, ozone-based chemiluminescence and ELISA were employed for plasma detection of the ascorbate free radical (A(·-)), NO metabolites and 3-nitrotyrosine (3-NT). Fourteen subjects were diagnosed with AMS and three of four HAPE-susceptible subjects developed HAPE. Ascent decreased the arterio-central venous concentration difference (a-cv(D)) resulting in a net transpulmonary loss of ascorbate, α-tocopherol and bioactive NO metabolites (P < 0.05 vs. LA). This was accompanied by an increased a-cv(D) and net output of A(·-) and lipid hydroperoxides (P < 0.05 vs. sea level, SL) that correlated against the rise in PASP (r = 0.56-0.62, P < 0.05) and arterial 3-NT (r = 0.48-0.63, P < 0.05) that was more pronounced in HAPE. These findings suggest that increased PASP and vascular resistance observed at HA are associated with a free radical-mediated reduction in pulmonary NO bioavailability.

Polymorphisms of human vascular endothelial growth factor gene in high‐altitude pulmonary oedema susceptible subjects

Based on the reported biological properties and function of vascular endothelial growth factor (VEGF) in hypoxic conditions, many investigations have studied the hypothesis that VEGF has an important role in the pathogenesis of high altitude sicknesses, including high-altitude pulmonary oedema (HAPE). Unfortunately, the results are inconsistent. Therefore, the association of VEGF gene single nucleotide polymorphisms (SNP) with being susceptible to HAPE was investigated. The study included 53 HAPE-susceptible subjects (HAPE-s) and 69 HAPE-resistant mountaineer controls (HAPE-r). Subjects were Japanese and the two groups were comparable in terms of age and gender. The SNP of the VEGF gene, namely C-2578A, G-1154A and T-460C in the promoter, G + 405C in the 5'-untranslated region and C936T in the 3'-untranslated region, were examined by allele discrimination experiments. In addition, arterial oxygen tension (PaO(2)) and pulmonary haemodynamic data were available for 21 of the HAPE-s subjects. There were no statistically significant differences in the allele frequencies, genotype distributions or haplotype frequencies of VEGF SNP between the HAPE-s and HAPE-r groups. Furthermore, neither PaO(2) nor pulmonary haemodynamic parameters were associated with the VEGF SNP in the 21 HAPE-s subjects. This genetic study did not provide evidence that functional SNP of the VEGF gene are associated with susceptibility to HAPE in a Japanese population.

Effect of Altitude on the Heart and the Lungs

This review focuses on the effects of altitude exposure from 1 to several days or weeks as occurs in tourists, trekkers, and mountaineers who visit high altitude and normally reside near sea level. We briefly review the acute physiological adjustments and early acclimatization that occur in the cardiovascular system and the lungs of healthy individuals. These ensure life-sustaining oxygen delivery to the tissues despite a reduction in the partial pressure of inspired oxygen between 20% and 60% at 2500 and 8000 m, respectively. One of the acute adjustments, hypoxic pulmonary vasoconstriction (HPV), may be disadvantageous in those with a vigorous response and lead to 2 potentially lethal illnesses, high-altitude pulmonary edema (HAPE) and subacute mountain sickness (SAMS), which we present in more detail. Finally, on the basis of knowledge about the acute physiological adjustments and acclimatization and, when available, a review of the literature, we discuss the high-altitude tolerance of patients with coronary artery disease, congestive heart failure, arrhythmias, systemic hypertension, and pulmonary hypertension. ### Circulation The major effects of acute hypoxia on the heart and lung are shown in Figure 1. Hypoxia directly affects the vascular tone of the pulmonary and systemic resistance vessels and increases ventilation and sympathetic activity via stimulation of the peripheral chemoreceptors.1 Interactions occur between the direct effects of hypoxia on blood vessels and the chemoreceptor-mediated responses in the systemic and pulmonary circulation. Figure 1. Effects of hypoxia on systemic and pulmonary circulation. Unraveling the underlying mechanisms of the hypoxic vasodilatation of systemic arterioles is an active area of research. Several mechanisms appear to regulate local oxygen delivery according to the needs of the tissues2,3; for instance, the release of ATP from red blood cells and the generation of NO by various ways appear to regulate local oxygen delivery according to the needs …

Acute Changes in Pulmonary Artery Pressures Due to Exercise and Exposure to High Altitude Do Not Cause Left Ventricular Diastolic Dysfunction

Altitude-induced pulmonary hypertension has been suggested to cause left ventricular (LV) diastolic dysfunction due to ventricular interaction. In this study, we evaluate the effects of exercise- and altitude-induced increase in pulmonary artery pressures on LV diastolic function in an interventional setting investigating high-altitude pulmonary edema (HAPE) prophylaxis. Among 39 subjects, 29 were HAPE susceptible (HAPE-S) and 10 served as control subjects. HAPE-S subjects were randomly assigned to prophylactic tadalafil (10 mg), dexamethasone (8 mg), or placebo bid, starting 1 day before ascent. Doppler echocardiography at rest and during submaximal exercise was performed at low altitude (490 m) and high altitude (4,559 m). The ratio of early transmitral inflow peak velocity (E) to atrial transmitral inflow peak velocity (A), pulmonary venous flow parameters, and tissue velocity within the septal mitral annulus during early diastole (E') were used to assess LV diastolic properties. LV filling pressures were estimated by E/E'. Systolic right ventricular to atrial pressure gradients (RVPGs) were measured in order to estimate pulmonary artery pressures. At 490 m, E/A decreased similarly with exercise in HAPE-S and control subjects (HAPE-S, 1.5 +/- 0.3 to 1.3 +/- 0.3; control, 1.7 +/- 0.4 to 1.3 +/- 0.3; p = 0.12 between groups) [mean +/- SD], whereas RVPG increased significantly more in HAPE-S subjects (20 +/- 5 to 43 +/- 9 mm Hg vs 18 +/- 3 to 28 +/- 3 mm Hg, p < 0.001). Changes in RVPG levels during exercise did not correlate with changes in E/A (p > 0.1). From 490 to 4,559 m, no correlations between changes in RVPG and changes in E/A or atrial reversal (both p > 0.1) were observed. Neither of the groups showed an increase in E/E' from 490 to 4,559 m. Increased pulmonary artery pressure associated with exercise and acute exposure to 4,559 m appears not to cause LV diastolic dysfunction in healthy subjects. Therefore, ventricular interaction seems not to be of hemodynamic relevance in this setting.

Platelet count and function at high altitude and in high-altitude pulmonary edema

Platelet aggregation is the key process in primary hemostasis. Certain conditions such as hypoxia may induce platelet aggregation and lead to platelet sequestration primarily in the pulmonary microcirculation. We investigated the influence of high-altitude exposure on platelet function as part of a larger study on 30 subjects with a history of high-altitude pulmonary edema (HAPE) and 10 healthy controls. All participants were studied in the evening and the next morning at low altitude (450 m) and after an ascent to high altitude (4,559 m). Platelet count, platelet aggregation (platelet function analyzer PFA100; using epinephrine and ADP as activators), plasma soluble P (sP)-selectin, and the coagulation parameters prothrombin fragments 1+2 and thrombin-antithrombin complex were measured. High-altitude exposure decreased the platelet count, shortened the platelet function analyzer closure time by approximately 20%, indicating increased platelet aggregation, increased sP-selectin levels to approximately 250%, but left plasma coagulation unaffected. The HAPE-susceptible subjects were prophylactically treated with either tadalafil (a phosphodiesterase 5 inhibitor), dexamethasone, or placebo in a double-blind way. Subgroup analyses between these different treatments and comparisons of the seven placebo-treated individuals developing HAPE and controls revealed no differences in platelet count, platelet aggregation, or sP-selectin values. We conclude that exposure to high altitude activates platelets, which leads to platelet aggregation, platelet consumption, and decreased platelet count. These effects are, however, not more pronounced in individuals with a history of HAPE or actually suffering from HAPE than in controls and therefore may not be a pathophysiological mechanism of HAPE.

Heterogeneous pulmonary blood flow in response to hypoxia: A risk factor for high altitude pulmonary edema?

High altitude pulmonary edema (HAPE) is a rapidly reversible hydrostatic edema that occurs in individuals who travel to high altitude. The difficulties associated with making physiologic measurements in humans who are ill or at high altitude, along with the idiosyncratic nature of the disease and lack of appropriate animal models, has meant that our understanding of the mechanism of HAPE is incomplete, despite considerable effort. Bronchoalveolar lavage studies at altitude in HAPE-susceptible subjects have shown that mechanical stress-related damage to the pulmonary blood gas barrier likely precedes the development of edema. Although HAPE-susceptible individuals have increased pulmonary arterial pressure in hypoxia, how this high pressure is transmitted to the capillaries has been uncertain. Using functional magnetic resonance imaging of pulmonary blood flow, we have been able to show that regional pulmonary blood flow in HAPE-susceptible subjects becomes more heterogeneous when they are exposed to normobaric hypoxia. This is not observed in individuals who have not had HAPE, providing novel data supporting earlier suggestions by Hultgren that uneven hypoxic pulmonary vasoconstriction is an important feature of those who develop HAPE. This brief review discusses how uneven hypoxic pulmonary vasoconstriction increases regional pulmonary capillary pressure leading to stress failure of pulmonary capillaries and HAPE. We hypothesize that, in addition to the well-documented increase in pulmonary vascular pressure in HAPE-susceptible individuals, increased perfusion heterogeneity in hypoxia results in lung regions that are vulnerable to increased mechanical stress.

Identification of individuals susceptible to high-altitude pulmonary oedema at low altitude

Individuals susceptible to high-altitude pulmonary oedema (HAPE) are characterised by an abnormal increase of pulmonary artery systolic pressure (PASP) in hypoxia and during normoxic exercise, reduced hypoxic ventilatory response, and smaller lung volume. In 37 mountaineers with well-documented altitude tolerance, it was investigated whether any combination of these noninvasive measurements, including exercise in hypoxia, could improve the identification of HAPE-susceptible subjects at low altitude. HAPE-susceptible subjects showed a significant higher increase of PASP during hypoxia at rest (48+/-10 mmHg) compared with controls (38+/-3 mmHg), as well as during normoxic exercise (57+/-14 versus 38+/-7 mmHg) and hypoxic exercise (69+/-13 versus 49+/-8 mmHg). PASP could not be assessed in three and eight subjects during normoxic or hypoxic exercise, respectively, due to insufficient Doppler profiles or systemic arterial hypertension. Sensitivity (77-94%) and specificity (76-93%) were not significantly different between the various testing conditions. Additional assessment of hypoxic ventilatory response and lung function parameters did not improve identification of HAPE-susceptible subjects in a multivariate analysis. Due to the greater number of missing values in pulmonary artery systolic pressure measurements during hypoxic exercise, it was concluded that pulmonary artery systolic pressure measurements at rest during hypoxia or exercise in normoxia are most feasible for the identification of high-altitude pulmonary oedema-susceptible subjects.

Polymorphisms of Renin-Angiotensin System Genes With High-Altitude Pulmonary Edema in Japanese Subjects

The renin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT(1)R), plays an important role in the pathogenesis of pulmonary hypertension, which is suggested to be critical in the development of high-altitude pulmonary edema (HAPE). Investigating the associations of the polymorphisms in the genes of RAS with HAPE is to elucidate the genetic background underlying this disease. A cross-sectional, case-control study. Shinshu University Hospital, Matsumoto, Japan. Forty-nine HAPE-susceptible (HAPE-s) subjects with a history of HAPE, and 55 healthy climbers with HAPE resistance (HAPE-r). Twenty-one of 49 HAPE-s subjects underwent right cardiac catheterization. The insertion/deletion polymorphism in the ACE gene (ACE-I/D) was investigated by polymerase chain reaction (PCR). There was no significant difference of the distribution of the ACE-I/D polymorphism between the HAPE-s and HAPE-r groups. The A(1166)C and G(1517)T single-nucleotide polymorphisms (SNPs) in AT(1)R gene were investigated by the PCR following digested by corresponding restricted endonuclease enzymes. The distribution of the G(1517)T SNP was significantly different between the two groups (p = 0.012). The pulmonary hemodynamics of the 21 HAPE-s subjects were retrospectively examined. The pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and PVR index (PVRI) were all significantly increased on hospital admission. Moreover, the PVR and PVRI were significantly higher in the HAPE-s subjects with D positivity than in the HAPE-s subjects with I positivity (PVR, p = 0.015; PVRI, p = 0.028), while the PAP did not show any significant difference between the two subgroups. The ACE-I/D polymorphism is not associated with HAPE susceptibility in Japanese subjects. The AT(1)R gene polymorphisms may likely associate with HAPE susceptibility. The D allele of the ACE-I/D polymorphism probably contributes to the hyperresponsive PVR and PVRI to acute hypoxia.

Altered ion transporter expression in bronchial epithelium in mountaineers with high-altitude pulmonary edema.

Hypoxia inhibits activity and expression of transport proteins of cultured lung alveolar epithelial cells. Here we tested whether hypoxia at high altitude affected the expression of ion transport proteins in tissues obtained from controls and mountaineers with high-altitude pulmonary edema (HAPE) at the Capanna Margherita (4,559 m). Expression was determined by RT-PCR and Western blots from brush biopsies of bronchial epithelium and from leukocytes obtained before and during the stay at high altitude. At low altitude, amounts of mRNAs were not different between control and HAPE-susceptible subjects. At high altitude, the amount of mRNA of Na-K-ATPase, CFTR, and beta-actin of brush biopsies did not change in controls but decreased significantly (-60%) in HAPE-susceptible subjects. There was no change in Na channel mRNAs at high altitude in controls and HAPE. No statistically significant correlation was found between the expression of Na transporters and PO2 and O2 saturation. In leukocytes, 28S-rRNA and Na-K-ATPase decreased at altitude in control and HAPE-susceptible subjects, but no significant change in Na-K-ATPase protein was found. Hypoxia-inducible factor-1alpha mRNA and GAPDH mRNA tended to increase in leukocytes obtained from HAPE-susceptible subjects at high altitude but did not change in controls. These results show that hypoxia induces differences in mRNA expression of ion transport-related proteins between HAPE-susceptible and control subjects but that these changes may not necessarily predict differences in protein concentration or activity. It is therefore unclear whether these differences are related to the pathophysiology of HAPE.