Acute changes in cardiac dimensions, function, and longitudinal mechanics in healthy individuals with and without high-altitude induced pulmonary hypertension at 4559 m.

BACKGROUND: High-altitude pulmonary hypertension (HAPH) has a prevalence of approximately 10%. Changes in cardiac morphology and function at high altitude, compared to a population that does not develop HAPH are scarce. METHODS: Four hundred twenty-one subjects were screened in a hypoxic chamber inspiring a FiO2  = 12% for 2 h. In 33 subjects an exaggerated increase in systolic pulmonary artery pressure (sPAP) could be confirmed in two independent measurements. Twenty nine of these, and further 24 matched subjects without sPAP increase were examined at 4559 m by Doppler echocardiography including global longitudinal strain (GLS). RESULTS: SPAP increase was higher in HAPH subjects (∆ = 10.2 vs. ∆ = 32.0 mm Hg, p < .001). LV eccentricity index (∆ = .15 vs. ∆ = .31, p = .009) increased more in HAPH. D-shaped LV (0 [0%] vs. 30 [93.8%], p = .00001) could be observed only in the HAPH group, and only in those with a sPAP ≥50 mm Hg. LV-EF (∆ = 4.5 vs. ∆ = 6.7%, p = .24) increased in both groups. LV-GLS (∆ = 1.2 vs. ∆ = 1.1 -%, p = .60) increased slightly. RV end-diastolic (∆ = 2.20 vs. ∆ = 2.7 cm2 , p = .36) and end-systolic area (∆ = 2.1 vs. ∆ = 2.7 cm2 , p = .39), as well as RA end-systolic area index (∆ = -.9 vs. ∆ = .3 cm2 /m2 , p = .01) increased, RV-FAC (∆ = -2.9 vs. ∆ = -4.7%, p = .43) decreased, this was more pronounced in HAPH, RV-GLS (∆ = 1.6 vs. ∆ = -.7 -%, p = .17) showed marginal changes. CONCLUSIONS: LV and LA dimensions decrease and left ventricular function increases at high-altitude in subjects with and without HAPH. RV and RA dimensions increase, and RV longitudinal strain increases or remains unchanged in subjects with HAPH. Changes are negligible in those without HAPH.

Clinical Implications for Exercise at Altitude Among Individuals With Cardiovascular Disease: A Scientific Statement From the American Heart Association.

An increasing number of individuals travel to mountainous environments for work and pleasure. However, oxygen availability declines at altitude, and hypoxic environments place unique stressors on the cardiovascular system. These stressors may be exacerbated by exercise at altitude, because exercise increases oxygen demand in an environment that is already relatively oxygen deplete compared with sea-level conditions. Furthermore, the prevalence of cardiovascular disease, as well as diseases such as hypertension, heart failure, and lung disease, is high among individuals living in the United States. As such, patients who are at risk of or who have established cardiovascular disease may be at an increased risk of adverse events when sojourning to these mountainous locations. However, these risks may be minimized by appropriate pretravel assessments and planning through shared decision-making between patients and their managing clinicians. This American Heart Association scientific statement provides a concise, yet comprehensive overview of the physiologic responses to exercise in hypoxic locations, as well as important considerations for minimizing the risk of adverse cardiovascular events during mountainous excursions.

Genetic Predisposition to High-Altitude Pulmonary Edema.

Background: Exaggerated pulmonary arterial hypertension (PAH) is a hallmark of high-altitude pulmonary edema (HAPE). The objective of this study was therefore to investigate genetic predisposition to HAPE by analyzing PAH candidate genes in a HAPE-susceptible (HAPE-S) family and in unrelated HAPE-S mountaineers. Materials and Methods: Eight family members and 64 mountaineers were clinically and genetically assessed using a PAH-specific gene panel for 42 genes by next-generation sequencing. Results: Two otherwise healthy family members, who developed re-entry HAPE at 3640 m during childhood, carried a likely pathogenic missense mutation (c.1198T>G p.Cys400Gly) in the Janus Kinase 2 (JAK2) gene. One of them progressed to a mild form of PAH at the age of 23 years. In two of the 64 HAPE-S mountaineers likely pathogenic variants have been detected, one missense mutation in the Cytochrome P1B1 gene, and a deletion in the Histidine-Rich Glycoprotein (HRG) gene. Conclusions: This is the first study identifying an inherited missense mutation of a gene related to PAH in a family with re-entry HAPE showing a progression to borderline PAH in the index patient. Likely pathogenic variants in 3.1% of HAPE-S mountaineers suggest a genetic predisposition in some individuals that might be linked to PAH signaling pathways.

The Hen or the Egg: Impaired Alveolar Oxygen Diffusion and Acute High-altitude Illness?

Individuals ascending rapidly to altitudes >2500 m may develop symptoms of acute mountain sickness (AMS) within a few hours of arrival and/or high-altitude pulmonary edema (HAPE), which occurs typically during the first three days after reaching altitudes above 3000-3500 m. Both diseases have distinct pathologies, but both present with a pronounced decrease in oxygen saturation of hemoglobin in arterial blood (SO2). This raises the question of mechanisms impairing the diffusion of oxygen (O2) across the alveolar wall and whether the higher degree of hypoxemia is in causal relationship with developing the respective symptoms. In an attempt to answer these questions this article will review factors affecting alveolar gas diffusion, such as alveolar ventilation, the alveolar-to-arterial O2-gradient, and balance between filtration of fluid into the alveolar space and its clearance, and relate them to the respective disease. The resultant analysis reveals that in both AMS and HAPE the main pathophysiologic mechanisms are activated before aggravated decrease in SO2 occurs, indicating that impaired alveolar epithelial function and the resultant diffusion limitation for oxygen may rather be a consequence, not the primary cause, of these altitude-related illnesses.

Altered Left Ventricular Geometry and Torsional Mechanics in High Altitude-Induced Pulmonary Hypertension: A Three-Dimensional Echocardiographic Study.

BACKGROUND: Changes in left ventricular (LV) torsion have been related to LV geometry in patients with concomitant long-standing myocardial disease or pulmonary hypertension (PH). We evaluated the effect of acute high altitude-induced isolated PH on LV geometry, volumes, systolic function, and torsional mechanics. METHODS: Twenty-three volunteers were prospectively studied at low altitude and after the second (D3) and third night (D4) at high altitude (4,559 m). LV ejection fraction, multidirectional strains and torsion, LV volumes, sphericity, and eccentricity were derived by speckle-tracking on three-dimensional echocardiographic data sets. Pulmonary pressure was estimated from the transtricuspid pressure gradient (TRPG), LV preload from end-diastolic LV volume, and transmitral over mitral annular E velocity (E/e'). RESULTS: At high altitude, oxygen saturation decreased by 15%-20%, heart rate and cardiac index increased by 15%-20%, and TRPG increased from 21 ± 2 to 37 ± 9 mm Hg (P < .01). LV volumes, preload, ejection fraction, multidirectional strains, and sphericity remained unaffected, but diastolic (1.04 ± 0.07 to 1.09 ± 0.09 on D3/D4, P < .05) and systolic (1.00 ± 0.06 to 1.08 ± 0.1 [D3] and 1.06 ± 0.07 [D4], P < .05) eccentricity slightly increased, indicating mild septal flattening. LV torsion decreased from 2.14 ± 0.85 to 1.34 ± 0.68 (P < .05) and 1.65 ± 0.54 (P = .08) degrees/cm on D3/D4, respectively. Changes in torsion showed a weak inverse relationship to changes in systolic (r = -0.369, P = .013) and diastolic (r = -0.329, P = .032) eccentricity but not to changes in TRPG, heart rate or preload. CONCLUSIONS: High-altitude exposure was associated with mild septal flattening of the LV and reduced ventricular torsion at unchanged global LV function and preload, suggesting a relation between LV geometry and torsional mechanics.

Soluble Urokinase-Type Plasminogen Activator Receptor Plasma Concentration May Predict Susceptibility to High Altitude Pulmonary Edema.

Introduction. Acute exposure to high altitude induces inflammation. However, the relationship between inflammation and high altitude related illness such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS) is poorly understood. We tested if soluble urokinase-type plasminogen activator receptor (suPAR) plasma concentration, a prognostic factor for cardiovascular disease and marker for low grade activation of leukocytes, will predict susceptibility to HAPE and AMS. Methods. 41 healthy mountaineers were examined at sea level (SL, 446 m) and 24 h after rapid ascent to 4559 m (HA). 24/41 subjects had a history of HAPE and were thus considered HAPE-susceptible (HAPE-s). Out of the latter, 10/24 HAPE-s subjects were randomly chosen to suppress the inflammatory cascade with dexamethasone 8 mg bid 24 h prior to ascent. Results. Acute hypoxic exposure led to an acute inflammatory reaction represented by an increase in suPAR (1.9 ± 0.4 at SL versus 2.3 ± 0.5 at HA, p < 0.01), CRP (0.7 ± 0.5 at SL versus 3.6 ± 4.6 at HA, p < 0.01), and IL-6 (0.8 ± 0.4 at SL versus 3.3 ± 4.9 at HA, p < 0.01) in all subjects except those receiving dexamethasone. The ascent associated decrease in PaO2 correlated with the increase in IL-6 (r = 0.46, p < 0.001), but not suPAR (r = 0.27, p = 0.08); the increase in IL-6 was not correlated with suPAR (r = 0.16, p = 0.24). Baseline suPAR plasma concentration was higher in the HAPE-s group (2.0 ± 0.4 versus 1.8 ± 0.4, p = 0.04); no difference was found for CRP and IL-6 and for subjects developing AMS. Conclusion. High altitude exposure leads to an increase in suPAR plasma concentration, with the missing correlation between suPAR and IL-6 suggesting a cytokine independent, leukocyte mediated mechanism of low grade inflammation. The correlation between IL-6 and PaO2 suggests a direct effect of hypoxia, which is not the case for suPAR. However, suPAR plasma concentration measured before hypoxic exposure may predict HAPE susceptibility.

Does High Alveolar Fluid Reabsorption Prevent HAPE in Individuals with Exaggerated Pulmonary Hypertension in Hypoxia?

An exaggerated increase in pulmonary arterial systolic pressure (PAsP) is a highlight of high altitude pulmonary edema (HAPE). However, the incidence of HAPE at 4559 m was much lower in altitude-naïve individuals with exaggerated pulmonary vasoconstriction (HPV) in normobaric hypoxia than in known HAPE-susceptibles, indicating that elevated PAsP alone is insufficient to induce HAPE. A decreased nasal potential difference (NPD) has been found in HAPE-susceptibles, where, based on animal models, NPD serves as surrogate of alveolar epithelial ion transport. We hypothesize that those HAPE-resistant individuals with high HPV may be protected by elevated alveolar Na and fluid reabsorption, which might be detected as increased NPD. To test this hypothesis, we measured NPD in normoxia of subjects who were phenotyped in previous studies as high altitude tolerant (controls), known HAPE-susceptibles with high HPV (HP+HAPE), as well as individuals with high HPV but without HAPE (HP-no-HAPE) at 4559 m. NPD and amiloride-sensitive NPD were lower in HP+HAPE than in controls, whereas HP-no-HAPE were not different from either group. There were no differences in Cl-transport between groups. Our results show low nasal ion transport in HAPE but higher transport in those individuals with the highest HPV but without HAPE. This indicates that in some individuals with high PAsP at high altitude high alveolar fluid reabsorption might protect them from HAPE.

Exaggerated hypoxic pulmonary vasoconstriction without susceptibility to high altitude pulmonary edema.

BACKGROUND: Abnormally high pulmonary artery pressure (PAP) in hypoxia due to exaggerated hypoxic pulmonary vasoconstriction (HPV) is a key factor for development of high-altitude pulmonary edema (HAPE). It was shown that about 10% of a healthy Caucasian population has an exaggerated HPV that is comparable to the response measured in HAPE-susceptible individuals. Therefore, we hypothesized that those with exaggerated HPV are HAPE-susceptible. METHODS AND RESULTS: We screened 421 healthy Caucasians naïve to high altitude for HPV using Doppler echocardiography for assessment of systolic PAP in normobaric hypoxia (PASPHx; Po2 corresponding to 4500 m). Subjects with exaggerated HPV and matched controls were exposed to 4559 m with an identical protocol that causes HAPE in 62% of HAPE-S. Screening revealed 39 subjects with exaggerated HPV, of whom 33 (PASPHx 51±6 mmHg) ascended within 24 hours to 4559 m. Four (13%) of them developed HAPE during the 48 h-stay. This incidence is significantly lower than the recurrence rate of 62% previously observed in HAPE-S in the same setting. None of the control subjects (PASPHx 33±5 mmHg) developed HAPE. CONCLUSION: An exaggerated HPV cannot be considered a surrogate maker for HAPE-susceptibility although excessively elevated PAP is a hallmark in HAPE, while a normal HPV appears to protect from HAPE in this study.

Increased hepcidin levels in high-altitude pulmonary edema.

Low iron availability enhances hypoxic pulmonary vasoconstriction (HPV). Considering that reduced serum iron is caused by increased erythropoiesis, insufficient reabsorption, or elevated hepcidin levels, one might speculate that exaggerated HPV in high-altitude pulmonary edema (HAPE) is related to low serum iron. To test this notion we measured serum iron and hepcidin in blood samples obtained in previously published studies at low altitude and during 2 days at 4,559 m (HA1, HA2) from controls, individuals with HAPE, and HAPE-susceptible individuals where prophylactic dexamethasone and tadalafil prevented HAPE. As reported, at 4,559 m pulmonary arterial pressure was increased in healthy volunteers but reached higher levels in HAPE. Serum iron levels were reduced in all groups at HA2. Hepcidin levels were reduced in all groups at HA1 and HA2 except in HAPE, where hepcidin was decreased at HA1 but unexpectedly high at HA2. Elevated hepcidin in HAPE correlated with increased IL-6 at HA2, suggesting that an inflammatory response related to HAPE contributes to increased hepcidin. Likewise, platelet-derived growth factor, a regulator of hepcidin, was increased at HA1 and HA2 in controls but not in HAPE, suggesting that hypoxia-controlled factors that regulate serum iron are inappropriately expressed in HAPE. In summary, we found that HAPE is associated with inappropriate expression of hepcidin without inducing expected changes in serum iron within 2 days at HA, likely due to too short time. Although hepcidin expression is uncoupled from serum iron availability and hypoxia in individuals developing HAPE, our findings indicate that serum iron is not related with exaggerated HPV.

Sleeping in moderate hypoxia at home for prevention of acute mountain sickness (AMS): a placebo-controlled, randomized double-blind study.

OBJECTIVE: Acclimatization at natural altitude effectively prevents acute mountain sickness (AMS). It is, however, unknown whether prevention of AMS is also possible by only sleeping in normobaric hypoxia. METHODS: In a placebo-controlled, double-blind study 76 healthy unacclimatized male subjects, aged 18 to 50 years, slept for 14 consecutive nights at either a fractional inspired oxygen (Fio2) of 0.14 to 0.15 (average target altitude 3043 m; treatment group) or 0.209 (control group). Four days later, AMS scores and incidence of AMS were assessed during a 20-hour exposure in normobaric hypoxia at Fio2 = 0.12 (equivalent to 4500 m). RESULTS: Because of technical problems with the nitrogen generators, target altitude was not achieved in the tents and only 21 of 37 subjects slept at an average altitude considered sufficient for acclimatization (>2200 m; average, 2600 m). Therefore, in a subgroup analysis these subjects were compared with the 21 subjects of the control group with the lowest sleeping altitude. This analysis showed a significantly lower AMS-C score (0.38; 95% CI, 0.21 to 0.54) vs 1.10; 95% CI, 0.57 to 1.62; P = .04) and lower Lake Louise Score (3.1; 95% CI, 2.2 to 4.1 vs 5.1; 95% CI, 3.6 to 6.6; P = .07) for the treatment subgroup. The incidence of AMS defined as an AMS-C score greater than 0.70 was also significantly lower (14% vs 52%; P < .01). CONCLUSIONS: Sleeping 14 consecutive nights in normobaric hypoxia (equivalent to 2600 m) reduced symptoms and incidence of AMS 4 days later on exposure to 4500 m.

No correlation between plasma levels of vascular endothelial growth factor or its soluble receptor and acute mountain sickness.

Increased plasma levels of vascular endothelial growth factor (VEGF) due to lower levels of its soluble receptor (sFlt-1) had been suggested to cause vasogenic brain edema and thereby to cause the symptoms of acute mountain sickness (AMS). We tested this hypothesis after active ascent to high altitude. Plasma was collected from 31 subjects at low altitude (100 m) before (LA1) and after (LA2) 4 weeks of aerobic exercise training in normobaric hypoxia or normoxia, and one night after ascent to high altitude (4559 m). Training modalities (hypoxia or normoxia) did not influence VEGF- and sFlt-1-levels. Therefore, data of both training groups were analyzed together. After one night at 4559 m, 18 subjects had AMS (AMS+), 13 had no AMS (AMS-). In AMS+ and AMS-, VEGF was 110 ± 75 (SD) pg/ml vs. 104 ± 82 (p = 0.74) at LA1, 63 ± 40 vs. 73 ± 50 (p = 0.54) at LA2, and 88 ± 62 vs. 104 ± 81 (p = 0.54) at 4559 m, respectively. Corresponding values for sFlt-1 in AMS+ and AMS- were 81 pg/ml ± 13.1 vs. 82 ± 17 (p = 0.97), 79 ± 11 vs. 80 ± 16 (p = 0.92) and 139 ± 28 vs. 135 ± 31 (p = 0.70), respectively. Absolute values or changes of VEGF were not correlated and those of sFlt-1 slightly correlated with AMS scores. These data provide no evidence for a role of plasma VEGF and sFlt-1 in the pathophysiology of AMS. They do, however, not exclude paracrine effects of VEGF in the brain.

Transpulmonary plasma catecholamines in acute high-altitude pulmonary hypertension.

OBJECTIVE: High altitude leads to an increase in sympathetic nervous system (SNS) activity and pulmonary arterial pressure (PAP). We assessed whether the SNS contributes to this increase in PAP. METHODS: Sympathetic discharge to the pulmonary vasculature was assessed by measuring plasma norepinephrine concentrations in central venous blood entering the lung and systemic arterial blood leaving the lung (arterial-central venous difference; a - cv(diff)). Sympathetic activity in the adrenal gland was assessed by measuring systemic plasma epinephrine concentrations. The a - cv(diff) of epinephrine was assessed to investigate its metabolism across the lung. The measurements were performed in 34 mountaineers during both rest and exercise at low altitude and after 20 hours at high altitude (4559 m). Norepinehrine and epinephrine concentrations were measured by high-performance liquid chromatography. Pulmonary blood flow was assessed by inert gas rebreathing, and systolic PAP (PASP) by transthoracic Doppler-echocardiography. RESULTS: Exercise and high altitude increased PASP and increased arterial and central venous plasma norepinephrine. In contrast, exercise but not high altitude increased arterial and central venous epinephrine. There was no significant a - cv(diff) for norepinephrine and epinephrine during rest and exercise at low altitude, nor during rest at high altitude. However, during exercise at high altitude the a - cv(diff) for norepinephrine was positive. There was no correlation between the a - cv(diff) of both norepinephrine and epinephrine with PASP during exercise, high altitude or during a combination of both. CONCLUSIONS: The degree of pulmonary hypertension that occurs upon high-altitude exposure is largely independent of the SNS activity in the pulmonary vasculature and adrenal gland.

Acute in vitro hypoxia and high-altitude (4,559 m) exposure decreases leukocyte oxygen consumption.

Hypoxia impairs metabolic functions by decreasing activity and expression of ATP-consuming processes. To separate hypoxia from systemic effects, we tested whether hypoxia at high altitude affects basal and PMA-stimulated leukocyte metabolism and how this compares to acute (15 min) and 24 h of in vitro hypoxia. Leukocytes were prepared at low altitude and ∼24 h after arrival at 4559 m. Mitochondrial oxygen consumption (JO2) was measured by respirometry, oxygen radicals by electron spin resonance spectroscopy, both at a Po2 = 100 mmHg (JO2,100) and 20 mmHg (JO2,20). Acute hypoxia of leukocytes decreased JO2 at low altitude. Exposure to high altitude decreased JO2,100, whereas JO2,20 was not affected. Acute hypoxia of low-altitude samples decreased the activity of complexes I, II, and III. At high altitude, activity of complexes I and III were decreased when measured in normoxia. Stimulation of leukocytes with PMA increased JO2,100 at low (twofold) and high altitude (five-fold). At both locations, PMA-stimulated JO2 was decreased by acute hypoxia. Basal and PMA-stimulated reactive oxygen species (ROS) production were unchanged at high altitude. Separate in vitro experiments performed at low altitude show that ∼75% of PMA-induced increase in JO2 was due to increased extra-mitochondrial JO2 (JO2(,res); in the presence of rotenone and antimycin A). JO2(,res) was doubled by PMA. Acute hypoxia decreased basal JO2(,res) by ∼70% and PMA-stimulated JO2(,res) by about 50% in cells cultured in normoxia and hypoxia (1.5% O2; 24 h). Conversely, 24 h in vitro hypoxia decreased mitochondrial JO2,100 and JO2,20, extra-mitochondrial, basal, and PMA-stimulated JO2 were not affected. These results show that 24 h of high altitude but not 24 h in vitro hypoxia decreased basal leukocyte metabolism, whereas PMA-induced JO2 and ROS formation were not affected, indicating that prolonged high-altitude hypoxia impairs mitochondrial metabolism but does not impair respiratory burst. In contrast, acute hypoxia impairs respiratory burst at either altitude.

Can patients with coronary heart disease go to high altitude?

Tourism to high altitude is very popular and includes elderly people with both manifest and subclinical coronary heart disease (CHD). Thus, risk assessment regarding high altitude exposure of patients with CHD is of increasing interest, and individual recommendations are expected despite the lack of sufficient scientific evidence. The major factor increasing cardiac stress is hypoxia. At rest and for a given external workload, myocardial oxygen demand is increased at altitude, particularly in nonacclimatized individuals, and there is some evidence that blood-flow reserve is reduced in atherosclerotic coronary arteries even in the absence of severe stenosis. Despite a possible imbalance between oxygen demand and oxygen delivery, studies on selected patients have shown that exposure and exercise at altitudes of 3000 to 3500 m is generally safe for patients with stable CHD and sufficient work capacity. During the first days at altitude, patients with stable angina may develop symptoms of myocardial ischemia at slightly lower heart rate x blood-pressure products. Adverse cardiac events, however, such as unstable angina coronary syndromes, do not occur more frequently compared with sea level except for those who are unaccustomed to exercise. Therefore, training should start before going to altitude, and the altitude-related decrease in exercise capacity should be considered. Travel to 3500 m should be avoided unless patients have stable disease, preserved left ventricular function without residual capacity, and above-normal exercise capacity. CHD patients should avoid travel to elevations above 4500 m owing to severe hypoxia at these altitudes. The risk assessment of CHD patients at altitude should always consider a possible absence of medical support and that cardiovascular events may turn into disaster.

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.

Training in normobaric hypoxia and its effects on acute mountain sickness after rapid ascent to 4559 m.

In a randomized, placebo-controlled, double-blind study, we tested a 4-week program in normobaric hypoxia that is commercially offered for the prevention of acute mountain sickness (AMS). Twenty-two male and 18 female healthy subjects [mean age 33 +/- 7 (SD) years] exercised 70 min, 3 x /week for 3 weeks on a bicycle ergometer at workloads of 60% VO2max either in normoxia (normoxia group, NG) or in normobaric hypoxia (hypoxia group, HG), corresponding to altitudes of 2500, 3000, and 3500 m during weeks 1, 2, and 3, respectively. Four passive exposures of 90 min in normoxia (NG) or hypoxia corresponding to 4500 m (HG) followed in week 4. Five days after the last session, subjects ascended within 24 h from sea level to 4559 m (one overnight stay at 3611 m) and stayed there for 24 h. AMS was defined as LL (Lake Louise score) > or =5 and AMS-C > or =0.70. The AMS incidence (70% in NG vs. 60% in HG, p = 0.74), LL scores (7.1 +/- 4.3 vs. 5.9 +/- 3.4, p = 0.34), and AMS-C scores (1.50 +/- 1.22 vs. 0.93 +/- 0.81, p = 0.25) at the study endpoint were not significantly different between the groups. However, the incidence of AMS at 3611 m (6% vs. 47%, p = 0.01) and the functional LL score at 4559 m were lower in HG. SpO2 at 3611 m, heart rate during ascents, and arterial blood gases at 4559 m were not different between groups. We conclude that the tested program does not reduce the incidence of AMS within a rapid ascent to 4559 m, but our data show that it prevents AMS at lower altitudes. Whether such a program would prevent AMS at higher altitudes, but with slower ascent, remains to be tested.

Transpulmonary plasma ET-1 and nitrite differences in high altitude pulmonary hypertension.

Berger, Marc M., Christoph Dehnert, Damian M. Bailey, Andrew M. Luks, Elmar Menold, Christian Castell, Guido Schendler, Vitalie Faoro, Heimo Mairbäurl, Peter Bärtsch, and Eric R. Swenson. Transpulmonary plasma ET-1 and nitrite differences in high altitude pulmonary hypertension. High Alt. Med. Biol. 10:17-24, 2009.- Thirty-four mountaineers were studied at low (110 m) and high altitude (4559 m) to evaluate if increased pulmonary artery systolic pressure (PASP) at high altitude is associated with increased pulmonary endothelin-1 (ET-1) availability and alterations in nitrite metabolism across the lung. Blood samples were obtained using central venous and radial artery catheters for plasma ET-1 and nitrite. Pulmonary blood flow was measured by inert gas rebreathing to calculate transpulmonary exchange of plasma ET-1 and nitrite, and PASP was assessed by transthoracic Doppler echocardiography. After ascent to high altitude, PASP increased from 23 +/- 4 to 39 +/- 10 mmHg. Arterial and central venous plasma ET-1 increased, while plasma nitrite did not change significantly. At low altitude there was a transpulmonary loss of plasma ET-1, but a transpulmonary gain at high altitude. In contrast was a transpulmonary gain of plasma nitrite at low altitude and a transpulmonary loss at high altitude. PASP positively correlated with a transpulmonary gain of plasma ET-1 and negatively correlated with a transpulmonary loss of plasma nitrite. These results suggest that a transpulmonary gain of plasma ET- 1 is associated with higher PASP at high altitude. Transpulmonary loss of plasma nitrite indicates either less pulmonary nitric oxide (NO) production, which contributes to higher PASP, or increased NO bioavailability arising from nitrite reduction, which may oppose ET-1-mediated vasoconstriction.

Microhemorrhages in nonfatal high-altitude cerebral edema.

Vasogenic edema in the corpus callosum is a characteristic finding in high-altitude cerebral edema (HACE). Furthermore, microhemorrhages have been found at autopsies in brains of HACE victims. The objective of this study was to determine if microhemorrhages also occur in nonlethal HACE. Consequently, magnetic resonance imaging (MRI) was performed in patients who had suffered from HACE and in patients who had suffered from severe acute mountain sickness (AMS) by applying imaging techniques highly susceptible to blood or blood remnants. Two experienced neuroradiologists independently evaluated the exams blinded to clinical data. The MRI was performed 2 to 31 months after the event. The MRI of the HACE patients revealed multiple hemosiderin depositions in the brain--predominantly found in the corpus callosum--indicative of microhemorrhages. These changes were not present in the three AMS patients. In summary, hemosiderin deposits detectable by MRI predominantly in the corpus callosum indicate that microhemorrhages occur in nonlethal HACE, which may serve as a novel diagnostic MRI sign for HACE even many months after the event.