Asymmetric and symmetric dimethylarginine in high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE).

Introduction: High altitude exposure may lead to high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE). The pathophysiologic processes of both entities have been linked to decreased nitric oxide (NO) availability. Methods: We studied the effect of acute high altitude exposure on the plasma concentrations of asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-arginine, L-ornithine, and L-citrulline in two independent studies. We further investigated whether these biomarkers involved in NO metabolism were related to HAPH and HAPE, respectively. Fifty (study A) and thirteen (study B) non-acclimatized lowlanders were exposed to 4,559 m for 44 and 67 h, respectively. In contrast to study A, the participants in study B were characterized by a history of at least one episode of HAPE. Arterial blood gases and biomarker concentrations in venous plasma were assessed at low altitude (baseline) and repeatedly at high altitude. HAPE was diagnosed by chest radiography, and HAPH by measuring right ventricular to atrial pressure gradient (RVPG) with transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and the AMS-C score. Results: In both studies SDMA concentration significantly increased at high altitude. ADMA baseline concentrations were higher in individuals with HAPE susceptibility (study B) compared to those without (study A). However, upon high altitude exposure ADMA only increased in individuals without HAPE susceptibility, while there was no further increase in those with HAPE susceptibility. We observed an acute and transient decrease of L-ornithine and a more delayed but prolonged reduction of L-citrulline during high altitude exposure. In both studies SDMA positively correlated and L-ornithine negatively correlated with RVPG. ADMA was significantly associated with the occurrence of HAPE (study B). ADMA and SDMA were inversely correlated with alveolar PO2, while L-ornithine was inversely correlated with blood oxygenation and haemoglobin levels, respectively. Discussion: In non-acclimatized individuals ADMA and SDMA, two biomarkers decreasing endothelial NO production, increased after acute exposure to 4,559 m. The observed biomarker changes suggest that both NO synthesis and arginase pathways are involved in the pathophysiology of HAPH and HAPE.

Prevalence and knowledge about acute mountain sickness in the Western Alps.

OBJECTIVE: To assess the prevalence of acute mountain sickness (AMS) in 1370 mountaineers at four different altitudes in the Western Alps. We also examined the influence of potential risk factors and the knowledge about AMS on its prevalence. METHODS: In this observational cross-sectional study AMS was assessed on the day of ascent by the Lake Louise score (LLS, cut-off ≥3, version 2018) and the AMS-Cerebral (AMS-C) score of the environmental symptom questionnaire (cut-off ≥0,70). The latter was also obtained in the next morning. Knowledge regarding AMS and high-altitude cerebral edema (HACE) and the potential risk factors for AMS were evaluated by questionnaires. RESULTS: On the day of ascent, the prevalence of AMS assessed by the LLS and AMS-C score was 5.8 and 3.9% at 2850 m, 2.1 and 3.1% at 3050 m, 14.8 and 10.1% at 3650 m, and 21.9 and 15% at 4559 m, respectively. The AMS prevalence increased overnight from 10.1 to 14.5% and from 15 to 25.2% at 3650 m and 4559 m, respectively, and was unchanged at 2850 m and 3050 m. A history of AMS, higher altitude, lower degree of pre-acclimatization, and younger age were identified as risk factors for developing AMS. Slow ascent was weakly associated with AMS prevalence, and sex and knowledge about AMS and HACE were indistinct. CONCLUSION: AMS is common at altitudes ≥ 3650 m and better knowledge about AMS and HACE was not associated with less AMS in mountaineers with on average little knowledge.

Effects of acetazolamide on pulmonary artery pressure and prevention of high-altitude pulmonary edema after rapid active ascent to 4,559 m.

Acetazolamide prevents acute mountain sickness (AMS) by inhibition of carbonic anhydrase. Since it also reduces acute hypoxic pulmonary vasoconstriction (HPV), it may also prevent high-altitude pulmonary edema (HAPE) by lowering pulmonary artery pressure. We tested this hypothesis in a randomized, placebo-controlled, double-blind study. Thirteen healthy, nonacclimatized lowlanders with a history of HAPE ascended (<22 h) from 1,130 to 4,559 m with one overnight stay at 3,611 m. Medications were started 48 h before ascent (acetazolamide: n = 7, 250 mg 3 times/day; placebo: n = 6, 3 times/day). HAPE was diagnosed by chest radiography and pulmonary artery pressure by measurement of right ventricular to atrial pressure gradient (RVPG) by transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and AMS-C score. The incidence of HAPE was 43% versus 67% (acetazolamide vs. placebo, P = 0.39). Ascent to altitude increased RVPG from 20 ± 5 to 43 ± 10 mmHg (P < 0.001) without a group difference (P = 0.68). Arterial Po2 fell to 36 ± 9 mmHg (P < 0.001) and was 8.5 mmHg higher with acetazolamide at high altitude (P = 0.025). At high altitude, the LLS and AMS-C score remained lower in those taking acetazolamide (both P < 0.05). Although acetazolamide reduced HAPE incidence by 35%, this effect was not statistically significant, and was considerably less than reductions of about 70%-100% with prophylactic dexamethasone, tadalafil, and nifedipine performed with the same ascent profile at the same location. We could not demonstrate a reduction in RVPG compared with placebo treatment despite reductions in AMS severity and better arterial oxygenation. Limited by small sample size, our data do not support recommending acetazolamide for the prevention of HAPE in mountaineers ascending rapidly to over 4,500 m.NEW & NOTEWORTHY This randomized, placebo-controlled, double-blind study is the first to investigate whether acetazolamide, which reduces acute mountain sickness (AMS), inhibits short-term hypoxic pulmonary vasoconstriction, and also prevents high-altitude pulmonary edema (HAPE) in a fast-climbing ascent to 4,559 m. We found no statistically significant reduction in HAPE incidence or differences in hypoxic pulmonary artery pressures compared with placebo despite reductions in AMS and greater ventilation-induced arterial oxygenation. Our data do not support recommending acetazolamide for HAPE prevention.

Rapid Ascent to 4559 m Is Associated with Increased Plasma Components of the Vascular Endothelial Glycocalyx and May Be Associated with Acute Mountain Sickness.

Background: The stress of high altitude alters vascular permeability, which may be related to structural changes in the endothelial glycocalyx. We aimed to study these changes by measuring plasma concentrations of several glycocalyx components upon exposure to high altitude. Methods: Plasma collected from 17 subjects at low altitude (423 m) and at three time points (7, 20, and 44 hours) after rapid ascent to high altitude (4559 m) were evaluated for concentrations of three glycocalyx components: syndecan-1, intercellular adhesion molecule-1 (ICAM-1), and heparan sulfate. Vital signs and echocardiographic measurement of systolic pulmonary artery pressure (sPAP) and cardiac output were also obtained at low and high altitudes. Results: Mean age of the study population was 35.5 ± 11.2 years with a body mass index of 22.7 ± 2.5 kg/m2. Concentrations of ICAM-1 and heparan sulfate increased from baseline to 7 hours after arrival at high altitude; the ICAM-1 rise persisted at 20 hours. Syndecan-1 concentrations were increased only at 44 hours. Increased ICAM-1 concentrations correlated with sPAP and peripheral edema. Elevations in heparan sulfate appeared to correlate with acute mountain sickness (AMS). Conclusions: Levels of circulating glycocalyx components increase after exposure to high altitude and may correlate with AMS. Measuring plasma concentrations of various glycocalyx components could serve as a useful tool for further evaluation of vascular endothelial injury and repair in illness at high altitude.