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.

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.

Strengthening Altitude Knowledge: A Delphi Study to Define Minimum Knowledge of Altitude Illness for Laypersons Traveling to High Altitude.

Berendsen, Remco R., Peter Bärtsch, Buddha Basnyat, Marc Moritz Berger, Peter Hackett, Andrew M. Luks, Jean-Paul Richalet, Ken Zafren, Bengt Kayser, and the STAK Plenary Group. Strengthening altitude knowledge: a Delphi study to define minimum knowledge of altitude illness for laypersons traveling to high altitude. High Alt Med Biol. 23:330-337, 2022. Introduction: A lack of knowledge among laypersons about the hazards of high-altitude exposure contributes to morbidity and mortality from acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE) among high-altitude travelers. There are guidelines regarding the recognition, prevention, and treatment of acute-altitude illness for experts, but essential knowledge for laypersons traveling to high altitudes has not been defined. We sought expert consensus on the essential knowledge required for people planning to travel to high altitudes. Methods: The Delphi method was used. The panel consisted of two moderators, a core expert group and a plenary expert group. The moderators made a preliminary list of statements defining the desired minimum knowledge for laypersons traveling to high altitudes, based on the relevant literature. These preliminary statements were then reviewed, supplemented, and modified by a core expert group. A list of 33 statements was then presented to a plenary group of experts in successive rounds. Results: It took three rounds to reach a consensus. Of the 10 core experts invited, 7 completed all the rounds. Of the 76 plenary experts, 41 (54%) participated in Round 1, and of these 41 a total of 32 (78%) experts completed all three rounds. The final list contained 28 statements in 5 categories (altitude physiology, sleeping at altitude, AMS, HACE, and HAPE). This list represents an expert consensus on the desired minimum knowledge for laypersons planning high-altitude travel. Conclusion: Using the Delphi method, the STrengthening Altitude Knowledge initiative yielded a set of 28 statements representing essential learning objectives for laypersons who plan to travel to high altitudes. This list could be used to develop educational interventions.

An update on environment-induced pulmonary edema - "When the lungs leak under water and in thin air".

Acute pulmonary edema is a serious condition that may occur as a result of increased hydrostatic forces within the lung microvasculature or increased microvascular permeability. Heart failure or other cardiac or renal disease are common causes of cardiogenic pulmonary edema. However, pulmonary edema may even occur in young and healthy individuals when exposed to extreme environments, such as immersion in water or at high altitude. Immersion pulmonary edema (IPE) and high-altitude pulmonary edema (HAPE) share some morphological and clinical characteristics; however, their underlying mechanisms may be different. An emerging understanding of IPE indicates that an increase in pulmonary artery and capillary pressures caused by substantial redistribution of venous blood from the extremities to the chest, in combination with stimuli aggravating the effects of water immersion, such as exercise and cold temperature, play an important role, distinct from hypoxia-induced vasoconstriction in high altitude pulmonary edema. This review aims at a current perspective on both IPE and HAPE, providing a comparative view of clinical presentation and pathophysiology. A particular emphasis will be on recent advances in understanding of the pathophysiology and occurrence of IPE with a future perspective on remaining research needs.

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.

Midkine release during hemodialysis is predictive of hypervolemia and associates with excess (cardiovascular) mortality in patients with end-stage renal disease: a prospective study.

BACKGROUND: In end-stage renal disease, a high cardiovascular risk profile and endothelial damage prevails. The heparin-binding growth factor midkine stimulates neo-angiogenesis in ischemic diseases, coordinates neutrophil influx, and raises blood pressure through stimulated angiotensin synthesis. METHODS: We determined changes of midkine serum levels during hemodialysis sessions under the assumption that endothelial cell-derived midkine is released. Periprocedural differences (∆midkine) were calculated and correlated with cardiovacular biomarkers and fluid status (clinical assessment, V. cava collapse, comet tail phenomenon), cardiovascular morbidities, mortality rates. Blood was collected before and after dialysis from hemodialysis patients (n = 171; diabetes: n = 70; hypervolemia: n = 83; both: n = 32). RESULTS: Baseline midkine levels were ~ fourfold elevated compared to healthy controls (n = 100). Further, on average a tenfold rise was detected during dialysis, the extent of which was partially related to non-fractionated heparin application (r2 = 0.17). Inter-individual differences were highly reproducible. Hypervolemic patients responded with a less than average rise in midkine levels during dialysis (p < 0.02), this difference became more obvious with co-existing diabetes (p < 0.001 for long dialysis-free interval) and was confirmed in an independently enrolled dialysis cohort (n = 88). In Kaplan Meier survival curves, low delta midkine levels correlated with cardiovascular/overall mortality rates, similar to elevated uPAR levels, whereas other markers (NTproANP, galectin, tenascin-C) were less predictive. Following intervention with successful fluid removal in hypervolemic dialysis patients to optimize fluid homeostasis, midkine values increased (p < 0.002), which was not observed in patients that failed to decrease weight. CONCLUSION: Thus, for dialysis patients inadequate periprocedural midkine upregulation is linked with hypervolemia and associates with cardiovascular events.

The Impact of Nocebo and Placebo Effects on Reported Incidence of Acute Mountain Sickness.

Bärtsch Peter. The impact of nocebo and placebo effects on reported incidence of acute mountain sickness. High Alt Med Biol. 23:8-17, 2022.-Well comparable studies reporting acute mountain sickness (AMS) in nonacclimatized, acutely exposed individuals performed at 3,450-3,650 m (9 studies) and 4,559-4,675 m (18 studies) at real altitude or in hypobaric or in normobaric hypoxic chambers were analyzed with the hypothesis that the study design impacts occurrence of AMS. Individual symptoms and overall scores of AMS were not different between the three modalities of exposure to a comparable degree of hypoxia, indicating that hypobaria has, if at all, minimal influence on AMS. Studies not focusing versus those focusing on AMS report lower scores and prevalence of AMS at 3,500 m, but not at 4,559 m, while frequent assessment may be associated with more severe AMS. These data suggest that focusing on AMS creates expectations of getting AMS (nocebo effects) and increases its prevalence, while not paying attention reduces negative expectations and thus AMS. On the other hand, interventions promising improvement may cause positive expectations (placebo effect). Information about purpose and dangers of a study, repeated assessments for AMS, previous experiences of AMS, and observation of illness in other study participants are major factors contributing to negative expectations and thus nocebo effects increasing AMS. They should be considered when designing studies and subject information and be reported in detail in publications of studies on AMS.

Exposure to 16 h of normobaric hypoxia induces ionic edema in the healthy brain.

Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, stroke, or traumatic brain injury, cerebral edema can develop. The exact nature and genesis of hypoxia-induced edema in healthy individuals remain unresolved. We examined the effects of prolonged, normobaric hypoxia, induced by 16 h of exposure to simulated high altitude, on healthy brains using proton, dynamic contrast enhanced, and sodium MRI. This dual approach allowed us to directly measure key factors in the development of hypoxia-induced brain edema: (1) Sodium signals as a surrogate of the distribution of electrolytes within the cerebral tissue and (2) Ktrans as a marker of blood-brain-barrier integrity. The measurements point toward an accumulation of sodium ions in extra- but not in intracellular space in combination with an intact endothelium. Both findings in combination are indicative of ionic extracellular edema, a subtype of cerebral edema that was only recently specified as an intermittent, yet distinct stage between cytotoxic and vasogenic edemas. In sum, here a combination of imaging techniques demonstrates the development of ionic edemas following prolonged normobaric hypoxia in agreement with cascadic models of edema formation.

No renal dysfunction or salt and water retention in acute mountain sickness at 4,559 m among young resting males after passive ascent.

This study examined the role and function of the kidney at high altitude in relation to fluid balance and the development of acute mountain sickness (AMS), avoiding confounders that have contributed to conflicting results in previous studies. We examined 18 healthy male resting volunteers (18-40 yr) not acclimatized to high altitude while on a controlled diet for 24 h at Lausanne (altitude: 560 m) followed by a period of 44 h after reaching the Regina Margherita hut (4,559 m) by helicopter. AMS scores peaked after 20 h at 4,559 m. AMS was defined as functional Lake Louise score ≥ 2. There were no significant differences between 10 subjects with and 8 subjects without AMS for urinary flow, fluid balance, and weight change. Sodium excretion rate was lower in those with AMS after 24 h at altitude. Microalbuminuria increased at altitude but was not different between the groups. Creatinine clearance was not affected by altitude or AMS, whereas clearances of sinistrin and p-aminohippuric acid decreased slightly, somewhat more in those without AMS. Plasma concentrations of epinephrine, norepinephrine, atrial natriuretic factor, and vasopressin increased whereas renin activity, angiotensin, and aldosterone decreased at altitude. Circulating hormone concentrations did not differ between those with and without AMS. Summarizing, in healthy resting young men flown by helicopter to 4,559 m, renal function was not affected by hypoxia except for minor microalbuminuria, high altitude diuresis did not occur, and AMS was not associated with salt and water retention or renal dysfunction.NEW & NOTEWORTHY Kidney function remained essentially unaffected and acute mountain sickness (AMS) was not associated with salt and water retention in healthy young men flown to and resting at the Margherita hut (4,559 m) under strictly controlled conditions maintaining water, salt, and food intake at pre-exposure levels. Thus, renal dysfunction and fluid retention are not essential factors contributing to the pathophysiology of AMS.

No Relevant Analogy Between COVID-19 and Acute Mountain Sickness.

Berger, Marc Moritz, Peter H. Hackett, and Peter Bärtsch. No relevant analogy between COVID-19 and acute mountain sickness. High Alt Med Biol. 21:315-318, 2020.-Clinicians and scientists have suggested therapies for coronavirus disease-19 (COVID-19) that are known to be effective for other medical conditions. A recent publication suggests that pathophysiological mechanisms underlying acute mountain sickness (a syndrome of nonspecific neurological symptoms typically experienced by nonacclimatized individuals at altitudes >2500 m) may overlap with the mechanisms causing COVID-19. In this short review, we briefly evaluate this mistaken analogy and demonstrate that this concept is not supported by scientific evidence.

Ontogeny of electric organ and electric organ discharge in Campylomormyrus rhynchophorus (Teleostei: Mormyridae).

The aim of this study was a longitudinal description of the ontogeny of the adult electric organ of Campylomormyrus rhynchophorus which produces as adult an electric organ discharge of very long duration (ca. 25 ms). We could indeed show (for the first time in a mormyrid fish) that the electric organ discharge which is first produced early during ontogeny in 33-mm-long juveniles is much shorter in duration and has a different shape than the electric organ discharge in 15-cm-long adults. The change from this juvenile electric organ discharges into the adult electric organ discharge takes at least a year. The increase in electric organ discharge duration could be causally linked to the development of surface evaginations, papillae, at the rostral face of the electrocyte which are recognizable for the first time in 65-mm-long juveniles and are most prominent at the periphery of the electrocyte.

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.

Acute mountain sickness: Do different time courses point to different pathophysiological mechanisms?

Acute mountain sickness (AMS) is a syndrome of nonspecific symptoms (i.e., headache, anorexia, nausea, vomiting, dizziness, and fatigue) that may develop in nonacclimatized individuals after rapid exposure to altitudes ≥2,500 m. In field studies, mean AMS scores usually peak after the first night at a new altitude. Analyses of the individual time courses of AMS in four studies performed at 3,450 m and 4,559 m revealed that three different patterns are hidden in the above-described overall picture. In 41% of those who developed AMS (i.e., AMS-C score >0.70), symptoms peaked on day 1, in 39%, symptoms were most prominent on day 2, and in 20%, symptoms were most prominent on day 3. We suggest to name the different time courses of AMS type I, type II, and type III, respectively. Here, we hypothesize that the variation of time courses of AMS are caused by different pathophysiological mechanisms. This assumption could explain why no consistent correlations between an overall assessment of AMS and single pathophysiological factors have been found in a large number of studies over the past 50 yr. In this paper, we will briefly review the fundamental mechanisms implicated in the pathophysiology of AMS and discuss how they might contribute to the three different AMS time courses.

Endurance Athletes Are at Increased Risk for Early Acute Mountain Sickness at 3450 m.

INTRODUCTION: Acute mountain sickness (AMS) may develop in nonacclimatized individuals after exposure to altitudes ≥2500 m. Anecdotal reports suggest that endurance-trained (ET) athletes with a high maximal oxygen uptake (V˙O2max) may be at increased risk for AMS. Possible underlying mechanisms include a training-induced increase in resting parasympathetic activity, higher resting metabolic rate (RMR), and lower hypoxic ventilatory response (HVR). METHODS: In 38 healthy, nonacclimatized men (19 ET and 19 untrained controls [UT], V˙O2max 66 ± 6 mL·min·kg vs 45 ± 7 mL·min·kg; P < 0.001) peripheral oxygen saturation (SpO2), heart rate variability, RMR, and poikilocapnic HVR were assessed at 424 m and during 48 h at 3450 m after passive ascent by train (~2 h). Acute mountain sickness was evaluated by AMS cerebral (AMS-C) score. RESULTS: On day 1 at altitude, ET presented with a higher AMS incidence (42% vs 11%; P < 0.05) and severity (AMS-C score: ET, 0.48 ± 0.5 vs UT, 0.21 ± 0.2; P = 0.03), but no group difference was found on days 2 and 3. SpO2 decreased upon arrival at altitude (ET: 82% ± 6% vs UT: 83% ± 4%; ptime <0.001) with a significantly different time course between ET and UT (ptime × group = 0.045). Parasympathetic activity decreased at altitude (P < 0.001) but was always higher in ET (P < 0.05). At altitude RMR increased (P < 0.001) and was higher in ET (P < 0.001). Hypoxic ventilatory response increased only in ET (P < 0.05) and was greater than in UT after 24 and 48 h (P < 0.05). CONCLUSIONS: Endurance-trained athletes are at higher risk for developing AMS on the first day after passive and rapid ascent to 3450 m, possibly due to an increased parasympathetic activity and an increased RMR, while HVR appeared to be of minor importance. Differences in AMS time course and physiological responses should be taken into consideration when ET are planning high-altitude sojourns.

Characteristics of Headache and Relationship to Acute Mountain Sickness at 4559 Meters.

The goals of this study were to characterize headache at high altitude in relation to the severity of acute mountain sickness (AMS), to investigate whether a history of migraine or nonmigrainous headache at low altitude is a risk factor for AMS and to estimate its effect size in relation to established major risk factors. We performed a secondary, extended analysis of data obtained from 1320 mountaineers staying overnight at the Capanna Margherita (4559 m). Headache at low and high altitude was classified according to the criteria of the International Headache Society. About 45% of the mountaineers suffered from headache in the evening of the arrival day at 4559 m. In those with headache, tension type headache decreased from 62% to 29% and 13% with no AMS (AMS-C <0.70), moderate AMS, and more severe AMS (AMS-C ≥1.5), while headache fulfilling the criteria of migraine increased correspondingly from 14% to 34% and 69%. A history of migraine or any type of headache at low altitude is a minor predictor of AMS that does not significantly contribute to AMS risk in a multivariate analysis including the major risk factors such as history of AMS, rate of ascent, and degree of preacclimatization in this population of alpine mountaineers. The association between more severe AMS and migrainous headache may be due to common nonspecific symptoms but a common underlying pathophysiology of AMS and migraine cannot be excluded. Despite this association a history of migraine or other headache at low altitude is not a major risk factor for AMS.

The STAR Data Reporting Guidelines for Clinical High Altitude Research.

Brodmann Maeder, Monika, Hermann Brugger, Matiram Pun, Giacomo Strapazzon, Tomas Dal Cappello, Marco Maggiorini, Peter Hackett, Peter Baärtsch, Erik R. Swenson, Ken Zafren (STAR Core Group), and the STAR Delphi Expert Group. The STARdata reporting guidelines for clinical high altitude research. High AltMedBiol. 19:7-14, 2018. AIMS: The goal of the STAR (STrengthening Altitude Research) initiative was to produce a uniform set of key elements for research and reporting in clinical high-altitude (HA) medicine. The STAR initiative was inspired by research on treatment of cardiac arrest, in which the establishment of the Utstein Style, a uniform data reporting protocol, substantially contributed to improving data reporting and subsequently the quality of scientific evidence. MATERIALS AND METHODS: The STAR core group used the Delphi method, in which a group of experts reaches a consensus over multiple rounds using a formal method. We selected experts in the field of clinical HA medicine based on their scientific credentials and identified an initial set of parameters for evaluation by the experts. RESULTS: Of 51 experts in HA research who were identified initially, 21 experts completed both rounds. The experts identified 42 key parameters in 5 categories (setting, individual factors, acute mountain sickness and HA cerebral edema, HA pulmonary edema, and treatment) that were considered essential for research and reporting in clinical HA research. An additional 47 supplemental parameters were identified that should be reported depending on the nature of the research. CONCLUSIONS: The STAR initiative, using the Delphi method, identified a set of key parameters essential for research and reporting in clinical HA medicine.