Pathogenesis Of High-altitude Pulmonary Edema Research Articles

Clinical and Pathophysiological Features of High-altitude Pulmonary Edema in the Japanese Population: A Review of Studies on High-altitude Pulmonary Edema in Japan.

High-altitude pulmonary edema (HAPE) is a life-threatening, noncardiogenic pulmonary edema that occurs in unacclimatized individuals rapidly ascending to high altitudes above 2,500 m above sea level. Until the entity of HAPE was first identified in a case report published in Japan in 1966, the symptoms of severe dyspnea or coma occurring in climbers of the Japan Alps were incorrectly attributed to pneumonia or congestive heart failure. The Shinshu University Hospital serves as the central facility for rescuing and treating patients with HAPE in the region. Over the past 50 years, a series of studies have been conducted at Shinshu University to gain a better understanding of the characteristics of HAPE. This review summarizes the major achievements of these studies, including their clinical features, management, and pathogenesis of HAPE, particularly in the Japanese population.

Mitochondrial DNA sequencing reveals association of variants and haplogroup M33a2\u20323 with High altitude pulmonary edema susceptibility in Indian male lowlanders

High Altitude Pulmonary Edema (HAPE) is a threatening disorder caused due to acute exposure to high altitude above 3000 m. Apart from multiple factors involved, the genetic factors also play an important function in the pathogenesis of HAPE. This study aims to evaluate the role of mtDNA polymorphism and their association with haplogroup in understanding the etiology of HAPE. In this study, all the HAPE susceptible and acclimatized control subjects could be classified into nine haplogroups pertaining mostly to Macrohaplogroup M and U. The frequency of haplogroup M was significantly higher in HAPE susceptibles whereas the haplogroup M33a2′3 was found only in HAPE susceptibles. The variant G4491A and A4944G of MT-ND2, A14002G of MT-ND5, and C8562T of MT-ATP8, were definition site of haplogroup M33a2′3. The frequency of A10398G of MT-ND3, A8701G of MT-ATP6 and C14766T of MT-CYB genes were significantly higher in HAPE susceptibles. mtDNA copy number also plays a significant synergistic role in HAPE susceptibility. Our findings suggests that variants in MT-ND2 and MT-ND5 were predicted to confer decreased protein stability in HAPE susceptibles and in particular, highly conserved variants G4491A, A4944G and A14002G associated with haplogroup M33a2′3 may be the primary cause of susceptibility to HAPE in Indian male lowlanders.

Role of mtDNA3010 A/G genotype variation in pathogenesis of high-altitude pulmonary edema

Role of mtDNA3010 A/G genotype variation in pathogenesis of high-altitude pulmonary edema

High altitude pulmonary edema (HAPE) with pulmonary embolism

High altitude pulmonary edema (HAPE) is a life-threatening condition occurring at heights above 2500 meter mostly within 2-4 days of entry in high altitude. Postmortem studies showed evidence of thrombi in cases of HAPE suggesting possible role of thrombosis in the pathogenesis of HAPE. Here, we are presenting the two cases of HAPE with pulmonary embolism, and the possibility of pulmonary embolism should be considered in cases of HAPE with persistent radiographic opacities despite oxygen or descent.

High-altitude pulmonary edema: review.

At High altitude (HA) (elevation >2,500 m), hypobaric hypoxia may lead to the development of symptoms associated with low oxygen pressure in many sojourners. High-altitude pulmonary edema (HAPE) is a potentially fatal condition, occurring at altitudes greater than 3,000 m and affecting rapidly ascending, non-acclimatized healthy individuals. It is a multifactorial disease involving both environmental and genetic risk factors. Since thousands of lowlanders travel to high altitude areas for various reasons every year, we thought it would be interesting to review pathological aspects related to hypobaric hypoxia, particularly HAPE. Since the pathogenesis of HAPE is still a subject of study, we systematically identified and categorized a broad range of facets of HAPE such as its incidence, symptoms, physiological effects, pathophysiology including physiological and genetic factors, prevention and treatment. This review focuses on HA-related health problems in general with special reference to HAPE, which is one of the primary causes of deaths at extreme altitudes. Hence, it is extremely important, as it summarizes the literature in this area and provides an overview of this severe HA malady for evaluation of physiological, biochemical and genetic responses during early induction and acclimatization to HA. This article could be of broad scientific interest for researchers working in the field of high altitude medicine.

Rare Mitochondrial DNA Polymorphisms are Associated with High Altitude Pulmonary Edema (HAPE) Susceptibility in Han Chinese

The role of genetics in determining an individual's susceptibility to high altitude pulmonary edema (HAPE) is unclear. However a number of genetic polymorphisms have recently been found to be overrepresented in patients with HAPE. Changes at the mitochondrial level may play an important role in the human body's adaptation to hypoxia. Polymorphisms of mitochondrial DNA (mtDNA) have been shown to be responsible for differences in organelle function. Therefore, the frequency of mtDNA 3397A/G and 3552T/A polymorphisms were studied to determine their potential role in HAPE. To further study the role of mtDNA 3397A/G and 3552T/A variations of reduced nicotinamide adenosine dinucleotide dehydrogenase 1 in HAPE susceptibility. The single-nucleotide polymorphisms of mtDNA 3397 and 3552 in patients with HAPE (n = 132) and their matched control subjects (n = 233) were studied using polymerase chain reaction sequencing. The frequency of mtDNA 3397G in the HAPE group (2.3%) was significantly higher than that of the control group (0%; P = .021; odds ratio, 2.806; 95% confidence interval, 2.443 to 3.223). The frequency of mtDNA 3552A in the HAPE group (6.8%) also was significantly higher than in the control group (1.7%; P = .012; odds ratio, 4.198; 95% confidence interval, 1.264 to 13.880). In this study, we present the first evidence of differences in mtDNA polymorphism frequencies between HAPE victims and healthy Han Chinese. Genotypes of mtDNA 3397G and 3552A were correlated with HAPE susceptibility. This result could contribute to defining the role of the mitochondrial genome in the pathogenesis of HAPE.

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.

New Insights in the Pathogenesis of High-Altitude Pulmonary Edema

High-altitude pulmonary edema is a life-threatening condition occurring in predisposed but otherwise healthy individuals. It therefore permits the study of underlying mechanisms of pulmonary edema in the absence of confounding factors such as coexisting cardiovascular or pulmonary disease, and/or drug therapy. There is evidence that some degree of asymptomatic alveolar fluid accumulation may represent a normal phenomenon in healthy humans shortly after arrival at high altitude. Two fundamental mechanisms then determine whether this fluid accumulation is cleared or whether it progresses to HAPE: the quantity of liquid escaping from the pulmonary vasculature and the rate of its clearance by the alveolar respiratory epithelium. The former is directly related to the degree of hypoxia-induced pulmonary hypertension, whereas the latter is determined by the alveolar epithelial sodium transport. Here, we will review evidence that, in HAPE-prone subjects, impaired pulmonary endothelial and epithelial NO synthesis and/or bioavailability may represent a central underlying defect predisposing to exaggerated hypoxic pulmonary vasoconstriction and, in turn, capillary stress failure and alveolar fluid flooding. We will then demonstrate that exaggerated pulmonary hypertension, although possibly a conditio sine qua non, may not always be sufficient to induce HAPE and how defective alveolar fluid clearance may represent a second important pathogenic mechanism.

Genetic interaction of Hsp70 family genes polymorphisms with high-altitude pulmonary edema among Chinese railway constructors at altitudes exceeding 4000 meters

Background High-altitude pulmonary edema (HAPE) is thought of as an independent clinical disorder with a constitutional or genetic component in its etiology. We focused on 5 common polymorphisms within HSPA1A (rs1043618 and rs1008438), HSPA1B (rs1061581 and rs539689) and HSPA1L (rs2227956) of Hsp70 family to explore their potential interaction upon susceptibility to HAPE in Chinese. Methods A total of 148 HAPE patients and 483 matched controls were recruited during the construction of Qinghai–Tibet railway from 2001 to 2006. Genotyping was performed using PCR-RFLP, PCR-SSCP and PCR-direct-sequencing techniques. Promoter activity was evaluated by luciferase reporter assays. Gene–gene interaction was conducted by MDR v.2.0, and haplotype–diplotype analysis by Haplo.stats v.1.4.0. Results Significant differences were observed in the genotype ( P = 0.0136) and allele ( P = 0.0299) distributions of rs1008438, and in rs1061581 allele distribution ( P = 0.0421) between HAPE patients and controls. Interaction analysis indicated that 3 polymorphisms (rs1061581, rs1043618 and rs1008438) shared strong synergism with a testing accuracy of 0.792 and cross-validation consistency 10 out of 10 ( P = 0.001). Haplotypes Hap4 (G–C–A, in order of rs1061581, rs1043618 and rs1008438) and Hap5 (G–G–A) had an 86% reduced risk ( P = 0.0009) against and Hap7 (A–C–C) had a 2.43-fold increased risk for HAPE. When considered as diplotypes, significance was noted for Dip5 (Hap1–Hap7) (OR = 3.39; 95% CI: 1.28–9.17; P = 0.0140). Functional assessment supported the involvement of rs1008438 in the pathogenesis of HAPE. Conclusion We demonstrated strong interaction of rs1061581, rs1043618 and rs1008438 polymorphisms within Hsp70 family upon susceptibility to HAPE in Chinese. Moreover, polymorphism rs1008438 might cause the development of HAPE via a change in HSPA1A promoter activity.

Synergistic effect of the genetic polymorphisms of the renin–angiotensin–aldosterone system on high-altitude pulmonary edema: a study from Qinghai-Tibet altitude

The pathogenesis of high-altitude pulmonary edema (HAPE) has been at least partially attributed to the local dysregulation of the renin-angiotensin-aldosterone system (RAAS) cascade. To address this issue, we conducted the largest nested case-control study to-date to explore the association between variations in RAAS genes and HAPE in Chinese population. We recruited 140 HAPE patients and 144 controls during the construction of Qinghai-Tibet railway and genotyped 10 gene polymorphisms evenly interspersed in 5 RAAS candidate genes. The data were analyzed by haplotype and multifactor dimensionality reduction (MDR). The single-locus analysis showed that CYP11B2 C-344T and K173R and ACE A-240T polymorphisms were significantly associated with HAPE after Bonferroni correction (P<0.005). The linkage analysis constructed a linkage block including C-344T and K173R polymorphisms in complete linkage disequilibrium with each other, while occurred with significantly different frequencies between HAPE and control groups. The gene-gene interaction analysis found the overall best model including ACE A-240T and A2350G and CYP11B2 C-344T polymorphisms with strong synergistic effect. This model had a maximum testing accuracy of 68.61% and a maximum cross validation consistency of 9 out of 10 (P=0.004). The homozygous genotype combination of -240AA, 2350GG and -344TT conferred high genetic susceptibility to HAPE, which was further strengthened by haplotype analysis. Our results add evidence for synergistic effect of RAAS gene polymorphisms on HAPE susceptibility. Moreover, we proposed a promising data-mining analytical approach (MDR) for detecting and characterizing gene-gene interactions.

Hypoxic Lung Whiteout: Further Clearing but More Questions from on High

In this issue, Maggiorini and colleagues explore several aspects of the pathogenesis of high-altitude pulmonary edema. Their study yields important practical answers and serendipitously generates n...

Inhibitors of hypoxic pulmonary vasoconstriction prevent high-altitude pulmonary edema in rats.

Rapid ascent to high altitude causes hypoxic pulmonary vasoconstriction (HPV) and leads to high-altitude pulmonary edema (HAPE) in susceptible humans. Vasodilating agents lessen HAPE (as evidenced by radiographic and gas exchange measurements), but data establishing their effectiveness on alveolar protein content and hemorrhage are lacking. This study was designed to assess whether preventing HPV reduces the alveolar-capillary barrier leak characteristic of HAPE. Rats were pretreated with saline (control group) or acetazolamide (20 mg/kg) or nickel chloride (60 mg/kg) (experimental groups) to prevent HPV and were exposed to high altitude (0.5 atm for 24 hours) in a hypobaric chamber. High-altitude pulmonary edema was then assessed by gravimetric analysis of heart and lung tissue, a visual score of lung hemorrhage, and measurement of protein content in bronchoalveolar lavage fluid. Saline-treated rats developed a mild protein leak indicative of early HAPE that was prevented by inhibition of HPV: protein in bronchoalevolar lavage fluid of saline-treated rats, 21.6 +/- 3.2 mg/dL (mean +/- SEM); HPV-inhibited rats, 12.6 +/- 0.7 mg/dL; air-exposed rats, 13.4 +/- 1.4 mg/ dL (P < .05 saline vs other groups, analysis of variance [ANOVA]). The lungs of saline-treated rats were also mildly hemorrhagic (3.4 +/- 0.9 on a scale of 1-9, where 1 is normal), and the lungs of HPV-inhibited rats appeared normal (1.2 +/- 0.1) (P = .032). Finally, right ventricle weight (adjusted for initial body weight) increased in saline-treated rats: saline-treated, 0.64 +/- 0.02; HPV-inhibited, 0.56 +/- 0.02; air-exposed, 0.59 +/- 0.02 (P < .05, saline vs HPV-inhibited group). The results demonstrate that treatment with NiCl2 or acetazolamide prevents HAPE in rats and are consistent with a role for elevated pulmonary artery pressure in the pathogenesis of HAPE.

A pig model of high altitude pulmonary edema.

High altitude pulmonary edema (HAPE) affects unacclimatized individuals ascending rapidly to high altitude. The pathogenesis of HAPE is not fully elucidated, and many investigative techniques that could provide valuable information are not suitable for use in humans; thus, an animal model is desirable. Rabbits, sheep, dogs, and ferrets have been shown not to consistently develop HAPE, and studies in rats are limited by the animal's small size and inconsistent response. Pigs develop a marked pulmonary vasoconstrictive response to hypoxia, and preliminary studies of HAPE in pigs have been promising. To determine the suitability of pigs as an animal model of HAPE, we exposed six subadult (20 to 25 kg) pigs to normobaric hypoxia (10% oxygen) for 48 hr. One week before, and immediately after exposure to hypoxia, under anesthesia, arterial blood gases were obtained and bronchoalveolar lavage (BAL) and chest x-ray were performed. Hypoxia increased alveolar-arterial pressure difference for oxygen from 22 +/- 9 to 38 +/- 5 torr, p < 0.01) and red cell (from 12.3 +/- 5.9 to 27.4 +/- 5.3 cells x 10(5)/mL(-1), p < 0.001) and white cell (from 1.59 +/- 0.90 to 7.88 +/- 3.36 cells x 10(5)/mL(-1), p < 0.05) concentrations in BAL in all animals. Total BAL protein concentration increased by 64% and fractional albumin by 38% (both p < 0.05) posthypoxia. One animal had evidence of pulmonary edema on X ray. Some pigs develop findings consistent with early HAPE when exposed to normobaric hypoxia. Increasing the duration of hypoxic exposure or exercising the animals in hypoxia may better model the disease process observed in humans with clinically significant HAPE.

Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor.

Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor.

Pathogenesis of High-Altitude Pulmonary Edema

The pathogenesis of high-altitude pulmonary edema (HAPE) is considered an altered permeability of the alveolar-capillary barrier secondary to intense pulmonary vasoconstriction and high capillary pressure, but previous bronchoalveolar lavage (BAL) findings in well-established HAPE are also consistent with inflammatory etiologic characteristics. To determine whether inflammation is a primary event in HAPE and to define the temporal sequence of events in HAPE. Case study from July through August 1999 of 10 subjects with susceptibility to HAPE and 6 subjects resistant to HAPE, all of whom are nonprofessional alpinists with previous mountaineering experience above 3000 m. Pulmonary artery pressure measurements and BAL findings at low altitude (490 m) and shortly before or at the onset of HAPE at an altitude of 4559 m. Subjects who were HAPE susceptible had higher mean (SD) pulmonary artery systolic blood pressures at 4559 m compared with HAPE-resistant subjects (66 vs 37 mm Hg; P =.004). Despite development of HAPE in the majority of HAPE-susceptible subjects, there were no differences in BAL fluid total leukocyte counts between resistant and susceptible subjects or between counts taken at low and high altitudes. Subjects who developed HAPE had BAL fluid with high concentrations of plasma-derived proteins and erythrocytes, but there was no increase in plasma concentrations of surfactant protein A and Clara cell protein. The chest radiograph score was 12.7 for the 3 HAPE-susceptible subjects who developed HAPE before BAL was performed; they were lavaged within 3 to 5 hours. The remainder of the HAPE-susceptible group was lavaged before edema was apparent on radiographs. However, 6 subjects from the HAPE-susceptible group who developed HAPE on the following day had a score on bronchoscopy of 1.5, which increased to 4.6, reflective of mild pulmonary edema. In HAPE cases, there were no elevations in a number of proinflammatory cytokines and eicosanoid and nitric oxide metabolites. Early HAPE is characterized by high pulmonary artery pressures that lead to a protein-rich and mildly hemorrhagic edema, with normal levels of leukocytes, cytokines, and eicosanoids. HAPE is a form of hydrostatic pulmonary edema with altered alveolar-capillary permeability.

Inflammation Doesn't Cause High-Altitude Pulmonary Edema

The role of increased pulmonary artery and pulmonary capillary hydrostatic pressures in the pathogenesis of high-altitude pulmonary edema (HAPE) has been established. However, the issue of whether inflammation is part of the pathophysiologic process is unresolved. These investigators conducted a prospective case study of 16 experienced mountaineers who were susceptible to HAPE (10 had …

Exaggerated endothelin release in high-altitude pulmonary edema.

Exaggerated pulmonary hypertension is thought to play an important part in the pathogenesis of high-altitude pulmonary edema (HAPE). Endothelin-1 is a potent pulmonary vasoconstrictor peptide that also augments microvascular permeability. We measured endothelin-1 plasma levels and pulmonary artery pressure in 16 mountaineers prone to HAPE and in 16 mountaineers resistant to this condition at low (580 m) and high (4559 m) altitudes. At high altitude, in mountaineers prone to HAPE, mean (+/-SE) endothelin-1 plasma levels were approximately 33% higher than in HAPE-resistant mountaineers (22.2+/-1.1 versus 16.8+/-1.1 pg/mL, P<0.01). There was a direct relationship between the changes from low to high altitude in endothelin-1 plasma levels and systolic pulmonary artery pressure (r=0.82, P<0.01) and between endothelin-1 plasma levels and pulmonary artery pressure measured at high altitude (r=0.35, P=0.05). These findings suggest that in HAPE-susceptible mountaineers, an augmented release of the potent pulmonary vasoconstrictor peptide endothelin-1 and/or its reduced pulmonary clearance could represent one of the mechanisms contributing to exaggerated pulmonary hypertension at high altitude.

Inflammatory cytokines in BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema

To evaluate the pathogenesis of high-altitude pulmonary edema (HAPE), we performed bronchoalveolar lavage (BAL) and pulmonary hemodynamic studies in seven patients with HAPE at its early stage. We measured cell counts, biochemical contents, and concentrations of pro-inflammatory cytokines including interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF)- α and of anti-inflammatory cytokines including IL-1 receptor antagonist (ra) and IL-10 in the BAL fluid (BALF). All patients showed increased counts for total cells, alveolar macrophages, neutrophils and lymphocytes, and markedly elevated concentrations of proteins, lactate dehydrogenase, IL-1 β, IL-6, IL-8, TNF- α and IL-1ra. The levels of IL-1 α and IL-10 were not increased. Patients also showed pulmonary hypertension with normal wedge pressure. Both the driving pressure obtained as pulmonary arterial pressure minus wedge pressure and the Pa O 2 under room air were significantly correlated with the concentrations of IL-6 and TNF- α in the BALF. These findings suggest that the inflammatory cytokines play a role at the early stage of HAPE and might be related to pulmonary hypertension.

Urinary Leukotriene E4 Levels in High-Altitude Pulmonary Edema: A Possible Role for Inflammation

<h3>Study objectives</h3> Inflammation may contribute to the pathogenesis of high-altitude pulmonary edema (HAPE). This study was designed to determine whether a marker of inflammation, urinary leukotriene E4 (LTE4), is elevated in patients with HAPE. <h3>Design</h3> We conducted a case-control study to collect clinical data and urine samples from HAPE patients and healthy control subjects at moderate altitude (≥2727 m), and follow-up urine samples from HAPE patients following their return to low altitude (≤1,600 m). <h3>Setting</h3> Five medical clinics in Summit County, Colorado. <h3>Patients</h3> Questionnaire data were evaluated in 71 HAPE patients and 36 control subjects. Urinary LTE4 levels were determined from a random subset of 38 HAPE patients and 10 control subjects presenting at moderate altitude, and on 5 HAPE patients who had returned to low altitude. <h3>Measurements and Results</h3> Using an enzyme immunoassay technique, urinary LTE4 levels were found to be significantly higher in HAPE patients (123 [16 to 468] pg/mg creatinine, geometric mean [range]) than in control subjects (69 [38 to 135]), p=0.02. Following return to low altitude, urinary LTE4 levels fell significantly from 122 (41.8 to 309) to 53.6 (27.6 to 104) pg/mg creatinine (p=0.05). Urinary LTE4 levels were not related to age, sex, time at altitude, physical condition or habitual exercise, recent use of alcohol or nonsteroidal anti-inflammatory drugs (NSAIDs), or oxygen saturation. Clinical factors associated with HAPE included male sex, regular exercise, and recent use of NSAIDs. <h3>Conclusions</h3> We conclude that urinary LTE4 levels are elevated in patients with HAPE, supporting the view that HAPE involves inflammatory mechanisms.

Susceptibility to high-altitude pulmonary edema in Madison and Hilltop rats. I. Ventilation and fluid balance

The pathogenesis of high-altitude pulmonary edema (HAPE) is not well understood. Ventilation and fluid-handling abnormalities at high altitude (HA) may play a role in HAPE. Because ventilatory and cardiopulmonary responses to chronic HA exposure in the Hilltop (H) strain of Sprague-Dawley rat are different from those in the Madison (M) strain, it was hypothesized that these strains would have different susceptibilities to developing HAPE. M and H rats were studied at sea level (SL) and in a hypobaric chamber after 9 and 12 h at a simulated altitude of 24,000 ft (barometric pressure = 295 mmHg) and 1, 12, and 24 h at a simulated altitude of 18,000 ft (barometric pressure = 380 mmHg). Both strains developed HAPE, but the M rat was more susceptible to HAPE, as demonstrated by a higher mortality rate from hemorrhagic pulmonary edema after 9 h at 24,000 ft and an earlier increase in lung water after exposure to 18,000 ft. Minute ventilation was similar in both strains at HA, but arterial PO2 was significantly higher in the M rat. Both strains had a significant decrease in fluid intake and negative sensible water balance at HA. No changes in plasma renin activity, aldosterone concentrations, antidiuretic hormone levels, and atrial natriuretic peptide levels were found at HA. The increased susceptibility of the M rat to HAPE is therefore not explained by ventilation or fluid-handling abnormalities.