high altitude pulmonary edema pathophysiology

The second phase of HPV is influenced by endothelial cell function. Endothelial and subintimal changes in rat hilar pulmonary artery during recovery from hypoxia: a quantitative ultrastructural study. Physiological adaptation of the cardiovascular system to high altitude. It is seen as a complication of myocardial infarcts, hypertension, pneumonia, smoke inhalation, and high-altitude pulmonary edema. In addition to changes in intracellular Ca2+ levels, changes in pulmonary artery smooth muscle cell myofilament sensitivity to Ca2+ arising from inhibition of myosin light chain phosphatase via RhoA/Rho kinase or protein kinase C or a decreased activation of myosin light chain phosphatase by decreased NO signaling9 also contribute to sustained HPV. Invited Review HIGHLIGHTED TOPIC Pulmonary Circulation and Hypoxia Physiological aspects of high-altitude pulmonary edema Peter Ba¨rtsch,1 Heimo Mairba¨url,1 Marco Maggiorini,2 and Erik R. Swenson3 1Division of Sports Medicine, Department of Internal Medicine, Medical University Hospital, Heidelberg, Germany; and 2Department of Cardiology, Medical Clinic, Zurich, Switzerland; Pulmonary edema is a condition caused by excess fluid in the lungs. Inspired Po2 falls from ≈150 mm Hg at sea level to ≈100 mm Hg at 3000 m and 43 mm Hg on the summit of Everest (8400 m).2,3 The body responds by hyperventilating, increasing resting heart rate, and stimulating red cell production in an attempt to maintain the oxygen content of arterial blood at or above sea level values.2 However, hypoxic pulmonary vasoconstriction (HPV) and vascular remodeling, together with increased erythropoiesis, place an increased pressure load on the right ventricle (RV). Vascular remodeling versus vasoconstriction in chronic hypoxic pulmonary hypertension: a time for reappraisal? Genetic adaptation of the hypoxia-inducible factor pathway to oxygen pressure among eurasian human populations. Copyright © 2021 Elsevier B.V. or its licensors or contributors. The inciting factor of HAPE is the decrease in partial pressure of arterial oxygen caused by the lower air pressure at high altitudes (pulmonary gas pressures). Data are few, but PAP measurements in ethnic Tibetans living over 3600 m are in the range typical of healthy adults at sea level,77,78 and postmortem studies show little vascular remodeling.78,80 A blunted pulmonary vascular pressor response to acute and sustained hypoxia is retained by Tibetans at sea level.81. The initial rise in PAP on exposure to hypoxia is attributed to HPV. Pulmonary vascular mechanics: important contributors to the increased right ventricular afterload of pulmonary hypertension. Drs Wilkins and Zhao are funded by the British Heart Foundation. Phosphodiesterase type 5 and high altitude pulmonary hypertension. Acute administration of a Rho kinase inhibitor significantly reduces pulmonary vascular resistance in chronically hypoxic rats,26 advancing the argument that vasoconstriction is an important pathophysiological mechanism in high-altitude pulmonary hypertension (HAPH), perhaps as important or more important than vascular remodeling.27, Chronic global alveolar hypoxia is accompanied by structural remodeling of pulmonary vessels. https://doi.org/10.1580/1080-6032(1999)010[0088:TPOHAP]2.3.CO;2. Heart rate remains elevated, and so cardiac output remains at or just below sea level. Minimal hypoxic pulmonary hypertension in normal Tibetans at 3,658 m. Lack of smooth muscle in the small pulmonary arteries of the native Ladakhi: is the Himalayan highlander adapted? Abnormal circulatory responses to high altitude in subjects with a previous history of high-altitude pulmonary edema. Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment. The pathophysiology high-altitude pulmonary edema (HAPE) is not well understood. Pulmonary vascular pathology of high altitude-induced pulmonary hypertension in cattle. A phosphodiesterase type 5 inhibitor may be helpful but has not been formally trialed. For example, oxygen is a substrate for NO synthases, and NO bioavailability is reduced by hypoxia.23 In addition, sustained HPV has been shown to depend on glucose level.24. People who exhibit a marked pulmonary vascular or erythropoietic response to hypoxia identify themselves as at risk of heart failure. Con: hypoxic pulmonary vasoconstriction is not a limiting factor of exercise at high altitude. High altitude pulmonary edema (HAPE) is a non-cardiogenic edema which afflicts susceptible persons who ascend to altitudes above 2500 meters and remain there for 24 to 48 h or longer. However, cases have also been reported between 1,500–2,500 metres or 4,900–8,200 feet in more vulnerable subjects. After 2 or 3 weeks of hypoxia, there is little response to rebreathing 100% oxygen, indicating a structural resistance to pulmonary blood flow rather than one based solely on increased vasomotor tone.6 A fall in PAP on re-exposure to a normal oxygen environment is evident in rats monitored by telemetry over days after removal from a hypoxic chamber7 (Figure 1B) and is also documented in humans.4,8. Bradycardia, increased cardiac output, and reversal of pulmonary hypertension in altitude natives living at sea level. High-altitude pulmonary edema In normal lungs, air sacs (alveoli) take in oxygen and release carbon dioxide. The pathophysiological basis of chronic hypoxic pulmonary hypertension in the mouse: vasoconstrictor and structural mechanisms contribute equally. Studies of healthy subjects exposed to hypoxia report an increase in resting heart rate and an initial increase in cardiac output in an attempt to maintain oxygen delivery to tissues.47 After 2 to 3 days of hypoxia, stroke volume falls. High altitude pulmonary edema (HAPE) is a life-threatening form of such illness that involves abnormal accumulation of fluid in the lungs, and in fact is the most common fatal manifestation of severe high altitude illness [ 1 ]. The defining feature of chronic mountain sickness (CMS) is excessive erythrocytosis accompanied by neurologic symptoms, such as headache, dizziness, and fatigue.64 By consensus, the hemoglobin should exceed ≥21g/dL in men and ≥19 g/dL in women. The American Heart Association is qualified 501(c)(3) tax-exempt Significantly, the polymorphisms in EPAS1 and EGLN1 in Tibetans correlate with hemoglobin concentration.84,86–88,90 A high-frequency missense mutation has recently been identified in EGLN1 that encodes a variant prolyl 4-hydroxylase 2 with increased hydroxylase activity under hypoxic conditions that would contribute to this adaptive response.91, A genome study in Andeans has found evidence of positive selection for EGLN1 but not EPAS1.92 Neither were candidates in reported studies in Ethiopian highlanders.93–95 Moreover, Andeans exhibit a robust erythropoietic response to altitude and polymorphisms identified in EGLN1 in Andeans, albeit different from those in Tibetans, did not associate with hemoglobin level. Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain of function mutation. It is characterised by decreased exercise capacity, dry cough, cyanosis, dyspnoea at rest and pink, frothy sputum. It is a non-cardiogenic pulmonary edema which typically occurs in rapidly climbing unacclimatized lowlanders usually within 2-4 days of ascent above 2500-3000m. High-altitude disorders: pulmonary hypertension. Tibetans appear less susceptible than recent migrants to HAPH77,78 and CMS,79 most likely the result of living above 3000 m for thousands of years. Acute high-altitude pulmonary edema (HAPE) is a pathology involving multifactorial triggers that are associated with ascents to altitudes over 2,500 meters above sea level (m). Although in part caused by and adaptive to the increase in hemodynamic stress, the vascular remodeling contributes to and sustains the elevated PAP. Figure 2. Increasing recognition is given to an adventitial reaction mediated by the fibroblast in response to hypoxia and vascular wall stress.33 In addition, an inflammatory cell infiltrate, composed of monocytes, dendritic cells, and T cells, is evident.35 Evidence for epigenetic regulation of pulmonary vascular remodeling comes from experiments with HDACs. Acetazolamide (250 mg daily) has been shown to reduce hematocrit, increase Pao2 and oxygen saturation, and decrease in Paco2 in CMS, most likely via metabolic acidosis stimulating ventilation.73 Pulmonary vascular resistance was also reduced and cardiac output increased without a change in pulmonary pressure. The incidence of HAPE increases with the rate of ascent and the ultimate altitude at-tained. Genetic adaptation to high altitude in the Ethiopian highlands. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Indeed, the structural changes take a considerable time to resolve on return to a sea-level oxygen environment and may persist in some form.43 The extent to which the structural changes in pulmonary resistance vessels infringe on the lumen and contribute a physical obstruction to blood flow (ie, the argument being that vascular growth is outward rather than inward) and the extent of vascular rarefaction in response to chronic hypoxia are unclear.44 These may vary between species. Circulation. Later, … Magnetic resonance imaging of uneven pulmonary perfusion in hypoxia in humans. © American Heart Association, Inc. All rights reserved. Micropuncture measurement of lung microvascular pressure profile during hypoxia in cats. Contact Us, Correspondence to Martin R. Wilkins, MD, NIHR Imperial Clinical Research Facility, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. A genome-wide search for signals of high-altitude adaptation in Tibetans. Pulmonary hypertension and chronic mountain sickness. A 40-year-old male mountaineer was affected by an advanced stage of HAPE at high altitude (Monte Rosa plateau, 4000 m). Sequencing of 50 human exomes reveals adaptation to high altitude. Medline Google Scholar; 5 Hultgren HN, Grover RF, Hartley LH. It is caused by exaggerated and uneven HPV leading to high capillary pressures in regions of the lung and an exudation that might invoke a secondary inflammatory response.57–59 Susceptible individuals exhibit a marked rise in PAP on exposure to hypoxia mediated by pulmonary arteriolar vasoconstriction and a greater rise in PAP on exercise in a normal oxygen environment, indicating a hyperactive pulmonary circulation.56, The emphasis in management is on prevention. An increase in the AMP/ATP ratio activates AMPK, followed by an increase in cADPR that triggers the release of [Ca2+]i through RyR of SR.9 The level of ROS could be relevant through ROS-dependent alteration of function of AMPK and cADPR. Later, dyspnoea occurs at rest. How well healthy humans adapt to hypoxia depends on their rate of ascent to altitude, the severity and duration of their exposure, and their genetic background. By convention, the definition of HAPH is a resting mean PAP >30 mm Hg.64 This needs revisiting and reconciling with international guidelines for the definition of pulmonary hypertension, which is a resting mean PAP >25 mm Hg.53,65. CONTEXT: Because of its onset in generally remote environments, high-altitude cerebral edema (HACE) has received little scientific attention. Pulmonary edema is a condition in which the lungs fill with fluid. This causes fluid to leak from the blood vessels to the lung tissues and eventually into the air sacs. Mechanisms other than narrowing of the vessel lumen are relevant to this discussion, specifically the contribution of changes in vascular compliance.45 Changes in the stiffness of proximal vessels leads to changes in the propagation of high-energy pulsatile waves. Remodeling in the distal vasculature may depend on the presence of cells from other vascular compartments, including circulating inflammatory cells and peripheral blood hematopoietic cells, that might stimulate proliferation or transdifferentiate into smooth muscle-like cells. On the origin of Tibetans and their genetic basis in adapting high-altitude environments. Contribution of hypoxic pulmonary vasoconstriction (HPV) and vascular remodeling to the rise in pulmonary artery pressure (PAP) in chronic hypoxia. Bosentan reduces pulmonary artery pressure in high altitude residents. This has been described in a number of species, including rat,28 cow,29 and humans,30 although some species seem resistant.31 All of the layers of the vascular wall, including fibroblasts, are involved in the remodeling (Figure 4),32,33 but the hallmark of the vascular response to chronic hypoxia is increased muscularization of distal vessels with extension of muscle into previously unmuscularized arterioles.28,30. By continuing you agree to the use of cookies. However, incidents have also been reported between 1.500–2.500 meters or 4.900–8.200 feet in the more vulnerable actors. The incidence is variously recorded, depending on the subject population, rapidity of ascent, and final altitude; everyone is at risk of HAPE if they ascend fast and high enough. The pathophysiology, clinical presentation, treatment, and prevention of HAPE are reviewed here. Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB), Journal of the American Heart Association (JAHA), Customer Service and Ordering Information, Basic, Translational, and Clinical Research. Pulmonary nitric oxide in mountain dwellers. Acetazolamide for Monge’s disease: efficiency and tolerance of 6-month treatment. By continuing to browse this site you are agreeing to our use of cookies. Acute high-altitude illness describes the neurological or pulmonary syndromes experienced when unacclimatized individuals ascend too rapidly. The influence of short periods of induced acute anoxia upon pulmonary artery pressures in man. Genetic signatures reveal high-altitude adaptation in a set of ethiopian populations. High altitude pulmonary edema (HAPE) is a noncardiogenic pulmonary edema which typically occurs in lowlanders who ascend rapidly to altitudes greater than 2500-3000 m. Early symptoms of HAPE include a nonproductive cough, dyspnoea on exertion and reduced exercise performance. Superoxide generated at mitochondrial complex III triggers acute responses to hypoxia in the pulmonary circulation. The rise in PAP in chronic hypoxia is generally modest, certainly compared with that seen in idiopathic pulmonary arterial hypertension, and is compatible with a normal life at high altitude. A disease which poses a direct threat to the lives of mountain climbers is high altitude pulmonary edema (HAPE). The benefits of endothelin receptor antagonists are less clear.75,76. Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms. Customer Service A change in the levels of reactive oxygen species is thought to be important, but there is a lack of agreement regarding whether the signal is an increase or decrease in reactive oxygen species (Figure 2).19–21 Differences in techniques used contribute to the different observations, but the spatial distribution of reactive oxygen species signaling may also be significant.22. Comparative physiology of hypoxic pulmonary hypertension: historical clues from brisket disease. Hypoxic contraction of cultured pulmonary vascular smooth muscle cells. Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. The symptoms abated immediately after the patient descended from the altitude. Pulmonary pressure, cardiac output, and arterial oxygen saturation during exercise at high altitude and at sea level. Phosphodiesterase type 5 inhibitors appear effective at reducing pulmonary vascular resistance,72 and acetazolamide73 and the Rho-kinase inhibitor, fasudil74, are promising. Hypoventilation leading to hypoxemia may stimulate red cell production,4 but an alternative possibility is that polycythemia is the primary abnormality, which, by reducing Pco2 drive, leads to hypoventilation. Figure 3. There are a number of potential pharmacologic treatments for managing less severe disease, but few have been formally trialed in HAPH. Arterial blood gases and oxygen content in climbers on Mount Everest. The genetic architecture of adaptations to high altitude in Ethiopia. Pulmonary vascular impedance and wave reflections in the hypoxic calf. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α. Published by Elsevier Inc. All rights reserved. Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt. Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. A number of attempts have been made to understand adaptation to high-altitude life based on differences in candidate pathways, such as the ability of Tibetans to preserve NO production at altitude82 and candidate genes,66,83 but this approach is selective and the data come from small subject numbers. Chronic global alveolar hypoxia is accompanied by structural remodeling of pulmonary vessels. Effects of fasudil in patients with high-altitude pulmonary hypertension. 5. The endothelium releases a variety of vasoactive mediators, such as endothelin 1, prostacyclin, and nitric oxide (NO; Figure 3),9,16 and their production is perturbed by hypoxia. There is widely believed to be a genetic predisposition to HAPE, but to date only candidate genes have been examined with no consensus observations.100. Hypoxia-inducible factor-1 in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation. Drs Weissmann and Ghofrani are funded by the German Research Foundation, Excellence Cluster Cardio-Pulmonary System (EXC 147). These are transmitted to the microcirculation, where they might perpetuate or potentially even cause the microcirculatory changes, as well as contribute to the burden on the RV.46. Pulmonary edema at high altitude: review, pathophysiology, and update. Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. Modified from Weissmann et al.5B, Elevated PAP in a telemetered rat takes days to return to baseline after removal from 2 weeks in a hypoxic chamber. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. An alternative to phlebotomy is acetazolamide. organization. There is no role for diuretics. It is a noncardiogenic form of edema that is linked with elevated capillary pressure and pulmonary hypertension. 1-800-AHA-USA-1 [1] HAPE is a noncardiogenic form of pulmonary edema resulting from a leak in the alveolar capillary membrane. Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) are manifestations of the brain pathophysiology, while high-altitude pulmonary edema (HAPE) is that of the lung. When treatment is required, consideration should be given to descent to a lower altitude coupled with supplemental oxygen (2–4 L/min) where possible.56,63 Nifedine is the standard treatment. The advent of high-throughput genome sequencing has enabled a less-biased strategy for investigating gene associations. Based on underlying cause Cardiogenic pulmonary edema Non-cardiogenic pulmonary edema Neurogenic PE High Altitude PE Post Aspiration PE Re-expansion PE Other ( inhaled toxins, lymphatic obstruction, post lung transplant, etc.) Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor (HIF) system and blunted physiological responses to hypoxia. 7272 Greenville Ave. Gene expression in chronic high altitude diseases. Clin Chest Med. Salmeterol for the prevention of high-altitude pulmonary edema. Hypoxic pulmonary vasoconstriction requires connexin 40-mediated endothelial signal conduction. Objective: 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. Class I HDAC inhibitors markedly decreased cytokine/chemokine mRNA expression levels in these cells proliferating adventitial fibroblasts and their ability to induce monocyte migration and inflammation.36 This in part may be attributed to modulation of microRNA-124 expression.37 ECAM indicates endothelial cell adhesion molecule; FGF, fibroblast growth factor; HDAC, histone deacetylase; GM-CSF, granulocyte macrophage colony stimulating factor; HIF, hypoxia-inducible factor; ICAM, intercellular adhesion molecule; IL-1β, interleukin 6; IL-6, interleukin 6; NO-sGC-cGMP, nitric oxide-soluble guanylate cyclase-cyclic GMP; PDGF, platelet-derived growth factor; PGI2, prostacyclin; ROS, reactive oxygen species; TRPC6, transient receptor potential cation channel 6; and VCAM, vascular cell adhesion molecule. The endothelium releases a variety of vasoactive mediators, such as endothelin 1, prostacyclin, and nitric oxide (NO),9,16 and their production is perturbed by hypoxia. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. The roles of activation of the sympathetic nervous system, hypovolemia (from hyperventilation and increased diuresis), hypocapnia (from hyperventilation), and myocardial contractility in this response are difficult to discern.47 On the whole, myocardial contractility is preserved, although reversible reductions in cardiac mass and myocardial phosphocreatine/ATP have been documented in healthy volunteers after a 17-day trek to 5300 m.48 Right heart failure is a risk in some previously healthy individuals, precipitated by more extreme pulmonary vascular responses to hypoxia, and also in the context of chronic mountain sickness (CMS), from pronounced erythrocytosis and fluid retention (from relatively higher Pco2). High-altitude illness may result from short-term exposures to altitudes in excess of 2000 m (6560 ft). Pulmonary blood flow heterogeneity during hypoxia and high-altitude pulmonary edema. Figure 1. When pulmonary edema … ADMA indicates asymmetrical dimethylarginine; cGMP, cyclic guanosine monophosphate; DDAH, dimethylarginine dimethylaminohydrolase; DMA, dimethylamine; ET-1, endothelin 1; EC, endothelial cell; MLC20, regulatory myosin light chain; MLCP, myosin light chain phosphatase; NO, nitric oxide; NOS, nitric oxide synthase; O2, oxygen; PASMC, pulmonary arterial smooth muscle cell; PGI2, prostacyclin; Rho, Ras homolog gene family; ROS, reactive oxygen species; and sGC, soluble guanylyl cyclase. Persons susceptible to Pathophysiology of high-altitude pulmonary edema HAPE have an exaggerated hypoxic pulmonary vaso constrictor response that leads to elevated pulmonary ar tery pressures at high altitudes. Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Heart failure has also been described in Indian soldiers posted at the high-altitude borders in China69 and occasionally in previously healthy travelers,70 and HAPH is thought to be the major factor.71, Descent to lower altitude is life saving for severe cases of heart failure. Everest Base Camp. Observations on the pulmonary arterial blood pressure of the cat. Of high altitude-induced pulmonary hypertension result of living above 3000 m for thousands of years contribute. Heterozygous deficiency of hypoxia-inducible factor–2α protects mice against pulmonary hypertension increased cardiac,!: historical clues from brisket disease in Andean highlanders humans can live a normal life high... Circulation at high altitude cerebral edema ( HAPE ) is responsible for most deaths related to altitude. Potential channel 6 ( TRPC6 high altitude pulmonary edema pathophysiology is not an etiologic factor the resultant is... 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