Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders

Abstract

Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension. Pulmonary hypertension due to an exaggerated hypoxic pulmonary vasoconstriction contributes to high altitude pulmonary edema (HAPE), a life-threatening disorder, occurring at high altitudes in non-acclimatized healthy individuals. Despite a strong physiologic rationale for using vasodilators for prevention and treatment of HAPE, no systematic studies of their efficacy have been conducted to date. Calcium-channel blockers are currently recommended for drug prophylaxis in high-risk individuals with a clear history of recurrent HAPE based on the extensive clinical experience with nifedipine in HAPE prevention in susceptible individuals. Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure. Further, pulmonary hypertension along with excessive erythrocytosis may complicate chronic mountain sickness, another high altitude maladaptation disorder. Importantly, other causes than hypoxia may potentially underlie and/or contribute to pulmonary hypertension at high altitude, such as chronic heart and lung diseases, thrombotic or embolic diseases. Extensive clinical experience with drugs in patients with pulmonary arterial hypertension suggests their potential for treatment of high altitude pulmonary hypertension. Small studies have demonstrated their efficacy in reducing pulmonary artery pressure in high altitude residents. However, no drugs have been approved to date for the therapy of chronic high altitude pulmonary hypertension. This work provides a literature review on the role of pulmonary hypertension in the pathogenesis of acute and chronic high altitude maladaptation disorders and summarizes current knowledge regarding potential treatment options.

Hypoxia and Inflammation: Insights From High-Altitude Physiology

“…HAPE occurs most commonly during rapid ascent. This is due to exaggerated HPV which causes acute pulmonary hypertension, increased capillary permeability, and alveolar fluid buildup ( Talbot et al, 2005 ; Dunham-Snary et al, 2017 ; Brito et al, 2020 ; Swenson, 2020 ; Sydykov et al, 2021 ). HAPE onset is primarily due to this non-inflammatory hydrostatic pulmonary edema ( Swenson et al, 2002 ).…”

An Exaggerated Rise in Pulmonary Artery Pressure in a High-Altitude Dweller during the Cold Season

“…Chronic hypoxia-induced sustained pulmonary vasoconstriction and pulmonary vascular remodeling lead to pulmonary artery pressure elevation in high-altitude residents, which is in most cases of mild-to-moderate degree [1]. However, in some of them, marked pulmonary hypertension may develop [12].…”

“…Excessive hypoxic pulmonary vasoconstriction is generally thought to contribute to marked pulmonary hypertension in sea-level residents with high-altitude pulmonary edema, and in high-altitude residents with chronic mountain sickness or high-altitude pulmonary hypertension [1,2]. Moreover, in chronic mountain sickness patients with slightly elevated resting pulmonary artery pressures compared to apparently healthy high-altitude dwellers, even light-intensity exercise was associated with an accentuated pulmonary artery pressure increase [3,4].…”

Exposomes to Exosomes: Exosomes as Tools to Study Epigenetic Adaptive Mechanisms in High-Altitude Humans

“…They show better tolerance to hypoxia and exceptional physical performance at altitude [6][7][8]. However, in some, this physiological adaptation fails and hypoxia triggers in them a maladaptive response that leads to various forms of acute and chronic high-altitude illness, such as high-altitude pulmonary edema or chronic mountain sickness [9]. Chronic mountain sickness or Monge's disease was first described by Carlos Monge in the Andes in 1925 and is the result of failure to physiologically adapt to high-altitude exposure.…”

“…It must be emphasized that causes other than hypoxia may potentially form the basis of and/or contribute to HAPH, such as chronic heart and lung diseases, thrombotic or embolic disease and some gene mutations or even epigenetic mechanisms, which can actually exacerbate the burden on the already hypoxia exposed lungs. Unfortunately, at present, there are no clinically approved drugs for the therapy of HAPH, although the pathological burden is high [9].…”