High-altitude pulmonary hypertension: a pathophysiological entity to different diseases

Abstract

High-altitude pulmonary hypertension: a pathophysiological entity to different diseases. M. Maggiorini, F. Léon-Velarde. #ERS Journals Ltd 2003. ABSTRACT: Pulmonary hypertension is a hallmark of high-altitude pulmonary oedema (HAPE) and of congestive right heart failure in subacute mountain sickness (SMS) and chronic mountain sickness (CMS) in the Himalayas and in the end-stage of CMS (Monge9s disease) in the Andes.There are studies to suggest that transmission of excessively elevated pulmonary artery pressure and/or flow to the pulmonary capillaries leading to alveolar haemorrhage is the pathophysiological mechanism of HAPE.In the Himalayas, HAPE was successfully prevented by extending the acclimatisation period from a few days to 5 weeks, however, this did not prevent the occurrence of congestive right heart failure after several weeks of stay at 6,000 m. This leads to the concept that rapid remodelling of the small precapillary arteries prevents HAPE but not the development of right heart failure in SMS and CMS.Unresponsiveness of pulmonary hypertension to oxygen at high altitude and its complete resolution only after weeks of stay at low altitude suggest that structural rather than functional changes are its pathophysiological mechanism. Since pulmonary hypertension at high altitude is the driving force leading to high-altitude pulmonary oedema and "high-altitude right heart failure" in newcomers and residents of high altitude, the authors propose to adjust current terminology accordingly. The physiological response of the pulmonary circulation to hypobaric and normobaric hypoxia is to increase pulmonary arteriolar resistance. The magnitude of hypoxic pulmonary vasoconstriction is highly variable between humans, probably based on genetics and adaptive mechanisms. Sites of hypoxic pulmonary vasoconstriction are small pulmonary arterioles and veins of a diameter of v900 mm, the veins accounting for y20% of the total increase in pulmonary vascular resistance caused by hypoxia [1,2]. The structural changes in small pulmonary arteries and veins appear to reflect this genetically based and adaptive process [3][4][5] in humans and animals. Excessive hypoxic pulmonary vasoconstriction, and thus susceptibility to develop a right heart failure within weeks at high altitude, was first described in Colorado cattle [6]. Indian soldiers stationed at an altitude between 5,800-6,700 m [7] and Han infants in Lhasa [8] develop severe congestive right heart failure within weeks or months after arrival at high altitude. An excessively elevated pulmonary artery pressure (PAP) has not only been reported to cause high altitude cor pulmonale within weeks, months, or years in newcomers, but also in high-altitude residents of the Andes and nonacclimatised climbers prone to high-altitude pulmonary oedema (HAPE) [9]. The results of these studies suggest that an excessive rise in PAP is a common denominator in HAPE [9], the syndrome described by SUI et al. [8] in infants and by ANAND et al. [7] in adults at 6,700 m and termed "subacute...

High-altitude pulmonary hypertension

“…The haemodynamic outcome (i.e. increased Ppa) is due to enhanced pulmonary vasoconstriction and pulmonary vascular remodelling, both of which cause reduction of the vascular lumen diameter and an increase in pulmonary vascular resistance [11,12]. In rats exposed to hypoxia, pre-capillary vessels of a diameter of ,25 mm, which normally do not have smooth muscle cells, begin to generate from adventitial fibroblasts within 24 h [20].…”

“…HAPH is characterised by increased pulmonary vascular resistance secondary to hypoxia-induced pulmonary vasoconstriction and vascular remodelling of pulmonary arterioles [11,12]. The vascular alterations involve all elements of the vessel wall and include endothelial dysfunction, extension of smooth muscle into previously non-muscular vessels and adventitial thickening [13,14].…”

Phosphodiesterase type 5 and high altitude pulmonary hypertension

“…4 5 The result is an increased pressure load on the right ventricle, reduced exercise capacity, and premature death from right ventricular failure. 6 The structural changes in the pulmonary vasculature are due, at least in part, to hypoxia associated smooth muscle cell proliferation and-together with increased pulmonary vascular tone-represent targets for therapeutic intervention. 6 The biochemical pathways underlying this pathophysiology are poorly understood, but a reduction in nitric oxide (NO) production is thought to have a role.…”

High-Altitude Pulmonary Vascular Diseases

“…58 In the Andes and in western China and Tibet, similar numbers have been reported. 59,60 The clinical presentation of HAPH is similar to any form of PH with exertional dyspnea as an early feature, but evolving as the disease progresses to general fatigue, anginal chest pain, syncopal episodes, and cor pulmonale in its late stages. Numerous genetic associations have been reported in small series of patients with HAPH, including gene polymorphisms in ACE (encoding angiotensin-converting enzyme), 61 EPAS1 (encoding HIF-2a), 62 GUCY1A3 (encoding soluble guanylate cyclase), 63 and EGLN1 (encoding prolyl hydroxylase 2).…”