Pathophysiology and Treatment of High-Altitude Pulmonary Vascular Disease

Abstract

582I t is estimated that >140 million people live above 2500 m in various regions of the world.1 There are many challenges to living at high altitude, but chronic exposure to alveolar hypoxia is prominent among them. Inspired Po 2 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). 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. Pathophysiology of Acclimatization to Hypoxia Pulmonary Vascular Response to HypoxiaFor most mammals, including humans, a rise in pulmonary artery pressure (PAP) is an early and inevitable consequence of ascent to high altitude. Resting mean PAP increases along a parabolic curve from 15 mm Hg at 2000 m to ≈30 mm Hg at 4500 m. 4 The exceptions and interindividual variation in the magnitude of response offer a natural experiment that might provide insight into fundamental underlying mechanisms (vide infra).The initial rise in PAP on exposure to hypoxia is attributed to HPV. With chronic hypoxia, other mechanisms that likely drive vascular remodeling soon contribute to the elevated pressure ( Figure 1A). 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 chamber 7 ( Figure 1B) and is also documented in humans. 4,8 Pulmonary Arteriolar Vasoconstriction Dominates the Acute Pulmonary Vascular Response to HypoxiaOxygen tension is a major regulator of pulmonary vascular tone and a physiological mechanism for matching perfusion with ventilation. A fall in alveolar Po 2 is the main stimulus for HPV, but a reduction in mixed venous and bronchial arterial Po 2 may also contribute. 9 Ventilation of intact lungs with a hypoxic gaseous mixture (eg, fraction of inspired oxygen=0.10) leads to acute pulmonary vasoconstriction throughout the pulmonary vascular bed, including nonmuscular arterioles, capillaries, and veins, but is most pronounced in small pulmonary arterioles. [10][11][12][13] That said, HPV is not distributed evenly throughout the lung and lung perfusion is inhomogeneous during hypoxia.14 HPV has at least 2 phases ( Figure 1A). An initial constrictor response that starts within seconds and reaches a maximum within minutes is followed by a sustained phase, which develops after 30 to 120 minutes. 9 A transient phase of vasodilation may be observed linking the two, an...

What people with Down Syndrome can teach us about cardiopulmonary disease

“…Pulmonary vascular diseases are wide-ranging in their aetiology and pathogenesis. Pulmonary embolism and pulmonary oedema are commonly found on computed tomography in pulmonary vascular diseases such as CHD, altitude sickness and pulmonary artery hypertension (PAH) [42][43][44][45][46]. Embolism and oedema in the lung secondary to left heart disease are thought to derive from changes in endothelial permeability and are probably related to potassium and calcium channel disturbances [47][48][49].…”

Thin Air Resulting in High Pressure: Mountain Sickness and Hypoxia-Induced Pulmonary Hypertension

“…On a cellular level, the remodeling of the small vessels is caused by increased proliferation and migration and decreased apoptosis of PASMC (Figure 1) [16], and the affected cells seem to comprise a specific subpopulation of PASMC that are not well differentiated. Additional alterations include increased proliferation and migration of fibroblasts that have the ability to differentiate into smooth muscle cell-like cells and secrete matrix proteins.…”

“…In addition, variants of the major upstream transcriptional regulator EPAS1 were also significantly associated with low hb concentrations in Tibetan highlanders [144]. The low hb concentration and concomitant reduction of blood viscosity compared with acclimatized lowlanders might be an important mechanism to maintain cardiopulmonary circulation in Tibetan highlanders [16]. …”

Myocardial infarction after carotid endarterectomy

“…Высокая легочная гипертензия (ЛГ) отражает застой крови по малому кругу кровообращения или серьезные фиброзные изменения в легочной ткани [14]. В связи с этим при резком повышении АД во время основного эта-па хирургической реконструкции шанс наступления де-компенсации сердечной деятельности чрезвычайно вы- сок, что приводит к ИМ.…”