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.

Keywords: chronic mountain sickness; high altitude; high altitude pulmonary edema; hypoxic pulmonary vasoconstriction; pulmonary hypertension.

Figure 1

Hypoxic pulmonary vasoconstriction. Hypoxic pulmonary vasoconstriction (HPV) is characterized by constriction of resistive pulmonary arteries (PA) upon exposure to hypoxia. Several factors have been shown to augment HPV, such as rapid and direct ascent to high altitude (HA), old age, transient perinatal hypoxia, assisted reproductive treatment, and iron deficiency. Some measures have been shown to attenuate HPV, such as slow gradual ascent, staged acclimatization, limitation of physical activity, and pharmacological prevention. Exaggerated HPV has been shown to result in several adverse consequences, including reduced physical activity, high altitude pulmonary edema (HAPE) development, right ventricular (RV) dysfunction, and, in the case of prolonged stay at hypoxic condition, HPV may transit to chronic pulmonary hypertension (PH).

Figure 2

High altitude pulmonary edema. High altitude pulmonary edema (HAPE) develops upon acute exposure to high altitude hypoxia due to exaggerated hypoxic pulmonary vasoconstriction (HPV) and increased capillary damage and leakage due to increased capillary hydrostatic pressure. Several factors have been shown to be associated with increased incidence HAPE, including rapid and direct ascent, male sex, preexisting lung and cardiac disorders, constitutional predisposition, preceding viral upper respiratory tract infection, cold exposure, and strenuous physical activity. Few preventive measures have been shown to attenuate HPV and prevent HAPE development such as slow staged ascent with acclimatization at moderate altitude, lower sleeping altitude, limitation of physical activities, and pharmacological drugs mitigating HPV. Several management strategies have been developed to treat HAPE, such as immediate descent to lower altitude, supplemental oxygen, portable hyperbaric chambers, and pharmacological drugs.

Figure 3

Targets of potential pharmacological agents to prevent or reverse HPV. Upon exposure to hypoxic condition, in pulmonary artery endothelial cells (PAECs), endothelin converting enzyme (ECE) increases endothelin-1 (ET-1) levels, which in turn causes pulmonary artery smooth muscle cell (PASMC) contraction via ET-1 A and B receptors (ETA and ETB). ETA and ETB can be blocked by endothelin receptor antagonists such as bosentan to inhibit hypoxia induced PASMC contraction. Similarly, nitric oxide synthase (NOS) activity is also impaired in hypoxic PAECs, leading to decreased levels of nitric oxide (NO). Further, decreased bioavailability of NO for the activity of soluble guanylate cyclase (sGC) results in decreased levels of cyclic guanosine monophosphate (cGMP) in PASMCs and PASMC contraction. NO level can be restored by either infusion of L-arginine, which is used by NOS as a substrate, or by NO inhalation, which directly activates sGC. To prevent cGMP degradation in PASMCs, phosphodiesterase type 5 (PDE5) can be inhibited by PDE5 inhibitors such as sildenafil and tadalafil. In addition, calcium influx and PASMC contraction can be inhibited with calcium channel blockers such as nifedipine.

Figure 4

Pulmonary hypertension in high altitude residents. Populations permanently living at high altitude (HA)—such as Tibetans, Andeans, Ethiopians, and Kyrgyz—and sea level residents chronically exposed to HA are at risk for the development of pulmonary hypertension (PH). In addition to chronic alveolar hypoxia, susceptibility to develop PH at HA can be increased by several factors, such as exaggerated and sustained hypoxic pulmonary vasoconstriction (HPV), erythrocytosis, altered HIF signaling, fetal programming, iron deficiency, and due to other respiratory and cardiovascular diseases. Several strategies have been suggested to prevent and treat PH at HA, including prevention of common causes of secondary PH, relocation the place of residence to lower altitude, early diagnosis and treatment of diseases leading in PH, and application of potential pharmacological treatment (nifedipine, bosentan, sildenafil, acetazolamide, and fasudil).