High-altitude pulmonary hypertension

High-altitude pulmonary hypertension (HAPH) due to chronic exposure to high altitude is a designated subset of pulmonary hypertension (PH) according to the third clinical classification of PH, which was approved during a conference in 2003 in Venice, Italy [1].

It is estimated that more than 140 million people live 2,500 m above sea level, and the number of temporary visitors to mountains is close to 40 million [2, 3]. Due to the substantial population exposed to the effects of high altitude, HAPH has become a public health problem in mountainous regions throughout the world. There are three specific locations where high-altitude studies have recently been performed: 1) the Himalayas of Asia; 2) the Andes of South America; and 3) the Rocky Mountains of North America. The present review will focus on the epidemiology, pathophysiology, pathogenesis, clinical characteristics and treatment of HAPH.

DEFINITION

HAPH is a clinical syndrome seen in adults and children residing in high-altitude regions. As chronic mountain syndrome (CMS) is characterised by severe hypoxaemia, excessive polycythaemia and marked PH [4], HAPH is regarded as an important subset of CMS. However, the definition and diagnostic criteria of HAPH remain somewhat vague. According to the 2003 conference on PH, HAPH is classified in the third group of PH (table 1⇓) [1]. Thus, right heart catheterisation is required to establish the diagnosis of HAPH (PH is defined by a mean pulmonary artery pressure (P̄ _pa) of >25 mmHg at rest or >30 mmHg with exercise) [5].

EPIDEMIOLOGY

Although HAPH is not a rare disorder in high-altitude residents and systolic pulmonary pressure can be evaluated easily, PH is infrequently noted in most CMS studies. As a result, the prevalence of HAPH among general highland residents is still unknown.

Aldashev et al. [6] surveyed the prevalence of HAPH in 741 high-altitude permanent inhabitants in a Kyrgyz population and in 2002 reported that ECG signs of cor pulmonale were presented in 23% of males and 6% of females (p<0.0001). In total, 11 subjects (10 males and one female) from this cohort were further studied by right heart catheterisation. The P̄ _pa in this subgroup was 31.6±3.9 mmHg (range 20–64 mmHg). A resting P̄ _pa of >25 mmHg was detected in eight subjects. However, all subjects had a pulmonary vascular resistance of >200 dyn·s·m⁻⁵ (mean±sd 465±62 dyn·s·m⁻⁵, range 283–925 dyn·s·m⁻⁵).

Several studies have shown a prevalence of HAPH between 5 and 18% in the population living at ≥3,200 m on the Altiplano in South America [7, 8]. Wu and Ge 9] reported that in the Qinghai Province of China HAPH is more common in children than adults and the enhanced incidence of HAPH with increasing altitude is more pronounced in children than adults. However, fewer HAPH patients were found among both children and adults in a population of Tibetan natives [9]. In contrast, a study by Chen [10] in Tibet on 300 adult HAPH patients (289 males and 11 females) disclosed evidence of severe PH and enlargement of right or both ventricles as shown by ECG and chest radiographic examination. Furthermore, PH was found to be a common feature of high-altitude heart diseases.

PATHOLOGY

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]. Sites of hypoxic pulmonary vasoconstriction are small pulmonary arterioles and veins with a diameter of <900 μm. Venous changes account for ∼20% of the total increase in pulmonary vascular resistance caused by hypoxia [7, 8]. The result of these changes is an increased pressure load on the right ventricle leading to reduced exercise capacity and premature death from right ventricular failure. 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].

Histological examination of the pulmonary vessels in high-altitude residents who died from causes other than CMS showed persistence of the typical fetal patterns (thickened media) [15, 16]. The fact that high altitude-induced changes of the pulmonary vasculature and right heart are reversible upon relocation to a lower altitude suggests a rapid remodelling process of the pulmonary vessels in response to changes in atmospheric oxygen content [17]. Moreover, the fact that at high altitude supplemental oxygen significantly decreases pulmonary arterial pressure (P_pa), both in acclimatised healthy subjects and long-term high-altitude residents, also supports this remodeling concept [10, 18]. The study by Li and Sui [19] reported autopsy results of 20 adults and 100 infants from Tibet who had died of HAPH. The major findings included dilatation of the pulmonary artery trunk, atheromas and thrombosis of the pulmonary artery, and hypertrophy and dilation of the right ventricle and right atrium. Hypertrophy of both ventricles was also found in some cases. Compared with the normal age-matched controls, the ratio of right to left ventricular weight of these patients was significantly greater and the weight of the right ventricle even exceeded the left ventricle in some cases. Severe medial hypertrophy of the small pulmonary arteries with crenation of the elastic laminae was the most significant histological finding in the pulmonary vasculature.

PATHOPHYSIOLOGY

Sustained alveolar hypoxia, such as that experienced by high-altitude residents, has a marked physiological impact on the pulmonary vasculature. The haemodynamic outcome (i.e. increased P_pa) 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]. Light microscopic examination of non-muscular arterioles after exposure to hypoxia shows that smooth muscle begins to appear by day 2 at simulated altitude, with the proportion of muscularised arterioles corresponding to the increasing P_pa [21, 22]. Interestingly, these previous studies show that after returning to normoxia, smooth muscle cells persisted in normally non-muscularised arterioles, suggesting that the histological changes may persist for a very long time after chronic exposure to hypoxia. If confirmed in humans, these findings suggest that hypoxia-associated smooth muscle proliferation in originally weakly muscularised arterioles and normally non-muscular pulmonary vessels is likely to be a major pathophysiological mechanism for the development of HAPH.

PATHOGENESIS

The biochemical mechanisms underlying the pathogenesis of HAPH are poorly understood, but a reduction in nitric oxide (NO) production is thought to play a role [23]. Animal studies showed that the absence of endothelial NO synthase increased susceptibility to HAPH [24]. Anand et al. [25] demonstrated that inhaled NO can cause an acute decrease in P_pa, intrapulmonary shunting and improvement in oxygenation in high-altitude pulmonary oedema patients. The roles of endothelin-1 and prostaglandin I₂ pathways in the pathogenesis of HAPH are still not well characterised.

In the pulmonary vasculature, it appears that transmembrane ion flux plays an important role in controlling the cellular processes that underlie both vasoconstriction and medial hypertrophy and hyperplasia during hypoxic exposure [26]. Alteration in the transport of K⁺ and Ca²⁺ through their respective ion channels modulates these processes by affecting cell volume, membrane potential, cytosolic Ca²⁺ concentration, gene transcription, apoptosis and cell-cycle progression. Precisely how K⁺ and Ca²⁺ channels “sense” changes in oxygen tension or how their activity and expression somehow “adapt” at higher altitudes is unclear. Although pulmonary physiologists are attempting to define this mechanism, it is becoming increasingly apparent that ion channels themselves are probably not the actual oxygen sensors.

GENETICS

It is possible that individuals who develop high-altitude PH share common and, as yet, unidentified genes that influence the pulmonary arteriolar and/or venous response to hypoxia and the generation of smooth muscle cells from adventitial fibroblasts in weakly and non-muscularised pulmonary vessels. Previous studies have shown that Tibetan-native Chinese, compared to Han Chinese or South American high-altitude natives, have a remarkable lack of muscularisation of pulmonary arteries, and lower hypoxic pulmonary vasoconstrictive response and haemoglobin concentration [27]. This suggests that Tibetans’ protection from high altitude-related illnesses might be due to genetic factors. León-Velarde and MejÍa [28] summarised the available data on genes known to be regulated by hypoxia-inducible factor-1 and/or by hypoxia that have been studied in populations from high-altitude regions suffering from HAPH. Even though some alleles are more prevalent (G allele of endothelial NO synthase polymorphism Glu298Asp in Sherpas and angiotensin-converting enzyme (ACE)I allele in HAPH Kyrgyz) or less prevalent (ACE D allele in high-altitude Andeans) in the different high-altitude populations, data published to date are inconclusive regarding these gene polymorphisms in HAPH [28].

CLINICAL PRESENTATIONS

TREATMENTS

The ideal management for HAPH is migration to low altitude. However, for patients who choose to remain at high altitude, other means of reducing PH may be attempted, although their efficacy has not been fully established.

A number of treatments including oxygen supplementation, calcium channel blockers (such as nifedipine), NO inhalation, prostacyclins and endothelin-receptor antagonists, as well as phosphodiesterase inhibitors, have been demonstrated to decrease hypoxaemia, PH and the alveolar–arterial gradient in PAH. However, the efficacy of these treatments for HAPH needs to be further evaluated.

NO has vasorelaxant and antiproliferative effects that are mediated by cyclic guanosine monophosphate (cGMP). cGMP is hydrolysed by phosphodiesterases (PDEs). PDE5 is the major PDE subtype present in pulmonary vasculature and is more abundant in the lungs than in other tissues [37]. This abundance of PDE5 in the lungs provides a mechanism for relatively selective pulmonary vasodilatation with little systemic hypotension. Agents with PDE5 inhibitory activity reduce P_pa in animal models [38]. Aldashev et al. [39] studied the effects of sildenafil in 14 HAPH patients and reported a reduction in P̄ _pa, with an improvement in 6-min walk distance and an increase in cardiac index after 3 months. Therefore, PDE5 is an attractive drug target for the treatment of HAPH. Long-term treatment with a PDE5 inhibitor, such as sildenafil, maybe a promising therapy for HAPH.

Although endothelin-receptor antagonists have been proven to reduce P_pa and increase exercise capacity in patients with PAH, their effects on exercise capacity at altitude are unknown. Recently, Seheult et al. [40] demonstrated that bosentan therapy initiated 5 days prior to ascent to high altitude did not improve exercise capacity or reduce systolic pulmonary arterial hypertension, and worsened arterial oxygen saturation measured by pulse oximetry during high-intensity exercise at altitude.

A number of studies have emphasised the mechanisms by which acetazolamide and angiotensin-converting enzyme inhibitors may be effective agents for the treatment of high-altitude pulmonary hypertension. Richalet et al. [41] demonstrated that acetazolamide reduces hypoventilation, improves pulmonary circulation and decreases erythropoiesis. Its use as a chronic treatment for high-altitude pulmonary hypertension has been shown to be efficacious and safe [42]. The low cost of acetazolamide may allow for wide adoption with a considerable positive impact on public health in high-altitude regions. The study of angiotensin-converting enzyme inhibitors in the treatment of high-altitude pulmonary hypertension is still ongoing.

Statement of interest

None declared.

Provenance

Submitted article, peer reviewed.