Altitude-Induced Pulmonary Hypertension

Etiology

At altitudes above 2500 meters (m), exposure to hypobaric hypoxia induces many physiologic changes. Please refer to the Pathophysiology section for more information.[2] In individuals who rapidly ascend to high altitude, these physiologic changes may lead to high-altitude pulmonary edema (HAPE), a commonly recognized severe form of high-altitude illness. Please see StatPearls' companion resource, "High-Altitude Cardiopulmonary Diseases," for further information. In individuals living at high altitude, similar physiologic changes occur but often manifest gradually, with minimal or insidious symptoms. The gradual onset of symptoms, in contrast to the rapid, dramatic changes observed in HAPE, leads to delays and difficulties in diagnosing HAPH. 

Individual susceptibility, genetic predisposition, and altitude influence the development of HAPH among people living at high altitude. For example, native populations with a long history of living at high altitudes are less susceptible to HAPH than individuals who previously lived at low altitudes and later relocated to high altitudes. Accordingly, as hypoxia increases at higher altitudes, so do rates of HAPH.[3] Results from other studies have shown increased rates of HAPH among young children, supporting the importance of age as a variable.[4] Although sex differences have been noted in acute altitude illnesses, there is little evidence to support sex differences in HAPH. However, a lower incidence of chronic mountain sickness has been reported among premenopausal women than among men living at high altitudes. This difference may be secondary to female sex hormones and an associated increase in ventilatory rate and drive.[5]

Individuals with comorbidities that reduce resilience to hypoxic insult or increase susceptibility to pulmonary hypertension are more vulnerable to the effects of the hypoxic vasoconstrictor response, increasing the risk of HAPH. Patients with elevated pulmonary artery pressures and existing pulmonary hypertension are more prone to developing HAPH.[6] Chronic cardiac conditions also increase susceptibility, as do chronic lung diseases such as chronic obstructive pulmonary disease or restrictive lung disease.[7][8]

Epidemiology

Altitude-related illnesses occur most frequently above 2500 m, with more severe forms rarely observed below 3000 m. High-altitude pulmonary hypertension is no exception, with a higher incidence at higher altitudes. The disease is likely underreported, and epidemiologic data are limited and variable. Furthermore, reported rates vary depending on the diagnostic criteria used. 

In results from one study, the prevalence of HAPH was 1.2% among native Tibetans, compared with 15.6% among Andean populations.[4] Results from another evaluation of the Central Asian highlander population reported an incidence of 6% to 35% at an altitude of 3250 m, depending on whether the inclusion criterion was chronic high-altitude disease (6%) or pulmonary artery hypertension with a mean pulmonary arterial pressure greater than 20 mm Hg (35%).[9] Among individuals residing at altitudes above 3200 m, HAPH incidence ranged from 5% to 18%.[10] When evaluating for chronic mountain sickness and associated pulmonary hypertension, the incidence was 5.6% in Chinese Han individuals and 6% to 8% among men in La Paz, Bolivia.[6] Another study evaluating miners with a mean of 14 years of intermittent exposure at altitudes of 4400 to 4800 m found that 23% had mean pulmonary artery pressures greater than 25 mm Hg, and 9% had pressures greater than 30 mm Hg.[11] 

Pathophysiology

Hypoxic stress at high altitudes induces a variety of physiological changes, including those that lead to HAPH with chronic exposure. The pulmonary system responds to hypoxia with increased pulmonary vasoconstriction, known as hypoxic pulmonary vasoconstriction.[12] Blood is shunted away from poorly oxygenated lung tissue toward healthy alveoli to minimize ventilation-perfusion mismatch.[13] This response is adaptive in the setting of lobar pneumonia or other focal lung disease processes. However, at high altitudes, reduced ambient oxygen levels result in global alveolar hypoxia. Resultant vasoconstriction throughout the pulmonary vasculature increases pulmonary artery pressure and contributes to pulmonary artery hypertension.[14] Increased pulmonary pressure leads to capillary overperfusion and vascular leak, resulting in noncardiogenic pulmonary edema.[15] 

Vascular remodeling plays a significant role in the pathophysiology of HAPH. Chronic hypoxia induces vascular remodeling by activating hypoxia-inducible factors, promoting pulmonary vasoconstriction, and increasing vascular resistance in the small pulmonary veins and arteries.[16] At the cellular level, chronic hypoxia induces channelopathies of potassium and calcium channels, thereby increasing intracellular calcium concentrations.[17] With these changes, smooth muscle proliferation occurs in the pulmonary vasculature.[1] Vascular remodeling can be a long-term and irreversible sequela of chronic hypoxia and persists despite the removal of the hypoxic stimulus.[18]

Endothelial nitric oxide is theorized to play a role in the development of HAPH. Longstanding hypoxia is known to decrease nitric oxide synthesis, contributing to the development of pulmonary hypertension.[1][19] Comparative analyses across subpopulations have shown that elevated endothelial nitric oxide concentrations are associated with a lower prevalence of HAPH. Furthermore, individuals from Tibet have high nitric oxide concentrations, which correlate with a lower prevalence of HAPH than the South American Andean population.[1]

History and Physical

High-altitude pulmonary hypertension presents with similar symptoms to other causes of pulmonary hypertension, and healthcare professionals should maintain a high index of suspicion even in young, previously healthy individuals who now reside at high altitudes.[20] By definition, individuals being evaluated for HAPH usually reside at altitudes greater than 2500 m. If the ascent to altitude was recent, high-altitude pulmonary edema should be considered instead. 

Dyspnea, hypoxia, and right heart strain are the hallmarks of HAPH, and the history and physical examination typically reflect these conditions. Dyspnea is often exertional, and patients may report exercise intolerance. There may be associated chest tightness or pain, syncope, fatigue, lower extremity edema, cough, or hemoptysis.[21]

On examination, patients may have signs of right-sided heart failure. A loud P₂, right ventricular heave, systolic murmur of tricuspid regurgitation, jugular venous distension, hepatojugular reflux, peripheral edema, hepatosplenomegaly, and ascites may be noted.[1][22] A thorough history and examination for signs and symptoms of other causes of pulmonary hypertension (eg, chronic lung disease, left-sided heart failure, valvular heart disease, drug- or toxin-induced pulmonary hypertension, thromboembolic disease) are necessary when evaluating patients for suspected HAPH.

Evaluation

Patients who present with shortness of breath, dyspnea, fatigue, or peripheral edema should be evaluated for congestive heart failure and pulmonary hypertension. To diagnose HAPH, the patient must reside at an elevation greater than 2500 m.[1] Initial diagnostic testing may include an electrocardiogram (ECG), laboratory testing, and chest radiography. More advanced diagnostic studies could include echocardiography. The gold standard for definitively diagnosing or excluding HAPH is a right-sided heart catheterization with direct measurements of pulmonary artery pressures. However, right heart catheterization is more costly and carries higher risks of complications than less invasive measures.[22] 

ECG findings in pulmonary hypertension, if present, are consistent with right ventricular strain. These potential findings include right ventricular hypertrophy, right axis deviation, right bundle branch block, an S wave in lead I associated with a Q wave and inverted T wave in lead III, T-wave inversions in inferior leads, peaked P waves (P pulmonale), or ST-segment depressions.[23] Normal ECG findings do not exclude HAPH. There are no laboratory biomarkers that confirm pulmonary hypertension, but laboratory testing may be helpful to exclude other causes of dyspnea and fatigue, such as anemia or renal disease. Brain natriuretic peptide levels are often elevated in pulmonary hypertension, but they are not specific to HAPH. Chest radiographic findings may be normal or may show cardiomegaly, pulmonary vascular enlargement, or pulmonary vascular congestion.[1] 

On echocardiography, findings may include dilation of the right atrium and ventricle, right ventricular hypertrophy, increased interventricular septal thickness with septal flattening, and a D-shaped left ventricular appearance. Patients with pulmonary hypertension commonly have tricuspid regurgitation and pulmonic valvular regurgitation.[24] Echocardiography can also be used to indirectly estimate mean pulmonary artery pressure (mPAP) and systolic pulmonary artery pressure (sPAP). However, it is less accurate than a right heart catheterization.[22] When evaluating suspected HAPH with echocardiography, left ventricular function and ejection fraction must also be assessed to exclude left-sided heart failure. 

Although right heart catheterization with pulmonary artery pressure measurements is generally considered the gold standard for evaluating HAPH, the diagnostic criteria are controversial. The expert consensus definition of chronic high-altitude illness defines HAPH as a mPAP greater than 30 mm Hg or sPAP greater than 50 mm Hg.[25] Some authors consider these cutoffs too conservative relative to the standard definitions of pulmonary hypertension. Historically, pulmonary hypertension diagnostic criteria included an mPAP greater than 25 mm Hg, but more recent literature has proposed a cut-off of mPAP greater than 20 mm Hg for diagnosis.[26] This diagnostic uncertainty contributes to variability in the epidemiologic data available. 

Treatment / Management

Nonpharmacologic Treatment

As the underlying pathophysiologic process of HAPH is driven by hypoxia and altitude, descent to a lower altitude and supplemental oxygen therapy are the mainstays of nonpharmacologic treatment. Patients with HAPH should be advised to move to lower altitudes. Results from several studies demonstrate that mPAP can normalize within a few years after relocating to lower altitudes, although some patients with more severe disease may never recover despite relocation.[27][28] Most patients who relocate to a lower altitude do not require ongoing pharmacologic therapies.[29] Data are limited regarding the timeframe for reversal of symptoms and mPAP with descent. 

Pharmacologic Treatment

No pharmacologic therapies exist specifically for HAPH, although medications used to treat pulmonary hypertension may provide beneficial effects. Phosphodiesterase-5 inhibitors are commonly used and increase nitric oxide availability, leading to pulmonary artery vasodilation and a decrease in mPAP.[10][30] Endothelin receptor antagonists are also used in treatment, acting on pulmonary artery smooth muscle cells to induce vasodilation and reduce mPAP.(A1)

Prostacyclin analogs may also be used to promote pulmonary vascular smooth muscle relaxation and decrease mPAP. Anti-inflammatory agents are effective in minimizing inflammation and vascular remodeling. Some studies support the use of acetazolamide, primarily to alleviate concurrent symptoms of chronic mountain sickness. The associated decrease in secondary polycythemia from chronic mountain sickness can reduce pulmonary vascular resistance and alleviate HAPH symptoms.[22] Despite all efforts and recommendations, if an individual develops irreversible pulmonary hypertension, the definitive treatment is a lung transplant.[31] 

Differential Diagnosis

High-altitude pulmonary hypertension can be challenging to diagnose due to its nonspecific symptoms and insidious onset. The evaluation should also consider other disorders that may present with similar symptoms, such as dyspnea and fatigue. If the patient has rapidly ascended to high altitude, high-altitude pulmonary edema is more likely. Underlying chronic lung diseases such as asthma, interstitial lung disease, and chronic obstructive pulmonary disease can be exacerbated by the hypoxic effects of altitude. Pulmonary function testing may help exclude other pulmonary etiologies. 

Cardiac disease is another common cause of dyspnea and should remain in the differential for HAPH. Underlying congenital heart disease, valvular disorders, or systolic or diastolic dysfunction may have overlapping symptoms with HAPH. Thromboembolic disease, such as a pulmonary embolism, can lead to right heart strain and secondary pulmonary hypertension. Metabolic derangements, electrolyte abnormalities, anemia, and other chronic disease states should also be considered as contributing factors. 

Prognosis

Few long-term studies have specifically assessed the prognosis of HAPH. Some research suggests that, in most individuals, mean pulmonary artery pressure normalizes and HAPH resolves after descent to lower altitudes. However, recurrence is common with a return to high elevation.[1][27][28]

If a patient declines to relocate to a lower altitude, early recognition and treatment are critical for the successful management of pulmonary hypertension. Treatments that decrease pulmonary artery pressures and maximize right ventricular function, such as pulmonary vasodilators, are the mainstay of management. Despite optimal medical management, many patients still experience some degree of exercise intolerance, and others develop irreversible pulmonary hypertension and require a lung transplant.[31] If left untreated, patients with HAPH will progress to worsening pulmonary function, hypoxia, and death. 

Complications

With relocation to a lower altitude, most patients with HAPH have resolution of the disease and a favorable prognosis. Without descent, exercise intolerance with progressive dyspnea upon exertion is the primary complication of this condition, affecting most patients even with optimal treatment. More severe complications include right ventricular failure, worsening pulmonary function, hypoxia, and death.[31]