Altitude-Induced Pulmonary Hypertension

Etiology

At altitudes above 2500 meters, the barometric pressure is lower, which decreases the partial pressure of oxygen in the air. Even though the FiO₂ remains at 21% at high altitudes, the amount of oxygen reaching the alveoli is much less than at sea level, resulting in hypoxia and hypoxemia.[3] Hypoxia triggers pulmonary vasoconstriction and increases pulmonary artery pressures throughout the lung. The belief is that vascular remodeling secondary to abnormal smooth muscle production, a decrease in the intrinsic availability of nitric oxide, and poorly understood genetic predisposition all contribute to the development of HAPH.

Epidemiology

While some individuals experience the spectrum of acute mountain sickness, HAPH develops mainly in those who reside at high altitudes for extended periods. Those with preexisting pulmonary hypertension are at an even greater risk of developing acute mountain sickness because of worsening ambient hypoxia-associated hemodynamics exacerbating previously elevated high pulmonary artery pressures.[4] Only a limited amount of epidemiologic data regarding at-risk populations for HAPH is available. Some studies of South American populations report a prevalence of 18 to 55%, and the condition tends to be more common in men.[1][5]  Lower rates of HAPH have been reported in premenopausal women compared to men living at high altitudes. The difference in reported incidence may be secondary to female sex hormones and an associated increase in ventilatory rate and drive.[6]

Pathophysiology

Hypoxic stress at high altitudes induces a variety of physiological changes. Many organ systems utilize vasodilation to enhance oxygen delivery in hypoxia. In contrast, the lung responds to hypoxia with increased pulmonary vasoconstriction. Blood is shunted away from poorly oxygenated lung zones towards healthy alveoli to minimize V/Q mismatch.[7] This intuitively makes sense in the setting of lobar pneumonia or other focal disease processes involving the lung. In HAPH, all lung fields experience the same degree of hypoxia. Significant vasoconstriction in all parts of the lung and elevated pulmonary artery pressures lead to pulmonary hypertension.[8] The increased pulmonary pressure forces fluid into the lungs, causing acute pulmonary edema. 

Vascular remodeling plays a major role in the pathophysiology of HAPH. Hypoxia ultimately leads to vascular remodeling by triggering pulmonary vasoconstriction and increased vascular resistance in the small pulmonary veins and arteries. At the cellular level, chronic hypoxia causes channelopathy of both potassium and calcium channels, increasing intracellular calcium. The proliferation of smooth muscle within the pulmonary vasculature occurs, a structure normally devoid of smooth muscle cells (fibroblasts).[1] Vascular remodeling can be a long-term and irreversible sequela of chronic hypoxia and persist despite the removal of the hypoxic stimulus.[9]

Endothelial nitrous oxide is theorized to play a role in the development of HAPH. Longstanding hypoxia is known to decrease nitrous oxide synthesis, contributing to the development of pulmonary hypertension.[10][1] Research and comparison of different subpopulations have demonstrated that increased nitrous oxide concentrations in pulmonary endothelium decrease the prevalence of HAPH. Studies have shown that individuals from Tibet have high nitrous oxide concentrations, which correlates with a lower prevalence of HAPH than the South American Andean population.[1]

History and Physical

HAPH presents with similar symptoms to other causes of pulmonary hypertension. The patient may present with 1 or more of the following symptoms: exertional dyspnea, cough, hemoptysis, chest tightness, fatigue, lower extremity swelling, or syncope. On examination, there are signs of right-sided heart failure. Specifically, a loud P2, a right ventricular heave, tricuspid regurgitation, jugular venous distension, peripheral edema, and ascites.[1] All these findings are sequelae of right ventricular hypertrophy and right-sided heart failure. A thorough history and examination looking for signs and symptoms of other additional causes of pulmonary hypertension (autoimmune pathology, valvular heart disease, drug-induced PH, and infectious disease) are necessary when evaluating patients for suspected HAPH.

Evaluation

Patients who present with signs and symptoms of shortness of breath, dyspnea, fatigue, or peripheral edema should be evaluated for heart failure and pulmonary hypertension. To diagnose HAPH, the patient must reside at an elevation greater than 2,500 meters.[1] Other diagnoses besides pulmonary hypertension should always be considered. Diagnostic tests that can be utilized are an EKG, echocardiogram, chest X-ray, pulmonary function tests, or a right-sided heart catheterization with pulmonary angiography. 

• An EKG can be consistent with chronic right heart strain and have findings of right ventricular hypertrophy, right bundle branch block, and tall p-waves in inferior leads. 
• An echocardiogram can show a dilated right ventricle and right atrium and increased pulmonary artery pressure. Left ventricular function and ejection fraction must also be assessed to rule out left-sided heart failure. 
• The chest X-ray may be normal or show signs of cardiomegaly or pulmonary vascular congestion.
• Pulmonary function tests are useful in excluding diagnoses such as chronic obstructive pulmonary disease, asthma, or other interstitial lung diseases. 

Right-sided heart catheterization and pulmonary angiography are the most important diagnostic tools for establishing a definitive diagnosis. A mean pulmonary artery pressure (mPAP) greater than 30 mmHg or systolic PAP of greater than 50 mmHg is diagnostic for pulmonary hypertension.[1] If possible, it is important to attempt catheterization and angiography at the altitude of residence. 

Treatment / Management

Limited data is currently available to guide the long-term management of HAPH. Several studies have shown that some treatments recommended for managing other causes of pulmonary hypertension have improved symptoms and mPAPs. Patients suffering from HAPH should be advised to move to lower altitudes. Some studies have shown that mPAPs for patients have normalized within 2 years of returning to lower altitudes.[11]  Pharmacological treatments for HAPH can include phosphodiesterase and carbonic anhydrase inhibitors. 

• Phosphodiesterase inhibitors (ie, Sildenafil) block the breakdown of nitrous oxide, promote pulmonary artery vasodilation, and decrease mPAP.[12]
• Carbonic Anhydrase Inhibitors (ie, Acetazolamide) are useful in preventing acute mountain sickness. Studies have also shown a decrease in pulmonary vascular resistance.[1] However, Acetazolamide has not been studied specifically for treating HAPH, and the benefits may be minimal. Due to Acetazolamide's low side effect profile, it is safe to incorporate as a treatment option. 
• Endothelin receptor blockers (ie, Bosentan) have also been used to treat pulmonary hypertension.
(A1)

Some studies have shown that venovenous extracorporeal membrane oxygenation can be beneficial for severe cases in the acute setting. Despite all efforts and recommendations, if an individual develops irreversible pulmonary hypertension, the mainstay of treatment is pulmonary transplantation.[13]

Differential Diagnosis

Patients with HAPH can present with dyspnea on exertion, fatigue, chest pain, and peripheral edema. Other causes of heart failure and pulmonary hypertension to consider are:

• Asthma
• Congenital heart disease
• Connective tissue disease
• Chronic obstructive pulmonary disease
• Diastolic dysfunction
• Interstitial lung disease
• Systolic dysfunction

Prognosis

Early recognition and treatment are critical for the successful management and outcomes of any form of pulmonary hypertension. Treatments that decrease pulmonary artery pressures and maximize the right ventricle, such as pulmonary vasodilators, are the mainstay of chronic management. Despite optimal medical management, many patients still experience some degree of exercise intolerance, and others develop irreversible pulmonary hypertension and require pulmonary transplantation.[13] After transplantation, patients have a median survival of 10.7 years.[13] If unsuccessful, various palliative procedures can aid in maximizing right ventricular cardiac output. Few long-term studies have assessed the prognosis of HAPH. Some research suggests that mean pulmonary artery pressures can normalize in as little as 2 years after descent to lower altitudes but can increase with a return to high elevation.[1] 

Complications

The most common complication of the condition is exercise intolerance, which most patients experience to some degree, regardless of optimized treatment and therapy. More severe complications of the condition include the advancement of the disease, right ventricular failure, and death.[13]