Group 3 Pulmonary Hypertension

According to the 2018 6th World Symposium on Pulmonary Hypertension in Nice, France, group 3 pulmonary hypertension (mean pulmonary artery pressure ≥20 mm Hg) comprises cases of pulmonary hypertension due to lung diseases and/or hypoxia.[1] Such conditions include chronic pulmonary obstruction (chronic obstructive pulmonary disease [COPD]), interstitial lung disease (ILD), sleep-disordered breathing disorders, alveolar hypoventilation disorders, and long-term exposure to high altitude. As with the other subgroups of pulmonary hypertension, individuals with group 3 pulmonary hypertension can develop exercise-induced symptoms of right-sided heart failure, such as dyspnea or fatigue, which can later progress to persistent symptoms at rest.

The pathogenesis of group 3 pulmonary hypertension is multifactorial; however, pulmonary hypoxic vasoconstriction plays a key role in all group 3 conditions. The body’s natural response to hypoxia is to cause pulmonary vasoconstriction and systemic vasodilation. Pulmonary hypoxic vasoconstriction is a physiologic process aimed at optimizing ventilation-perfusion matching during times of relative hypoxia by constricting intrapulmonary arteries in poorly ventilated segments of lung to divert blood to well-ventilated areas of lung.[2] The oxygen-sensing organelle mediating pulmonary hypoxic vasoconstriction is hypothesized to be located in the mitochondria.[3] In response to alveolar hypoxia, the mitochondria in the pulmonary artery smooth muscle cells change reactive oxygen species and redox couples, which inhibits potassium channels, depolarizes the cell, activates voltage-gated calcium channels, and increases the calcium concentration within the cell to cause vasoconstriction.[2, 4, 5, 6] This physiologic response to hypoxia is vital to maintaining an adequate partial pressure of oxygen (PO2) during times of focal atelectasis, pneumonia, and single-lung anesthesia by reducing perfusion of the hypoxic segment of the lung. Once hypoxia has resolved (ie, resolution of pneumonia or completion of single-lung ventilation), constriction of intrapulmonary arteries quickly reverses without increasing pulmonary artery pressure. However, sustained hypoxia activates intracellular mediators that reinforce vasoconstriction, such as rho kinase and hypoxia-inducible factor 1α (HIF-1α), leading to pulmonary vascular remodeling and increased pulmonary vascular resistance, which can ultimately result in pulmonary hypertension.[2, 7]

The importance of hypoxic pulmonary vasoconstriction is well illustrated in a genetic disorder called Chuvash disease. This condition is caused by a missense mutation in the von Hippel-Lindau gene that leads to enhanced hypoxic pulmonary vasoconstriction, effectively causing individuals with Chuvash disease to function as if they were chronically exposed to hypoxia despite being in an environment with normal oxygenation. The result of chronic up-regulation of hypoxic pulmonary vasoconstriction is polycythemia and pulmonary hypertension.[2, 8, 9, 10]

Long-term exposure to high altitude

Chronic up-regulation of hypoxic pulmonary vasoconstriction is also the primary mechanism for pulmonary hypertension due to long-term exposure to high altitude. This is best exemplified by the yak, native to the Himalayan region of Central Asia, compared with domestic cattle native to the lowlands, when exposed to long-term high altitude (>2,500 m). Yaks have adapted to life in high altitude by blunting pulmonary vasoconstriction in response to chronic hypoxia, which allows them to maintain low pulmonary arterial pressure. Unlike the yak, when domestic cattle native to the lowlands are exposed to long-term high altitude, they exhibit substantial hypoxic pulmonary vasoconstriction resulting in pulmonary vascular remodeling, pulmonary hypertension, peripheral edema (neck swelling), right-sided heart failure, and eventually death; a phenomenon known as brisket disease.[2, 11] It is hypothesized that the amount of time spent adapting to life at high altitude is inversely proportional to the magnitude of hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension.[2] This is exemplified by native Tibetans living at altitudes over 4,000 m for 25,000 years displaying minimal hypoxic pulmonary hypertension or polycythemia.[12] The Quechua Indians, however, have a high prevalence of hypoxic pulmonary hypertension, despite living at 3,500 m in the Andean highlands for the past 13,000 years.[13, 14] It is hypothesized that variations in the expression and function of components of the oxygen-sensing pathway is responsible for resistance to chronic hypoxia, producing minimal hypoxic pulmonary hypertension and polycythemia in populations that have adapted to life at high altitude.[2, 12]

COPD and ILD

A combination of prolonged hypoxic pulmonary vasoconstriction, mechanical stress, inflammation due to repeated stretching of hyperinflated lungs, pulmonary vascular endothelial dysfunction,[15] and the toxic effects of cigarette smoke are thought to play a role in the development of pulmonary hypertension in patients with COPD.[16, 17, 18] Chronic injury to the alveolar capillary membrane resulting in hypoxia and the release of mediators that promote the onset of pulmonary fibrosis and vascular remodeling resulting in the inability to reestablish normal lung architecture is thought to contribute to the development of pulmonary hypertension in association with ILD.[19] Inflammation resulting from cigarette smoking and gastroesophageal reflux disease may also promote the development of pulmonary hypertension in patients with ILD.[15]

Sleep-related breathing disorders

Sleep-related breathing disorders is a spectrum of conditions that includes habitual snoring, increased upper airway resistance syndrome, hypoventilation syndromes (eg, obesity-hypoventilation syndrome, neuromuscular disease, kyphoscoliosis), obstructive sleep apnea, and central sleep apnea. Pulmonary hypertension due to sleep-related breathing disorders is a multifactorial process including hypoxic pulmonary vasoconstriction, mechanical changes resulting from hyperinflated lungs, capillary loss, inflammation, and endothelial dysfunction as seen in other group 3 conditions.[20] Pulmonary hypertension due to sleep-related breathing is uniquely and strongly correlated with the severity and duration of hypoxemic episodes in sleep apnea, resulting in repetitive increases in pulmonary artery pressures. The recurrent and persistent pressure and volume strains on the right heart increases wall tension in the right ventricle, leading to myocardial hypertrophy. Eventually, the right ventricle becomes unable to maintain adequate blood flow, heralding the onset of dyspnea on exertion, which can ultimately lead to complete right-sided ventricular failure and death in these patients.[20]

A systemic review of several studies among patients with COPD estimated the prevalence of pulmonary hypertension to be 10-30%.[21] The prevalence of pulmonary hypertension in idiopathic pulmonary fibrosis is 28-46% and as much as 85% within preselected patient cohorts.[22] A systemic review of several studies of patients with obstructive sleep apnea estimated the prevalence of pulmonary hypertension to be 15-20%.[23] The prevalence of pulmonary hypertension in patients with any sleep-related breathing disorder is 17-53%.[24, 25]

The BODE (body mass index, airflow obstruction, dyspnea, exercise capacity) index is better than the forced expiratory volume in 1 second (FEV1) at predicting the risk of death from any cause and from respiratory causes among patients with COPD.[26] Pulmonary hypertension has been found to be a poor prognostic indicator in chronic lung diseases.[27] The presence of preoperative pulmonary hypertension in interstitial pulmonary fibrosis lung-transplanted patients increases the risk of developing primary graft dysfunction and has an overall negative effect on survival. One study found that for every increase of 10 mm Hg in mean pulmonary artery pressure, the odds of primary graft dysfunction increase by 1.64.[28] The 5-year survival rate in patients with COPD without pulmonary hypertension is 62%, compared with 36% in patients with COPD and pulmonary hypertension.[29] In general, it is accepted that the worse the pulmonary hypertension, the higher the mortality.

Important medical history to be mindful of in patients suspected of having pulmonary hypertension secondary to a group 3 condition include the following:

• Chronic obstructive pulmonary disease (COPD)
• Obstructive or restrictive lung disease
• Interstitial lung disease (ILD)
• Obesity
• Daytime sleepiness
• Snoring
• Tonsillary hypertrophy
• Macroglossia
• Retrognathia/micrognathia
• Upper airway mass lesions
• Chest wall deformity
• Neuromuscular disease
• Kyphoscoliosis
• Long-term exposure to high altitude
• Opiate use (associated with central sleep apnea)
• Brainstem lesion

Symptoms that may be present in patients with pulmonary hypertension due to a group 3 condition include the following:

• Dyspnea upon exertion
• Fatigue
• Lethargy
• Syncope
• Cough
• Hoarseness

The intensity of the pulmonic component of the second heart sound (P2) may be increased, and the P2 may demonstrate fixed or paradoxic splitting. A systolic ejection murmur may be heard over the left sternal border. The murmur may be augmented by inspiration. A right ventricular heave may be palpated.

A prominent A wave may be observed in the jugular venous pulse. A right-sided fourth heart sound (S4) with a left parasternal heave may be auscultated.

Right ventricular failure leads to systemic venous hypertension and cor pulmonale. The signs of right ventricular failure include a high-pitched systolic murmur of tricuspid regurgitation, hepatomegaly, a pulsatile liver, ascites, and peripheral edema. In this scenario, a right ventricular third heart (S3) sound is also heard.

Signs of underlying cardiac, pulmonary, hepatic, or collagen-vascular disease are often present.

Patients with group 3 pulmonary hypertension often develop cor pulmonale, which further worsens hypoxemia and perpetuates pulmonary hypertension.

Findings from the history, physical examination, chest radiography, and electrocardiography (ECG) may suggest the presence of pulmonary hypertension and right ventricular dysfunction. Two-dimensional transthoracic echocardiography with Doppler analysis can be used to estimate the pulmonary artery pressure and assess ventricular function.

In patients without cardiac disease, pulmonary function tests should be performed, including blood gas determinations and assessment for possible nocturnal desaturation. Any abnormality should be evaluated further with computed tomography (CT) and possibly a lung biopsy. Patients with normal pulmonary function test results should undergo perfusion lung scanning, and if defects are present, pulmonary angiography or spiral CT should be performed.

Right-sided cardiac catheterization is recommended if noninvasive testing does not provide definitive results, if confirmation of pulmonary hypertension is necessary, or if further information is required for surgical intervention.

A complete blood cell (CBC) count, biochemistry panel, prothrombin time (PT), and activated partial thromboplastin time (aPTT) should be obtained at baseline. Arterial blood gas determinations should be performed to assess for hypoxemia.

Even in cases in which group 3 etiology of pulmonary hypertension seems most likely, laboratory studies evaluating for other causes of pulmonary hypertension should still be obtained. Collagen-vascular disease screening should be performed. This includes measuring the erythrocyte sedimentation rate (ESR), rheumatoid factor (RF) levels, antinuclear antibody (ANA) levels, antineutrophil cytoplasmic antibody (ANCA), and SCL70.

Synthetic liver function test results (ie, albumin levels, PT, and bilirubin levels) may indicate liver disease associated with portal hypertension.

Brain natriuretic peptide (BNP of NT-proBNP) should be performed on appropriate patients.

HIV testing and hepatitis serology tests should be performed on patients at risk.

The classic finding on a chest radiograph from a patient with pulmonary hypertension is enlargement of central pulmonary arteries, attenuation of peripheral vessels, and oligemic lung fields. Findings of right ventricular (diminished retrosternal airspace) and right atrial dilatation (prominent right heart border) are possible. Abnormalities may be followed up with spiral CT.

Two-dimensional

Echocardiography is generally used to screen patients for pulmonary hypertension. It is also used to rule out left ventricular and valvular dysfunction.

On two-dimensional echocardiography, signs of chronic right ventricular pressure overload are present, including increased thickness of the right ventricle and paradoxical bulging of the septum into the left ventricle during systole. In later stages, right ventricular dilatation occurs, leading to right ventricular hypokinesis. Right atrial dilatation, septal flattening, tricuspid regurgitation, pulmonic insufficiency, and midsystolic closure of the pulmonic valve may develop.

Doppler

Doppler echocardiography is the most reliable noninvasive method of estimating pulmonary arterial pressure.

Tricuspid regurgitation is usually present in patients with pulmonary arterial hypertension, which facilitates measurement of pulmonary arterial pressure with the modified Bernoulli equation. The efficacy of Doppler echocardiography depends on the ability to locate the tricuspid regurgitant jet. Furthermore, acoustic windows may be limited in patients who have other diseases (eg, chronic obstructive pulmonary disease [COPD]) or in those who are obese.

Tricuspid regurgitation is generally detected in more than 90% of patients with severe pulmonary hypertension, and a correlation of greater than 95% is observed when the pressure is measured by means of catheterization. Doppler echocardiography is a useful noninvasive test for long-term follow-up.

Visual inspection of the shape of the right ventricular Doppler flow velocity envelope provides insight into the hemodynamic basis of pulmonary arterial hypertension.[10] Midsystolic notch was associated with the most severe pulmonary vascular disease and right-sided heart dysfunction.

Ventilation-perfusion scanning should be performed to exclude chronic thromboembolic pulmonary hypertension. A high- or low-probability scan result is most useful, whereas intermediate-probability results should lead to the performance of pulmonary angiography.

Diffuse mottled perfusion can be observed in patients with pulmonary arterial hypertension, as opposed to the segmental or subsegmental mismatched defects observed in patients with chronic thromboembolic pulmonary hypertension.

Pulmonary function tests (ie, spirometry and diffusing capacity for carbon monoxide) should be performed in patients with pulmonary hypertension to exclude an underlying pulmonary disorder. Diffusing capacity is universally reduced in patients with pulmonary hypertension.

These tests may show an obstructive pattern suggestive of COPD or a restrictive pattern suggestive of an interstitial lung disease. Furthermore, the severity of the lung disorder may be established by pulmonary function test findings because these tests provide both qualitative and quantitative data.

Right-sided heart catheterization is the procedure of choice in the diagnosis, quantification, and characterization of pulmonary hypertension. Left-sided heart dysfunction and intracardiac shunts can be excluded, and the cardiac output can be measured.

The indications for right-sided cardiac catheterization are as follows:

• Difficulty in measuring pulmonary arterial hypertension accurately with Doppler echocardiography

• Need for a precise measurement of pulmonary vascular resistance to conduct a vasodilator trial for assessment of the acute response to vasodilators

Acute vasoreactivity is determined by administering a short-acting vasodilator such as prostacyclin, inhaled nitric oxide, or adenosine. An acute response often predicts a beneficial effect from oral agents, such as calcium channel blockers.[11]

Electrocardiography

On electrocardiography, signs of right ventricular hypertrophy or strain may be observed. These include right axis deviation, an R-to-S wave ratio greater than 1 in lead V1, increased P-wave amplitude, and an incomplete or complete right bundle-branch block pattern.

Pulmonary angioscopy

Pulmonary angioscopy findings have proven valuable for confirming the presence of chronic thromboembolic obstruction and determining whether it is amenable to surgical intervention. The pulmonary angioscope is a fiberoptic device that allows visualization of the pulmonary arteries to the segmental level.

Polysomnography

In patients with symptoms of suspected obstructive sleep apnea, polysomnography should be performed. Polysomnography may offer both diagnostic and therapeutic options for sleep-disordered breathing.

The histopathologic lesions in patients with group 3 pulmonary hypertension are similar to those observed in patients with primary pulmonary arterial hypertension. These pathologic changes are the result of longstanding hypertension rather than a consequence of different causes.

The plexiform lesion is observed in patients with all types of pulmonary arterial hypertension. These lesions consist of medial hypertrophy, eccentric or concentric laminar intimal proliferation and fibrosis, fibrinoid degeneration, and thrombotic lesions. Fresh or organized and recanalized thrombi may also be present. Diverse types of intimal and muscular lesions of the small muscular arteries may cause the clinical syndrome of pulmonary arterial hypertension, and a plexiform lesion reflecting the abrupt onset of pulmonary arterial hypertension is likely, rather than the lesion being a distinctive cause.

The therapy for group 3 pulmonary hypertension is primarily directed at the treatment of the underlying disease. Effective therapy should be instituted in the early stages, before irreversible changes in pulmonary vasculature occur. Once the cause of group 3 pulmonary hypertension has been established, management consists of specific interventional therapy, specific medical therapy, or general supportive therapy.

The use of a continuous positive airway pressure (CPAP) device in patients with obstructive sleep apnea has shown to significantly decrease the mean pulmonary artery pressures, suggesting potential reversibility of pulmonary hypertension upon treatment of obstructive sleep apnea.[20, 30]

Inhaled vasodilators are thought to improve ventilation-perfusion matching in patients with chronic obstructive pulmonary disease (COPD) by improving perfusion to well-ventilated areas of lung, primarily in the apices.[2] Results from the ASPIRE registry demonstrated that 19% of patients with severe pulmonary hypertension associated with COPD identified arbitrarily as having an objective response to vasodilator therapy based on improvements in WHO functional class or a greater than 20% fall in pulmonary vascular resistance had a superior survival compared with nonresponders and may represent a phenotype in which there is a greater degree of potentially treatment-responsive vasculopathy compared with emphysematous obliteration of the pulmonary microvascular bed.[31]

Preliminary data with inhaled iloprost, a prostacyclin analogue, appear promising, although frequent inhalations are required. Similarly, the use of almitrine, a drug that enhances pulmonary hypoxic vasoconstriction, increases the partial pressure of oxygen (Pa02) in COPD patients from 52 mm Hg to 59 mm Hg. However, ventilation-perfusion matching is worsened by systemic vasodilators and calcium channel blockers.[2, 32, 33]

Bosentan, an endothelin-1 receptor antagonist traditionally used to treat group 1 pulmonary arterial hypertension, was shown to negatively affect gas exchange in a randomized controlled trial performed on COPD patients.[34] Despite these discouraging results, traditional group 1 pulmonary arterial hypertension treatment may confer some benefit to COPD patients with “out-of-proportion” pulmonary hypertension, defined as mean pulmonary artery pressure 35-40 mm Hg or greater and relatively preserved lung function that cannot explain prominent dyspnea and fatigue.[32] However, more clinical trials are necessary to evaluate treatment efficacy in this specific subgroup of group 3 pulmonary hypertension patients.

Balloon atrial septostomy has been used with success in patients without evidence of right ventricular failure. The benefit (improved exercise function) occurs at the cost of a fall in arterial oxygen saturation (SaO2). The technique has been performed via a femoral catheter, with a Brockenbrough septal needle and Mansfield balloons to dilate the septostomy.

Oxygen has proved beneficial for reducing patient mortality in selected patients with pulmonary hypertension. Two large trials demonstrated a definite mortality benefit for patients with COPD, the most common cause of pulmonary hypertension. Survival rates are highest in COPD patients who have less severe pulmonary hypertension, patients in whom the pulmonary arterial pressure decreases, or patients in whom exercise capacity improves with oxygen therapy.

Although long-term study results are not available, it appears that oxygen administration may also benefit other groups of patients with pulmonary hypertension. Accordingly, long-term oxygen therapy should be prescribed for patients whose arterial oxygen tension (PaO2) is lower than 55 mm Hg at rest from any cause, those who have desaturation during exercise, and those who perform better on oxygen therapy.

Medicare indications for continuous long-term oxygen therapy include the following:

• PaO ₂ of 55 mm Hg or less or SaO ₂ of 88% or less
• PaO ₂ of 56-59 mm Hg or SaO ₂ of 89%, in the presence of evidence of cor pulmonale, right-sided heart failure, or erythrocytosis (hematocrit >55%)

Although lung transplantation is reserved for patients with severe pulmonary hypertension, a number of secondary pulmonary hypertension patients have undergone successful transplantation at several centers. These patients had secondary pulmonary hypertension due to collagen-vascular disease, drug-induced pulmonary hypertension, or pulmonary veno-occlusive disease. The stability of the underlying causative disorder and the ability of the patient to tolerate an extensive operation are prerequisites. Heart-lung transplantation has been performed in patients with secondary pulmonary hypertension due to congenital cardiac disease or severe left ventricular dysfunction.

Although lung transplantation has historically been the treatment of choice for severe pulmonary arterial hypertension, at present it is typically needed only for patients who are still in New York Heart Association (NYHA) functional class IV after 3 months of therapy with epoprostenol. The long-term outcomes of lung transplantation remain disappointing, with 50% survival at 5 years.