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.