From the Guidelines
Chronic low oxygen, or hypoxia, causes pulmonary hypertension through a process called hypoxic pulmonary vasoconstriction, which is a critical adaptation that can lead to permanent elevation of pulmonary arterial pressure and right heart failure if left untreated. This process occurs when oxygen levels in the blood are consistently low, causing the small arteries in the lungs to constrict and redirect blood flow to better-oxygenated areas. However, with prolonged hypoxia, these vessels undergo structural remodeling, including thickening of the vessel walls and proliferation of smooth muscle cells, as discussed in the guidelines for the diagnosis and treatment of pulmonary hypertension 1.
Pathophysiology of Hypoxic Pulmonary Vasoconstriction
The pathophysiology of hypoxic pulmonary vasoconstriction involves the release of vasoactive substances like endothelin-1 that promote vasoconstriction, while reducing production of vasodilators such as nitric oxide, as noted in the European Respiratory Journal 1. Inflammatory processes are also activated, further contributing to vascular remodeling. Over time, these changes lead to permanent elevation of pulmonary arterial pressure, right ventricular strain, and eventually right heart failure if left untreated.
Clinical Implications and Treatment
The development of pulmonary hypertension due to lung diseases and/or hypoxia is accompanied by a deterioration of exercise capacity, worsening of hypoxaemia, and shorter survival, as reported in the 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension 1. Treatment focuses on addressing the underlying cause of hypoxia, oxygen therapy, and sometimes pulmonary vasodilators like sildenafil or bosentan in severe cases. It is essential to refer patients with lung disease and pulmonary hypertension to a PH centre where there is also expertise in lung diseases to determine the best course of treatment.
Key Points
- Chronic low oxygen causes pulmonary hypertension through hypoxic pulmonary vasoconstriction
- Prolonged hypoxia leads to structural remodeling of pulmonary vessels, increasing resistance to blood flow
- Treatment focuses on addressing the underlying cause of hypoxia, oxygen therapy, and sometimes pulmonary vasodilators
- Referral to a PH centre with expertise in lung diseases is crucial for determining the best course of treatment, as noted in the guidelines from the American Heart Association and American Thoracic Society 1.
From the Research
Mechanisms of Chronic Low Oxygen-Induced Pulmonary Hypertension
- Chronic low oxygen, or hypoxia, leads to pulmonary hypertension through several mechanisms, including vasoconstriction of small pulmonary arteries and thickening of the smooth vascular layer, known as pulmonary vascular remodeling 2.
- The endothelium plays a crucial role in modulating these processes, and reactive oxygen species (ROS) are generated by pulmonary vascular wall cells in response to hypoxic exposure, contributing to chronic hypoxic pulmonary hypertension 3.
Role of Reactive Oxygen Species
- ROS are implicated in the pathogenesis of vascular remodeling and hypertension, with NADPH oxidase being a major source of ROS responsible for vascular remodeling and hypertension 3, 4.
- The clearance of ROS by superoxide dismutases, specifically extracellular superoxide dismutase, is also affected by chronic hypoxia, leading to an accumulation of ROS and contributing to pulmonary hypertension 3.
Vasoconstrictor Mechanisms
- Chronic hypoxia exposure leads to enhanced pulmonary vasoconstriction through both calcium-dependent and calcium sensitization mechanisms, with ROS participating in the augmentation of pulmonary arterial constriction 4.
- The activation of various Ca2+ and K+ channels and Rho kinase is involved in regulating Ca2+ influx and myofilament Ca2+ sensitivity, contributing to the development of pulmonary hypertension 4.
Therapeutic Implications
- Supplemental oxygen therapy (SOT) has been shown to improve hemodynamics and exercise performance in patients with pulmonary vascular disease, with growing evidence supporting its benefit for selected patients regarding exercise capacity and survival 5.
- Antioxidants have been shown to have beneficial therapeutic effects in animal models of pulmonary hypertension, supporting the role of ROS in the development of pulmonary hypertension 4.
- Novel vasoconstrictor pathways that are selective for the pulmonary circulation can be blocked to reduce hypoxic pulmonary hypertension without causing systemic hypotension, providing potential targets for therapeutic strategies 6.