10th March 2024

Group 3: Chronic lung disease

The strongest mechanism that drives the development of pulmonary hypertension in this group is hypoxic pulmonary vasoconstriction, a normal regulatory mechanism that has the aim of limiting blood flow to hypoxic alveoli to preserve ventilation-perfusion matching. The effects of this mechanism on pulmonary vascular pressure is dependent on the duration of the hypoxia. Chronic hypoxia causes pulmonary vasoconstriction by a variety of mechanisms (decrease in nitric oxide, increase in endothelin -1) and is often only partially reversible. Vascular remodelling (obliterative in nature) occurs over time and leads to a reduction in peripheral blood vessels and, consequently, increased peripheral vascular resistance. Additional mechanisms come into play in the setting of ILD-associated PH due to the additional element of vascular destruction caused by progressive parenchymal fibrosis, thrombotic angiopathy, and endothelial dysfunction. The mechanism of pulmonary hypertension in patients with sleep-related breathing disorders (e.g. OSAS) is thought to be related to hypoxic pulmonary vasoconstriction during nocturnal events. Daytime hypoxemia from coexistent chronic lung disease or diastolic heart failure may further contribute.

Diagnosis is only made if there is a high degree of suspicion, given the symptom overlap between pulmonary hypertension and lung disease. Of note, evaluation should always occur when patients are stable, rather than during an exacerbation of their primary lung pathology, as this can temporarily increase pulmonary pressures due to hypoxic vasoconstriction. Specific findings that should prompt consideration of PH in patients with lung disease are:

• Exertional dyspnoea/hypoxaemia not fully accounted for by extent of parenchymal disease or sleep disorder.
• Rapid decline of arterial oxygenation on exercising
• Clinical features of right-sided heart failure
• Imaging (especially HRCT) that shows enlarged pulmonary arteries, attenuation of peripheral pulmonary vasculature, or RV enlargement
• PFT showing severe reductions in DLCO, especially when out of proportion to the severity of the lung defect

The first diagnostic investigation to identify pulmonary hypertension is a TTE to detect elevated PASP as well as alterations in RV structure or function and lack of left-sided heart disease. If, on echocardiography, pulmonary hypertension is moderate or severe, the next step is referral to a centre with expertise in PH to proceed with right heart catheterisation. Several additional diagnostic tests may be performed to evaluate patients with suspected PH to identify specific pulmonary aetiologies and to exclude other aetiologies of PH. These may include overnight oximetry, polysomnography, V/Q scanning, CT pulmonary angiography, the six-minute walk test, and laboratory studies.

Treatment of the underlying condition is indicated in all groups with group 3 pulmonary hypertension. Disease-specific therapies are assumed to improve alveolar hypoxia, thus limiting the progression of pulmonary hypertension. Patients should be advised to exercise, receive routine vaccinations, be encouraged to stop smoking, and be treated with supportive measures such as oxygen and diuretics as needed. Supplemental oxygen has only been documented to improve survival and pulmonary vascular resistance in patients with COPD-associated pulmonary hypertension with hypoxemia.

Use of pharmacologic agents for PAH-directed therapy (iloprost, sildenafil, bosentan, etc.) have a limited efficacy in group 3 PH and may also be harmful in some cases. The poor performance of PAH-directed therapy in this population may be partially explained by vasodilatory effects that may exacerbate ventilation-perfusion abnormalities and worsen gas exchange.