What is the aetiology of pulmonary hypertension and its management?

From the Guidelines

Pulmonary hypertension (PH) is a complex condition that requires a comprehensive approach to management, with treatment depending on the underlying cause, and the primary goal of reducing morbidity, mortality, and improving quality of life. The etiology of PH is classified into five groups: Group 1 (pulmonary arterial hypertension) results from direct damage to pulmonary arterioles from genetic mutations, drugs/toxins, connective tissue diseases, HIV, or portal hypertension; Group 2 is caused by left heart disease leading to backward pressure transmission; Group 3 develops from chronic lung diseases and hypoxia; Group 4 occurs due to chronic thromboembolic disease; and Group 5 includes PH with unclear or multifactorial mechanisms 1.

Key Points in Management

• For Group 1, specific therapies include phosphodiesterase-5 inhibitors (sildenafil 20mg three times daily or tadalafil 40mg once daily), endothelin receptor antagonists (bosentan 62.5mg twice daily for 4 weeks, then 125mg twice daily), prostacyclin analogs (epoprostenol, treprostinil), and soluble guanylate cyclase stimulators (riociguat) 1.
• Group 2 PH requires treating the underlying heart condition, such as left ventricular systolic or diastolic dysfunction, valvular disease, or congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 1.
• Group 3 management focuses on optimizing respiratory disease treatment with oxygen therapy and bronchodilators, and addressing chronic obstructive pulmonary disease, interstitial lung disease, and other pulmonary diseases with mixed restrictive and obstructive pattern 1.
• Group 4 PH may benefit from pulmonary endarterectomy or balloon pulmonary angioplasty, with riociguat for inoperable cases 1.

Supportive Care

• Supportive care for all groups includes diuretics for fluid overload (furosemide 20-80mg daily), oxygen therapy to maintain saturation >90%, anticoagulation when indicated, and lifestyle modifications including supervised exercise 1.
• Advanced cases may require referral to specialized PH centers for combination therapy or evaluation for lung transplantation.
• Regular monitoring with echocardiography, 6-minute walk tests, and biomarkers is essential to assess treatment response and adjust management accordingly 1.

Classification of PH

• The classification of PH into different groups is crucial for guiding management, as each group has distinct underlying pathophysiological mechanisms and treatment approaches 1.
• The comprehensive clinical classification of pulmonary hypertension, as outlined in the 2015 ESC/ERS guidelines, provides a framework for understanding the different forms of PH and their associated conditions 1.

From the FDA Drug Label

CLINICAL PHARMACOLOGY 12. 1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. 12.1 Mechanism of Action Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation.

The aetiology of pulmonary hypertension is not directly addressed in the provided drug labels. The management of pulmonary hypertension can involve the use of medications such as sildenafil and epoprostenol, which work by:

• Vasodilation: relaxing the blood vessels in the lungs to reduce blood pressure
• Inhibition of platelet aggregation: preventing blood clots from forming These medications can help to reduce the symptoms of pulmonary hypertension and improve quality of life for patients. Key points to consider when managing pulmonary hypertension include:
• Dose selection: careful selection of the dose to ensure efficacy and minimize side effects
• Monitoring: regular monitoring of the patient's condition to adjust the treatment plan as needed
• Concomitant therapy: consideration of other medications or therapies that may be used in conjunction with sildenafil or epoprostenol 2, 3

From the Research

Aetiology of Pulmonary Hypertension

• Pulmonary hypertension (PH) is classified into 5 clinical subgroups: pulmonary arterial hypertension (PAH), PH due to left-sided heart disease, PH due to chronic lung disease, chronic thromboembolic PH (CTEPH), and PH with an unclear and/or multifactorial mechanisms 4
• A range of underlying conditions can lead to these disorders, including left-sided heart disease, chronic lung disease, and thromboembolic disease 4, 5
• PH affects approximately 1% of the global population, and over half of patients with heart failure may be affected 4

Diagnosis of Pulmonary Hypertension

• Routine tests in patients with symptoms and physical findings suggestive of PH include electrocardiography, chest radiography, and pulmonary function tests 4
• Transthoracic echocardiography is used to estimate the probability of PH 4
• Right-sided heart catheterization is essential for accurate diagnosis and classification 4
• All patients with suspected or confirmed PH, without confirmed left-sided heart or lung diseases, should have a ventilation-perfusion scan to exclude CTEPH 4

Management of Pulmonary Hypertension

• Surgical pulmonary endarterectomy is the treatment of choice for eligible patients with CTEPH 4
• Targeted treatments (phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclin analogues, and prostacyclin receptor agonists) are licensed for patients with PAH 4, 5, 6
• The soluble guanylate cyclase stimulator riociguat is the only licensed targeted therapy for patients with inoperable or persistent/recurrent CTEPH 4
• Management of PH resulting from left-sided heart disease primarily involves treatment of the underlying condition 4
• Standard treatment options for PAH include oral anticoagulation, diuretics, oxygen supplementation, and for a small percentage of patients, calcium channel blockers 5
• Newer treatments for PAH include prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors 5, 6

Treatment Strategies for PAH

• Infusions of the prostacyclin analogues epoprostenol and treprostinil appear to be the treatment of choice for moderate to severe PAH 6
• Agents with alternate routes of delivery such as inhaled iloprost may be advantageous in adjunctive roles 6
• Oral therapies such as sildenafil and bosentan have been effective in patients with mild to moderate symptoms 6
• Future trials that focus on the long-term effects of currently available agents, as well as on combination therapy, are needed 6

Current Evidence and Challenges

• Effective management of pulmonary hypertension begins with accurately diagnosing and classifying the disease in order to determine appropriate treatment 7
• The discovery of new disease pathways and modifiers affecting the pulmonary circulation is an ongoing area of intense investigation 7
• Critically-ill patients with pulmonary hypertension remain at high risk of adverse outcomes, requiring a diligent and thoughtful approach to diagnosis and treatment 8