Pulmonary Arterial HypertensionEdit

Pulmonary arterial hypertension (PAH) is a progressive, life-shortening condition defined by pre-capillary pulmonary hypertension arising from pathology of the small pulmonary arteries. In contemporary classifications, PAH is a subgroup of pulmonary hypertension (Group 1) and is distinguished by a mean pulmonary arterial pressure (mPAP) greater than 20 mmHg at rest, with a normal or near-normal pulmonary wedge pressure (≤ 15 mmHg) and a pulmonary vascular resistance (PVR) above 2 Wood units, as outlined in the latest guidelines from major international bodies such as the World Health Organization and the ESC/ERS guidelines.

PAH results in remodeling and narrowing of small pulmonary arteries, which raises the resistance to blood flow from the right ventricle. Over time, this increased afterload can lead to right heart strain and eventual right heart failure. The condition can be idiopathic, heritable, drug- or toxin-induced, or associated with other illnesses such as connective tissue diseases, congenital heart disease with shunts, HIV infection, or portal hypertension.

Epidemiology

PAH is a rare disease, with incidence and prevalence varying by region and diagnostic criteria. It most commonly affects adults, often presenting in the fourth or fifth decade of life, and shows a female predominance in several subtypes of idiopathic PAH and heritable PAH. Risk factors include connective tissue disease (e.g., systemic sclerosis), congenital heart disease with shunts, HIV infection, exposure to certain drugs or toxins, and genetic predispositions. Accurate epidemiologic data depend on recognition by clinicians and access to specialty testing, which can influence reported rates.

Pathophysiology

Mechanisms

Endothelin-1 pathway: Excess endothelin-1 promotes vasoconstriction and vascular remodeling, contributing to increased pulmonary vascular resistance. Endothelin-1 signaling is a central therapeutic target.
Nitric oxide and prostacyclin pathways: Reduced production of nitric oxide and prostacyclin shifts the balance toward vasoconstriction and pro-proliferative signaling, worsening pulmonary vascular remodeling. Links include Nitric oxide biology and Prostacyclin pathways.
Vascular remodeling: Proliferation and remodeling of the intima and media of small pulmonary arteries, with in-situ thrombosis contributing to narrowing of the vascular lumen.
Right heart load: Progressive elevation of afterload on the right ventricle leads to compensatory hypertrophy, diminished cardiac output, and signs of right heart failure.

Cellular and genetic factors

PAH can be associated with genetic variants (e.g., mutations in genes such as BMPR2 in some hereditary forms) and interacts with environmental and autoimmune factors to promote disease onset and progression. The net result is a complex vasculopathy that undermines the normal ability of the pulmonary circulation to adapt to increasing flow demands.

Clinical presentation

Patients with PAH typically present with nonspecific symptoms that progress over months to years: - Dyspnea on exertion, fatigue, and reduced exercise tolerance - Chest discomfort or near-syncope during activity - Signs of right heart strain on examination, including a loud P2 component of the second heart sound, right ventricular heave, jugular venous distension, peripheral edema, or ascites in advanced disease

Functional status is commonly graded by the World Health Organization (WHO) functional class, which correlates with prognosis and guides treatment decisions. Early recognition is essential, as delay can lead to irreversible right heart remodeling.

Diagnosis

The diagnostic workup for suspected PAH typically includes: - Screening and noninvasive testing: Transthoracic echocardiography to estimate pulmonary pressures and right heart function, and to assess for alternative causes of symptoms. Echocardiography is a key initial test. - Definitive hemodynamic testing: Right heart catheterization to confirm pre-capillary pulmonary hypertension, measure mPAP, assess wedge pressure, and calculate PVR. Right heart catheterization is considered the gold standard for diagnosis. - Laboratory and imaging studies: Baseline labs including natriuretic peptides (e.g., BNP or NT-proBNP) to assess right heart strain; chest imaging with CT or MRI to exclude other causes; ventilation-perfusion scanning or CT pulmonary angiography to evaluate for thromboembolic disease; and consideration of sleep studies or lung function testing to evaluate comorbidities. - Classification and differential diagnosis: Distinguishing Group 1 PAH from other forms of pulmonary hypertension (e.g., Group 2 due to left heart disease, Group 3 due to lung disease, Group 4 chronic thromboembolic pulmonary hypertension) is essential because management differs. Relevant terms include pulmonary hypertension, left heart disease, and chronic thromboembolic pulmonary hypertension.

Risk stratification for prognosis and therapy guidance uses a combination of functional status (e.g., WHO class, 6-minute walk distance), biomarkers (e.g., BNP/NT-proBNP), and imaging findings of right heart function.

Management

PAH therapy is tailored to disease severity, etiology, and patient comorbidities. The overarching goals are to alleviate symptoms, improve functional capacity, slow progression, and enhance quality of life, while monitoring for adverse effects and disease progression.

General measures

Vaccination and infection prevention, avoiding tobacco exposure and high-risk environments
Supplemental oxygen when indicated to maintain adequate oxygen saturation
Diuretics to manage volume overload in patients with signs of right heart failure
Pregnancy counseling due to high maternal and fetal risk
Exercise and rehabilitation programs adapted to PAH patients and supervised by specialists

Pharmacotherapy (targeted PAH therapies)

Targeted therapies act on the three main pathogenic pathways implicated in PAH.

Endothelin receptor antagonists (ERAs): Ambrisentan, bosentan, macitentan. By blocking endothelin-1 signaling, these drugs reduce vasoconstriction and vascular remodeling. See Ambrisentan, Bosentan, Macitentan.
Phosphodiesterase-5 inhibitors (PDE5 inhibitors): Sildenafil, tadalafil. These agents enhance the nitric oxide–cGMP pathway to promote vasodilation.
Soluble guanylate cyclase stimulators: Riociguat. This drug directly stimulates sGC to increase cyclic GMP and promote vasodilation.
Prostacyclin pathway therapies:
- Epoprostenol (intravenous): potent vasodilator with short half-life, requiring continuous infusion.
- Treprostinil (subcutaneous, intravenous, or inhaled): flexible delivery options.
- Iloprost (inhaled): inhaled formulation providing intermittent pulmonary vasodilation.
- Selexipag (oral prostacyclin receptor agonist): oral agent targeting prostacyclin pathways.
Combination therapy: In many patients, a combination approach directed at multiple pathways yields better symptom relief and functional improvement than monotherapy, and guidelines increasingly support initial combination therapy in selected patients. See Combination therapy in PAH.

Interventional and surgical options

Oxygen therapy and management of comorbid conditions when present
Lung transplantation or combined heart–lung transplantation in advanced, refractory PAH
Atrial septostomy and other palliative procedures are considered in selected cases with extreme right heart failure or as a bridge to transplantation; see Lung transplantation and Heart-lung transplantation.
Chronic thromboembolic pulmonary hypertension (group 4) is treated with surgical or endovascular thromboembolectomy when indicated; although not PAH per se, it is an important differential diagnosis and is treated with tailored therapies including surgical intervention when appropriate. See Chronic thromboembolic pulmonary hypertension.

Controversies and ongoing debates

The role of chronic anticoagulation in idiopathic or heritable PAH has been debated, with studies showing mixed results and bleeding risk concerns.
The sequencing and choice of initial therapy (monotherapy vs combination therapy) continue to be refined by trials and guidelines, balancing efficacy, safety, and cost.
Access and affordability of costlier targeted therapies pose real-world challenges, prompting discussions about health system design, insurance coverage, and patient selection.
The optimization of therapy in special populations (pregnant patients, those with coexisting lung or heart diseases) remains an area of active clinical judgment and research.

Prognosis and monitoring

Prognosis in PAH depends on the underlying etiology, response to therapy, and initial functional status. Risk stratification using a combination of functional class, exercise capacity, biomarker levels, and imaging findings guides treatment intensity and monitoring frequency. Regular follow-up aims to detect disease progression early, adjust therapy as needed, and assess for adverse effects from medications and procedures. Although PAH was once uniformly fatal, advances in targeted therapies have substantially improved outcomes for many patients, especially when treatment is started early and managed in specialized centers. See Prognosis in PAH and Risk stratification in PAH.