Residency · Residency · Respirology

Pulmonary Arterial Hypertension

Definition and Classification

Updated Hemodynamic Definition (6th WSPH 2018 / ESC 2022)

The hemodynamic definition of pulmonary hypertension was revised at the 6th World Symposium on Pulmonary Hypertension in 2018 and adopted by the ESC 2022 guidelines. Pulmonary hypertension is now defined by a mean pulmonary arterial pressure exceeding 20 mmHg, lowered from the previous threshold of 25 mmHg or greater. Precapillary pulmonary hypertension, which includes PAH, additionally requires a pulmonary artery wedge pressure of 15 mmHg or less and a pulmonary vascular resistance exceeding 2 Wood units. All measurements must be obtained at rest by right heart catheterization.

WHO Classification of Pulmonary Hypertension

The WHO classification organizes pulmonary hypertension into five groups. Group 1 encompasses pulmonary arterial hypertension, including idiopathic, heritable, drug- and toxin-induced, and forms associated with connective tissue disease, HIV, portal hypertension, congenital heart disease, and schistosomiasis, as well as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Group 2, pulmonary hypertension due to left heart disease, is the most common cause of PH overall. Group 3 comprises PH due to lung disease and/or hypoxia, including COPD, ILD, and combined patterns. Group 4 encompasses CTEPH and chronic thromboembolic pulmonary disease. Group 5 includes PH with unclear or multifactorial mechanisms, such as sarcoidosis, hematologic disorders, and metabolic diseases.

PAH Subgroups

Within Group 1, several important subgroups are recognized. Idiopathic PAH (IPAH) is the most common PAH subtype, with no identifiable cause. Heritable PAH (HPAH) is most commonly associated with BMPR2 mutations, which account for approximately 70% of familial cases, with other implicated genes including ALK1, ENG, SMAD9, CAV1, KCNK3, and TBX4. Drug- and toxin-associated PAH has definite associations with methamphetamine and historical anorexigens (aminorex, fenfluramine), and a notable association with dasatinib, which may be reversible upon discontinuation. Among connective tissue disease-associated PAH, systemic sclerosis is the most common CTD cause; SSc-PAH carries a worse prognosis than IPAH. Portopulmonary hypertension, PAH associated with portal hypertension, necessitates echocardiographic screening in liver transplant candidates. HIV-PAH has a prevalence of approximately 0.5% among HIV patients. Congenital heart disease-associated PAH includes Eisenmenger syndrome, characterized by irreversible shunt reversal, and corrected CHD with residual PAH.

Pathobiology

Vascular Pathology

The vascular pathology of PAH involves medial hypertrophy, intimal fibrosis, and adventitial thickening of the pulmonary arterioles. Plexiform lesions, representing disorganized endothelial cell proliferation, are pathognomonic for severe PAH. In situ thrombosis and vasoconstriction contribute to vascular obstruction. Three key pathway imbalances drive the disease process. The endothelin pathway demonstrates excess endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, targeted therapeutically by endothelin receptor antagonists. The nitric oxide pathway shows deficient NO and cGMP signaling, which normally mediates vasodilation, targeted by PDE5 inhibitors that prevent cGMP degradation and by riociguat that stimulates soluble guanylate cyclase directly. The prostacyclin pathway demonstrates deficient prostacyclin production, which normally promotes vasodilation and antiproliferation, targeted by prostanoid therapies and selexipag.

<image>A detailed diagram of the three molecular pathways targeted in PAH therapy. Show a pulmonary arteriolar endothelial cell and smooth muscle cell. Pathway 1 (Endothelin): show ET-1 binding to ETA/ETB receptors on smooth muscle causing vasoconstriction and proliferation; block with bosentan, ambrisentan, macitentan. Pathway 2 (Nitric oxide): show NO produced by endothelial NOS activating soluble guanylate cyclase (sGC) in smooth muscle, producing cGMP causing vasodilation; PDE5 degrades cGMP; block PDE5 with sildenafil/tadalafil; stimulate sGC with riociguat. Pathway 3 (Prostacyclin): show prostacyclin (PGI2) from endothelium activating IP receptor on smooth muscle, increasing cAMP causing vasodilation; augment with epoprostenol, treprostinil, iloprost, selexipag (IP receptor agonist). Show each drug class at its target with distinct colors. Include the concept of combination therapy targeting multiple pathways simultaneously.</image>

Diagnosis

Screening and Workup

The diagnostic workup begins with echocardiography, where an estimated right ventricular systolic pressure exceeding 35-40 mmHg or RV dysfunction triggers further investigation. A V/Q scan must be performed in all patients with pulmonary hypertension to exclude CTEPH, a step that should never be omitted. Pulmonary function tests exclude Group 3 PH, and the DLCO is often disproportionately low in PAH relative to spirometric abnormalities. Sleep studies should be pursued when obstructive sleep apnea or obesity hypoventilation syndrome is suspected. CT chest evaluates parenchymal lung disease and demonstrates characteristic features including an enlarged pulmonary artery diameter exceeding 29 mm and enlarged right atrium and right ventricle. Laboratory testing includes ANA, anti-Scl-70, and anti-centromere antibodies (systemic sclerosis screening), HIV serology, liver function tests (portopulmonary hypertension screening), and BNP or NT-proBNP. Right heart catheterization is mandatory for establishing the diagnosis and cannot be replaced by echocardiography, which may overestimate or underestimate PA pressures.

Vasoreactivity Testing

Vasoreactivity testing is performed during the initial right heart catheterization in patients with IPAH or HPAH only. Agents used include inhaled nitric oxide at 10-20 ppm, intravenous epoprostenol, or intravenous adenosine. A positive response is defined as a reduction in mPAP of 10 mmHg or more to an absolute value of 40 mmHg or less with preserved or improved cardiac output. Only approximately 10-12% of IPAH patients demonstrate vasoreactivity. Vasoreactive patients should undergo a trial of high-dose calcium channel blockers, with nifedipine at 120-240 mg daily, diltiazem at 240-720 mg daily, or amlodipine at 20 mg daily. Sustained response occurs in approximately 50% at one year. Verapamil is contraindicated due to its negative inotropic effect on the already stressed right ventricle.

Risk Assessment (ESC/ERS)

The ESC/ERS risk assessment stratifies patients into low, intermediate, and high risk based on predicted 1-year mortality. Low-risk status (less than 5% 1-year mortality) is characterized by WHO functional class I-II, six-minute walk distance exceeding 440 meters, BNP below 50 or NT-proBNP below 300, right atrial area below 18 cm2, no pericardial effusion, normal RV function, cardiac index of 2.5 or greater, mixed venous oxygen saturation exceeding 65%, and right atrial pressure below 8 mmHg. Intermediate risk (5-20%) corresponds to WHO functional class III, six-minute walk distance of 165-440 meters, and BNP of 50-800. High risk (greater than 20%) corresponds to WHO functional class IV, six-minute walk distance below 165 meters, BNP exceeding 800, pericardial effusion, cardiac index below 2.0, mixed venous oxygen saturation below 60%, and right atrial pressure exceeding 14 mmHg.

Treatment

General Measures

Supplemental oxygen is recommended when SpO2 falls below 90%, and patients should be counseled to avoid altitude and in-flight hypoxia. Diuretics, primarily loop diuretics, manage volume overload, though overdiuresis must be avoided as it reduces RV preload. Supervised exercise training through pulmonary rehabilitation improves six-minute walk distance and quality of life, supported by multiple randomized controlled trials. Anticoagulation remains controversial: traditionally recommended for IPAH based on observational data, it is not recommended in SSc-PAH or CHD-PAH, and the decision should be shared between clinician and patient. Pregnancy counseling is essential, as PAH carries a maternal mortality of 30-50%, and effective contraception is mandatory. Vaccination against influenza, pneumococcus, and COVID-19 is recommended.

Upfront Combination Therapy (ESC 2022 / AMBITION Era)

Upfront combination therapy has become the standard of care for newly diagnosed PAH, replacing the historical approach of sequential monotherapy. For patients at low or intermediate risk without significant cardiopulmonary comorbidities, initial dual combination therapy with an endothelin receptor antagonist plus a PDE5 inhibitor or riociguat is recommended. The AMBITION trial established this paradigm by demonstrating that initial combination of ambrisentan plus tadalafil reduced clinical failure by 50% compared to monotherapy with either agent. For high-risk patients, initial triple combination therapy adding intravenous or subcutaneous prostacyclin to an ERA and PDE5 inhibitor is recommended. The TRITON trial in 2024 evaluated initial triple therapy with macitentan, tadalafil, and selexipag but showed a non-significant trend toward improvement, with the interpretation and implications of these results still being debated.

PAH Drug Classes

ERA (Endothelin Receptor Antagonists)

Ambrisentan, a selective ETA antagonist dosed at 5-10 mg daily, was validated in the ARIES trials. Bosentan, a dual ETA/ETB antagonist dosed at 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily, requires monthly liver function monitoring due to a hepatotoxicity rate of approximately 10% and is teratogenic. Macitentan, a dual ERA dosed at 10 mg daily, was evaluated in the SERAPHIN trial, which demonstrated a 45% reduction in morbidity and mortality events, with lower hepatotoxicity than bosentan.

PDE5 Inhibitors and sGC Stimulator

Sildenafil, validated in the SUPER-1 trial, is dosed at 20 mg three times daily though frequently uptitrated to 40-80 mg three times daily in clinical practice. Tadalafil, evaluated in the PHIRST trial, is dosed at 40 mg daily and offers the advantage of once-daily dosing with a longer half-life. Riociguat, validated in the PATENT-1 trial, is dosed at 1-2.5 mg three times daily and cannot be combined with PDE5 inhibitors. The REPLACE trial demonstrated that switching from PDE5 inhibitors to riociguat improved clinical outcomes, and some guidelines prefer riociguat over PDE5 inhibitors.

Prostacyclin Pathway Agents

Epoprostenol, administered as a continuous intravenous infusion through a Hickman catheter, is the most potent prostacyclin analogue and the only PAH drug with randomized controlled trial data demonstrating a mortality benefit. Its half-life is approximately 6 minutes, typical doses range from 20-40 ng/kg/min, and abrupt discontinuation must never occur as it can precipitate rebound pulmonary hypertension and death. Treprostinil is available in multiple formulations: subcutaneous infusion (limited by painful site reactions), intravenous continuous infusion, inhaled (Tyvaso at 6-12 breaths four times daily, with a dry powder inhaler formulation also approved), and oral (Orenitram three times daily, with the FREEDOM-EV trial demonstrating improved exercise capacity when added to background ERA/PDE5i therapy). Iloprost, administered as 2.5-5 mcg inhaled 6-9 times daily, has a short duration of action and burdensome dosing schedule, as evaluated in the AIR trial. Selexipag, the first oral selective IP receptor agonist, is dosed at 200-1600 mcg twice daily with individualized titration. The GRIPHON trial demonstrated a 40% reduction in morbidity and mortality events. Side effects reflect prostacyclin receptor activation and include headache, jaw pain, diarrhea, and nausea.

<image>A comprehensive PAH treatment algorithm based on ESC 2022 guidelines. Start with confirmed PAH after RHC and V/Q scan. First: vasoreactivity testing in IPAH. If positive (10-12%): trial CCB (nifedipine/diltiazem). If negative or non-IPAH: risk stratification (low, intermediate, high). For low-intermediate risk: upfront dual combination (ERA + PDE5i/riociguat) - reference AMBITION trial. For high risk: upfront triple therapy including IV/SC prostacyclin (ERA + PDE5i + epoprostenol/treprostinil). Reassess at 3-6 months: if inadequate response (not reaching low-risk status): escalate - add prostacyclin pathway agent if not yet on one, maximize doses, consider IV prostacyclin. If refractory despite maximal medical therapy: lung transplant referral. Show a sidebar listing supportive measures: O2, diuretics, exercise, contraception, anticoagulation (selective). Include sotatercept as emerging therapy. Use red-yellow-green risk zones with corresponding treatment intensities.</image>

Emerging Therapies

Sotatercept (Winrevair)

Sotatercept represents a paradigm-shifting advance in PAH therapeutics as the first agent targeting a novel pathway beyond the traditional three. It functions as an activin signaling inhibitor, specifically an ActRIIA-Fc fusion protein, that rebalances TGF-beta superfamily signaling to promote antiproliferative and proapoptotic pathways in the pulmonary vasculature. The STELLAR trial in 2023 demonstrated that sotatercept added to background therapy improved six-minute walk distance by 40.8 meters, reduced PVR, improved NT-proBNP levels and WHO functional class, and prolonged time to clinical worsening compared to placebo. Dosing is 0.3-0.7 mg/kg administered subcutaneously every 3 weeks. Sotatercept received FDA approval in March 2024 for PAH in WHO functional class II-III. Side effects include erythrocytosis requiring hemoglobin monitoring, thrombocytopenia, telangiectasia, epistaxis, and dizziness. This agent represents the most significant addition to the PAH therapeutic armamentarium in over a decade and may be used in combination with existing therapies.

Right Heart Failure Management

Acute RV Failure in PAH

Management of acute right ventricular failure in PAH requires intensive care, with avoidance of intubation whenever possible due to the risk of hemodynamic collapse during induction. Volume management demands a cautious approach: while the right ventricle is preload-dependent, volume overload worsens ventricular interdependence and further compromises left ventricular filling. A 250 mL fluid bolus may be attempted judiciously. Norepinephrine is the preferred vasopressor as it maintains systemic vascular resistance without increasing PVR, with vasopressin as an adjunct. Inotropic support with dobutamine increases RV contractility while reducing PVR, and milrinone provides both inotropy and pulmonary vasodilation, though systemic hypotension is a risk. Inhaled nitric oxide or inhaled epoprostenol provide selective pulmonary vasodilation without systemic hypotensive effects. Intravenous epoprostenol should be initiated or uptitrated. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) serves as a bridge to transplant or recovery.

Key Clinical Pearls

• Right heart catheterization is MANDATORY for PAH diagnosis; echocardiography alone is insufficient and can overestimate or underestimate PA pressures
• Upfront combination therapy (ERA + PDE5i) is now standard of care for newly diagnosed PAH, not monotherapy (AMBITION trial)
• Sotatercept represents the first novel mechanism of action approved for PAH in over a decade; it targets the TGF-beta/activin pathway and is used as add-on therapy
• V/Q scan must be performed in ALL patients with pulmonary hypertension to exclude CTEPH, which is potentially curable with surgery
• Pregnancy carries 30-50% mortality in PAH; effective contraception is mandatory and should be discussed at every visit

References

1. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731.
2. Galie N, Barber JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(9):834-844. (AMBITION)
3. Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023;388(16):1478-1490. (STELLAR)
4. Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(26):2522-2533. (GRIPHON)
5. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med. 2013;369(9):809-818. (SERAPHIN)

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