Pulmonary Hypertension (PH) is a progressive and potentially fatal condition characterized by elevated pressure in the pulmonary arterial system.

This leads to increased pulmonary vascular resistance (PVR), right ventricular (RV) overload, and eventually right heart failure.

Clinically, PH is defined as a mean pulmonary arterial pressure (mPAP) ≥ 20 mmHg at rest, confirmed by right heart catheterization—the gold standard for diagnosis, as recommended by the 2022 ESC/ERS Guidelines.

The disease is not a single entity, it encompasses multiple clinical classifications. According to the WHO classification, PH is divided into five groups, with Group 1 (Pulmonary Arterial Hypertension or PAH) being idiopathic, heritable, or associated with conditions like connective tissue diseases. Other groups are linked to left heart disease, lung diseases, chronic thromboembolic events, or multi-factorial mechanisms.

Pathophysiological Insights

PH involves complex molecular and cellular mechanisms including endothelial dysfunction, smooth muscle proliferation, thrombosis in situ, and inflammation. Endothelin-1 overexpression, reduced nitric oxide synthesis, and diminished prostacyclin production play critical roles in the pathogenesis. These abnormalities contribute to vasoconstriction and vascular remodeling, which increase PVR and strain on the RV.

Clinical Presentation and Diagnostic Approach

Symptoms of PH are often nonspecific—progressive dyspnea on exertion, fatigue, chest pain, syncope, and signs of RV failure such as peripheral edema or ascites. This contributes to frequent delays in diagnosis. Diagnostic evaluation begins with echocardiography to estimate pulmonary pressures and assess RV function.

However, definitive diagnosis relies on right heart catheterization. Additional work-up includes pulmonary function tests, ventilation/perfusion scans (to rule out CTEPH), and serologic tests to evaluate for secondary causes such as connective tissue disease. Electrocardiograms and chest imaging may reveal right atrial, right axis deviation, and dilated pulmonary arteries, but these are neither sensitive nor specific.

Therapeutic Strategies by Disease Subtype

1. Group 1 (PAH) Treatment

Patients with Group 1 PAH benefit from targeted pharmacologic therapy. Current treatment strategies are based on risk stratification using parameters like WHO functional class, BNP/NT-proBNP levels, and hemodynamic markers.

- Endothelin Receptor Antagonists (ERAs) – e.g., bosentan, ambrisentan, and macitentan, block endothelin-mediated vasoconstriction and smooth muscle proliferation.

- Phosphodiesterase-5 Inhibitors (PDE5i) – sildenafil and tadalafil enhance nitric oxide signaling by inhibiting cGMP breakdown, promoting vasodilation.

- Prostacyclin Analogues and IP Receptor Agonists – such as epoprostenol, treprostinil, and selexipag, counteract reduced prostacyclin levels and provide potent vasodilatory and antiproliferative effects.

- Soluble Guanylate Cyclase Stimulators – like riociguat, are used especially in inoperable or persistent CTEPH (Group 4) but also show efficacy in PAH.

Combination therapy, including initial dual-agent regimens, has become standard for intermediate- and high-risk patients. The AMBITION trial demonstrated that initial therapy with ambrisentan and tadalafil significantly reduced clinical failure compared to monotherapy.

2. Groups 2–5 Management

For PH secondary to left heart disease (Group 2) or lung disease (Group 3), treatment focuses on the underlying condition. Targeted PAH therapies are not routinely recommended and may be harmful in these groups. Chronic thromboembolic PH (Group 4) is potentially curable with pulmonary endarterectomy. For patients not eligible for surgery, riociguat remains the only approved medical therapy. Balloon pulmonary angioplasty is emerging as a promising alternative.

Prognosis and Monitoring

Without treatment, the median survival of idiopathic PAH is approximately 2.8 years. However, with modern therapies and close monitoring, survival rates have improved significantly. Regular follow-up with right heart catheterization, 6-minute walk distance, echocardiography, and biomarker surveillance is essential.

Prognostic markers include worsening WHO functional class, rising NT-proBNP, declining exercise capacity, and echocardiographic evidence of RV dysfunction. Risk assessment tools like REVEAL 2.0 provide structured frameworks for clinical decision-making.

Emerging Therapies and Research Directions

Research is now focused on targeting inflammation and fibrosis in pulmonary vasculature. Experimental agents such as sotatercept, a fusion protein that modulates TGF-β signaling, have shown promise in early-phase trials by reversing vascular remodeling. Gene therapy, immunomodulation, and metabolic pathway targeting are also under exploration. Dr. Ioana Preston of Tufts Medical Center stresses that "PH must be treated not only as a hemodynamic disorder, but as a complex disease with immunologic and genetic underpinnings."

Pulmonary Hypertension represents a multifaceted clinical challenge with high morbidity and mortality. Accurate classification, early detection, and individualized treatment based on evolving evidence are crucial to improving outcomes. Continued advancements in translational research, combined with structured clinical protocols, offer renewed hope for patients with this once uniformly fatal disease.