Paradigm Shift in the Management of Pulmonary Arterial Hypertension

EP: 1.Pathophysiology of Pulmonary Arterial Hypertension

EP: 2.Differential Diagnosis of Pulmonary Arterial Hypertension

EP: 3.Importance of Early Detection and Monitoring for Disease Progression

EP: 4.The Importance of Patient-Centered Care

EP: 5.Strengths and Limitations of Current Therapeutic Options

EP: 6.Overview of Different Therapies for Patients with Pulmonary Arterial Hypertension

EP: 7.Sotatercept for Patients with Pulmonary Arterial Hypertension

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EP: 8.Paradigm Shift in the Management of Pulmonary Arterial Hypertension

Riociguat and Sotatercept Mechanisms

Current PAH therapeutics encompass four distinct pathway approaches: endothelin receptor antagonists, nitric oxide-cGMP pathway modulators (PDE5 inhibitors and sGC stimulators), prostacyclin pathway agents, and activin signaling inhibitors. These compounds demonstrate pulmonary vasodilatory properties and disease progression modification effects, with combination therapies generally proving more efficacious than monotherapy approaches. Each pathway offers unique mechanisms that can be strategically combined for optimal patient outcomes.

Sotatercept represents a breakthrough as the first activin signaling inhibitor, functioning as a fusion protein that binds activin A and B along with other growth differentiation factors. This novel mechanism appears to induce reverse remodeling of pulmonary vasculature through apoptosis of proliferative cells that obstruct pulmonary vessels. While reverse remodeling has been demonstrated in animal models, this represents the first potential reverse remodeling therapy available for human PAH patients.

Riociguat, targeting the nitric oxide pathway through soluble guanylate cyclase stimulation, is approved for both Group 1 PAH and Group 4 chronic thromboembolic pulmonary hypertension. In chronic thromboembolic disease, riociguat can be used in inoperable patients with distal clots or in combination with balloon pulmonary angioplasty. For PAH patients, riociguat is typically considered for intermediate-risk patients not achieving low-risk status, often as a substitution for PDE5 inhibitors in treatment algorithms.