Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by formation of chronic, organized thrombus in pulmonary arteries resulting in development of pulmonary hypertension. We describe the favorable recovery of a patient with inoperable CTEPH treated with combination riociguat and inhaled treprostinil.The patient is a 77 year old female who presented with bilateral pulmonary emboli and was anticoagulated with warfarin for six months. One year later the patient developed recurrent dyspnea and multiple bilateral pulmonary emboli were again noted. Pulmonary arterial pressure (PAP) was estimated at 91 mmHg by echocardiography. The patient was treated with warfarin and sildenafil. Eighteen months later the PAP was estimated at 106 mmHg with significant right ventricular enlargement. The patient was referred to our center for pulmonary hypertension consultation. Right heart catheterization confirmed severe pulmonary hypertension with preserved cardiac output. The patient was not a candidate for thromboendarterectomy due to the peripheral location of chronic obstructing thrombi. Systemic prostacyclin therapy was declined by the patient. Inhaled treprostinil was added to sildenafil and warfarin. The patient maintained good performance status for 2 years, but then developed progressive activity limitation with depressed cardiac output on right heart catheterization. Systemic prostacyclin therapy was declined again. Sildenafil was replaced with riociguat, and 1 year later the patient demonstrated significant recovery of functional capacity and improved hemodynamic profile.We describe significant recovery in a patient with inoperable, progressive CTEPH treated with riociguat and inhaled treprostinil after failing sequential addition of sildenafil and inhaled treprostinil to warfarin. The reported benefits may relate to riociguat's ability to directly stimulate production of cyclic GMP independent of nitric oxide levels in pulmonary artery smooth muscle. There may also be a unique interaction between riocguat and treprostinil that enhanced treatment outcome. Further investigation of this combination of agents may be warranted.

Type II pulmonary epithelial cells (T2P) in primary culture assemble a biologically active extracellular matrix (ECM) from endogenously synthesized components, including fibronectin. Fibronectin is a well-recognized attachment protein that mediates cell adhesion, migration, and cytodifferentiation. In some cell types, exogenous fibronectin also is incorporated into ECM. The latter pathway of ECM assembly was thus investigated in T2P. Cells were cultured for 3-days in Dulbecco's modified Eagle's medium (DMEM) with or without 10% fetal calf serum (FCS), a source of exogenous fibronectin. Cell and matrix fractions were harvested on culture days 1, 2, and 3 to determine synthesis of cell and matrix proteins and matrix fibronectin content. During 3 days in DMEM containing 10% FCS, T2P flattened and spread to confluence more rapidly than cells in DMEM; they also produced ECM with higher fibronectin content than did cells in DMEM alone. On culture days 2 and 3, 10% FCS doubled (on average) synthesis of ECM fibronectin; in contrast, ECM fibronectin content increased nearly 10-fold. These observations suggest that cultured type II cells incorporate exogenous fibronectin into newly assembled ECM to a greater extent than the newly synthesized glycoprotein. Components of both endogenous and exogenous origin may therefore contribute to T2P assembly of a biologically active ECM.

Oral treprostinil (ORE) is approved to delay disease progression and improve exercise capacity in pulmonary arterial hypertension (PAH). The ongoing ADAPT registry (NCT03045029) collects real-world use and tolerability of ORE. This analysis reports patient-reported incidence and treatment of five common adverse events (headache, diarrhea, nausea, extremity pain and flushing) associated with oral prostacyclin-class (PCY) therapy to better understand adverse event (AE) management and tolerability.

Pulmonary hypertension may develop as a disease process specific to pulmonary arteries with no identifiable cause or may occur in relation to other cardiopulmonary and systemic illnesses. The World Health Organization (WHO) classifies pulmonary hypertensive diseases on the basis of primary mechanisms causing increased pulmonary vascular resistance. Effective management of pulmonary hypertension begins with accurately diagnosing and classifying the disease in order to determine appropriate treatment. Pulmonary arterial hypertension (PAH) is a particularly challenging form of pulmonary hypertension as it involves a progressive, hyperproliferative arterial process that leads to right heart failure and death if untreated. Over the last two decades, our understanding of the pathobiology and genetics behind PAH has evolved and led to the development of several targeted disease modifiers that ameliorate hemodynamics and quality of life. Effective risk management strategies and more aggressive treatment protocols have also allowed better outcomes for patients with PAH. For those patients who experience progressive PAH with medical therapy, lung transplantation remains a life-saving option. More recent work has been directed at developing effective treatment strategies for other forms of pulmonary hypertension, such as chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary hypertension due to other lung or heart diseases. The discovery of new disease pathways and modifiers affecting the pulmonary circulation is an ongoing area of intense investigation.