Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and potentially fatal condition characterized by persistent unresolved pulmonary embolism, leading to increased pulmonary vascular resistance and right heart failure.

It is estimated that 0.1-9.1% of patients with acute pulmonary embolism will develop CTEPH. Current treatment options include surgical thromboendarterectomy and medical therapy with pulmonary vasodilators. However, emerging therapies for CTEPH are showing promise in improving outcomes for patients with this disease.

Epoprostenol

Epoprostenol is a prostacyclin analogue, and has been shown to improve exercise capacity and hemodynamics in patients with pulmonary arterial hypertension.

A randomized, placebo-controlled trial of epoprostenol in patients with inoperable CTEPH demonstrated a significant improvement in pulmonary vascular resistance and 6-minute walk distance. However, epoprostenol is associated with side effects such as headache, nausea, and hypotension, and requires continuous intravenous infusion.

Prostacyclin Analogues

Besides epoprostenol, several other prostacyclin analogues have also been studied in CTEPH.

Treprostinil is a subcutaneously administered prostacyclin analogue that has been shown to improve exercise capacity, hemodynamics, and quality of life in patients with CTEPH. Iloprost is an inhaled prostacyclin analogue that has been shown to improve hemodynamics and exercise capacity in patients with CTEPH. However, the optimal dosing and administration of these medications in patients with CTEPH is not yet clear.

Endothelin Receptor Antagonists

Endothelin receptor antagonists block the effects of endothelin, a potent vasoconstrictor that is upregulated in CTEPH.

In a randomized, placebo-controlled trial, bosentan, an endothelin receptor antagonist, improved exercise capacity and hemodynamics in patients with CTEPH. Ambrisentan, another endothelin receptor antagonist, has also been shown to improve exercise capacity and hemodynamics in CTEPH. However, both medications are associated with potential liver toxicity and require monitoring of liver function tests.

Guanylate Cyclase Stimulators

Guanylate cyclase stimulators increase levels of cyclic guanosine monophosphate (cGMP), resulting in vasodilation and decreased pulmonary artery pressure.

Riociguat is a guanylate cyclase stimulator that has been approved for the treatment of both pulmonary arterial hypertension and CTEPH. In a randomized, placebo-controlled trial, riociguat improved exercise capacity, hemodynamics, and quality of life in patients with CTEPH.

However, riociguat is associated with potential side effects such as headache, nausea, and hypotension, and requires careful monitoring of blood pressure.

Angiogenesis Inhibitors

Angiogenesis inhibitors such as thalidomide and lenalidomide have been shown to have anti-inflammatory and anti-proliferative effects, and may have a role in the treatment of CTEPH.

In a small pilot study, thalidomide was shown to improve pulmonary hemodynamics in patients with CTEPH. However, larger studies are needed to determine the safety and efficacy of these medications in CTEPH.

Cell-based Therapies

Cell-based therapies have emerged as a potential treatment for pulmonary hypertension. Mesenchymal stem cells (MSCs) have been shown to have anti-inflammatory and immunomodulatory effects, and may have a role in the treatment of CTEPH.

In a small pilot study, intravenous infusion of autologous MSCs was shown to improve pulmonary hemodynamics and exercise capacity in patients with CTEPH. However, larger randomized trials are needed to determine the safety and efficacy of this approach.

Gene Therapy

Gene therapy involves the transfer of genetic material to cells or tissues to treat or prevent disease.

In animal models of pulmonary hypertension, gene therapy has shown promise in promoting pulmonary vasodilation and inhibiting pulmonary artery smooth muscle cell proliferation. However, the safety and efficacy of gene therapy in humans with CTEPH has not yet been established.

Conclusion

Emerging therapies for CTEPH are showing promise in improving outcomes for patients with this disease.

Prostacyclin analogues, endothelin receptor antagonists, guanylate cyclase stimulators, angiogenesis inhibitors, cell-based therapies, and gene therapy all have potential as new treatment options for CTEPH. However, further research is needed to determine the safety and efficacy of these therapies in larger randomized trials.

Early identification and referral of patients with CTEPH to specialized centers is critical to improving outcomes in this rare and potentially life-threatening condition.