To the Editors:
Pulmonary arterial hypertension (PAH) is a devastating disease that is characterised by a progressive increase in pulmonary vascular resistance (PVR), chronic right heart failure and premature death. Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure (P̄pa) ≥25 mmHg at rest, and the haemodynamic definition discerns pre- and post-capillary PH [1]. Furthermore, PAH is distinguished from other forms of PH that may occur secondary to various underlying causes, including left heart disease, chronic lung disorders and thromboembolic disease [1]. Although the development of targeted PAH therapies, such as endothelin receptor antagonists, phosphodiesterase type-5 inhibitors (PDE5i) and prostanoids, has markedly improved the clinical situation and outcome of affected patients, the current medical treatment of PAH is not satisfactory.
Recently, tyrosine kinase inhibitors (TKIs), particularly imatinib, have been proposed as a potential novel treatment option in PAH [2–7]. Imatinib was the first TKI that achieved regulatory approval for the treatment of chronic myeloid leukaemia (CML) and has become the standard of care for patients with this disease, as it inhibits the hybrid BCR–ABL oncogene that is pathogenic in the development of CML. Imatinib inhibits several tyrosine kinases, including BCR–ABL, the platelet-derived growth factor receptor (PDGFR) and c-Kit. More recently, additional TKIs, including dasatinib and nilotinib, have been introduced for the treatment of CML in patients who are intolerant or unresponsive to imatinib.
The potential efficacy of imatinib in PAH is attributable to its inhibitory effect on the PDGFR. Platelet-derived growth factor (PDGF) is thought to play a pivotal role in the pathobiology of PAH by initiating and maintaining the underlying pulmonary vascular remodelling [7, 8]. Consistent with this, inhibition of PDGFR signalling by imatinib was recently shown to reverse PAH in animal models, and to …