Significant improvement of right ventricular function by imatinib mesylate in scleroderma-associated pulmonary arterial hypertension

Excerpt

Sirs: Pulmonary arterial hypertension (PAH) is a devastating disease that harbours a poor prognosis, particularly in patients with scleroderma-associated PAH. Although modern therapies such as endothelin receptor antagonists (ERA), phosphodiesterase type-5 inhibitors (PDE5i) and prostanoids have improved the clinical situation and outcome of affected patients [5], the current medical treatment of PAH is not satisfactory. Recent experimental data suggest that platelet-derived growth factor (PDGF) plays a pivotal role in the pathobiology of PAH by initiating and maintaining the underlying pulmonary vascular remodelling [9]. Consistently, inhibition of PDGF receptor (PDGFR) signalling by the tyrosine kinase inhibitor imatinib mesylate was recently shown to reverse PAH in animal models and to improve the clinical situation in selected patients [3, 7, 9, 10]. However, imatinib was also shown to exert significant cardiotoxicity in animals and humans through its inhibitory effect on the non-receptor Abelson tyrosine kinase (c-Abl) [4]. Further analyses of clinical studies revealed that congestive heart failure is a rare event in patients receiving imatinib therapy, but occurs more frequently in patients with pre-existing cardiac conditions [1]. The latter fact may be of particular significance in patients with PAH and impaired right ventricular function since the right ventricle responds particularly sensitive to hemodynamic and/or cardiotoxic impairment. In addition, patients with scleroderma-associated PAH harbour a lower right ventricular contractility as compared to those with idiopathic PAH [6]. …