Mechanisms of exertional dyspnoea in pulmonary veno-occlusive disease with EIF2AK4 mutations.

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To the Editor: Dyspnoea curtails daily-living activities in patients with pulmonary veno-occlusive disease (PVOD) [1, 2] and pulmonary arterial hypertension (PAH) [3–5]. It is a common clinical observation that PVOD patients may experience greater dyspnoea than PAH patients during daily activities [1, 2]. However, this clinical feature and its putative underlying mechanisms have not yet been explored. Cardiopulmonary exercise testing (CPET) is well suited for understanding mechanisms underlying dyspnoea during exercise both in research and clinical settings [4, 5]. In the present study, we hypothesised that the perceived clinical difference between PVOD and PAH regarding exertional dyspnoea would be reflected by a different physiological response to CPET. Building on recent advances obtained with CPET in PAH patients [4], we set out to evaluate the relationship between exertional dyspnoea and the physiological response to CPET in eight PVOD patients presenting with recessive mutations in EIF2AK4 , compared with 16 idiopathic or heritable PAH patients. We studied eight clinically stable patients referred to the French Reference Center for Pulmonary Hypertension (Le Kremlin-Bicetre, France) for management of PAH [6, 7]. Using whole-exome sequencing, we detected recessive mutations in the major gene linked to PVOD development, EIF2AK4 (also called GCN2 ), that co-segregated with PVOD in eight patients studied, as recently described [8]. 16 clinically stable patients with diagnosed idiopathic or heritable PAH [9] and without other concomitant diseases were also evaluated. Pulmonary function tests, cycle ergometer symptom-limited incremental CPET, and measurements at rest and at peak exercise of arterial oxygen tension ( P aO2) and arterial carbon dioxide tension ( P aCO2), the physiological dead space ( V D)/tidal volume ( V T) ratio, and the alveolar–arterial oxygen tension gradient ( P A–aO2) and …