Supplementation with Iron in Pulmonary Arterial Hypertension. Two Randomized Crossover Trials.

Rationale: Iron deficiency, in the absence of anemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin concentrations. The safety and benefit of parenteral iron replacement in this patient population is unclear. Objectives: To evaluate the safety and efficacy of parenteral iron replacement in PAH. Methods: In two randomized, double-blind, placebo-controlled 12-week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject) (1,000 mg or 15 mg/kg if weight <66.7 kg) or saline as placebo, and 17 patients in China received iron dextran (Cosmofer) (20 mg iron/kg body weight) or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by a serum ferritin <37 µg/L or iron <10.3 µmol/L or transferrin saturations <16.4%. Results: Both iron treatments were well tolerated and improved iron status. Analyzed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6-minute walk test) or cardiopulmonary hemodynamics, as assessed by right heart catheterization, cardiac magnetic resonance, or plasma NT-proBNP (N-terminal-pro hormone brain natriuretic peptide) at 12 weeks. Conclusions: Iron repletion by administration of a slow-release iron preparation as a single infusion to patients with PAH with iron deficiency without overt anemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).

The Cotton High-Affinity K+ Transporter, GhHAK5a, Is Essential for Shoot Regulation of K+ Uptake in Root under Potassium Deficiency.

Potassium (K) deficiency is a key limiting factor in cotton (Gossypium hirsutum) production. By grafting two contrasting cotton cultivars, CCRI41 (more susceptible to K+ deficiency) and SCRC22 (more tolerant of K+ deficiency), we established that cotton shoot plays a vital role in the regulation of root K+ uptake. To identify the genetic basis of this finding, we performed RNA sequencing (RNA-seq) of roots of CCRI41 self-grafts (CCRI41/CCRI41, scion/rootstock) and SCRC22/CCRI41 reciprocal-grafts exposed to K+ deficiency. We found that GhHAK5a, an orthologous of Arabidopsis thaliana high-affinity K+ transporter, AtHAK5, was significantly induced in the CCRI41 rootstock by the SCRC22 scion. This gene was mainly expressed in roots and was more highly induced by K+ deficiency in roots of SCRC22 than those of CCRI41. Agrobacterium-mediated virus-induced gene silencing and yeast complementary assay showed that GhHAK5a is a high-affinity K+ uptake transporter. Importantly, silencing of GhHAK5a in the CCRI41 rootstock almost completely inhibited the K+ uptake induced by SCRC22 scion in CCRI41 rootstock. We identified a key high-affinity K+ transporter, GhHAK5a in cotton, which is the essential target for shoot regulation of root K+ uptake under K+ deficiency.

Effect of calcium channel blockers evaluated by cardiopulmonary exercise testing in idiopathic pulmonary arterial hypertension responding to acute pulmonary vasoreactivity testing.

BACKGROUND: The baseline exercise capacity evaluated by cardiopulmonary exercise testing (CPET) and the change after administration of calcium channel blockers (CCB) therapy in patients with vasodilator-responsive idiopathic pulmonary arterial hypertension (VR-IPAH)are unknown. METHODS: 25 patients with newly diagnosed VR-IPAH from 1 January 2012 to 16 November 2015 were prospectively enrolled, and 28 age, sex and pulmonary vascular resistance matched newly diagnosed patients with vasodilator-nonresponsive idiopathic pulmonary arterial hypertension (VNR-IPAH) were enrolled. CPET was performed before and after 3.5 ± 0.8 months of CCB or sildenafil therapy. RESULTS: Ventilatory efficiency at rest, anaerobic threshold (AT), and peak were significantly higher (lower in V˙E/V˙CO2@AT and higher in PETCO2@AT) in VR-IPAH group than that in VNR-IPAH group. Peak V˙O2 (13.9 ± 2.9 mL kg-1·min-1 vs 16.4 ± 4.1 mL kg-1·min-1, p = 0.001), peak O2 pulse (5.5 ± 0.8 mL min-1·beat-1 vs 6.9 ± 1.3 mL min-1·beat-1, p = 0.001), V˙E/V˙CO2@AT (34.2 ± 5.0 vs 31.6 ± 3.1, p = 0.02) and PETCO2@AT (33.1 ± 4.0 mmHg vs 35.3 ± 3.2 mmHg, p = 0.02) were significantly improved after high dose of CCB therapy, along with improvement of WHO functional class, 6-min walking distance, NT-proBNP and tricuspid regurgitation pressure gradient. CONCLUSIONS: Ventilatory efficiency in patients with VR-IPAH is better than that in patients with VNR-IPAH. CCB can improve aerobic capacity and ventilatory efficiency during exercise in patients with VR-IPAH. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov:NCT02061787.