NO metabolites predict IPAH outcomes
medwireNews: Reduced nitric oxide (NO) synthesis appears to play a role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) and measuring plasma levels of the resulting nitrate and nitrite metabolites (NOx) could help predict outcome, research suggests.
“Our study showed that risk prediction using NOx concentration appears to be robust, even after adjustments for clinical characteristics, BMPR2 [bone morphogenetic protein-receptor type-2 mutation] and haemodynamics,” note Zhi-Cheng Jing (Peking Union Medical College and Chinese Academy Medical Science, Beijing, China) and fellow researchers.
They found significantly reduced plasma NOx levels, indicative of impaired NO metabolism, in 104 patients with IPAH, at a median 9.7 µmol/L versus 29.2 µmol/L in 110 healthy individuals (p<0.001).
Levels of NOx were reduced further still among the 19 IPAH patients who carried a mutation for BMPR2, a loss of function of which compromises the integrity of the endothelial barrier, contributing to endothelial dysfunction by mediating the activation of endothelial NO synthase (eNOS).
For these individuals, the median level was 7.3 µmol/L compared with 10.7 µmol/L for patients carrying wild-type BMPR2.
“Loss of BMPR2 may partially disrupt a larger complex of proteins that interact with eNOS, leading to inefficient or impaired signalling,” the team explains.
They report, in the European Respiratory Journal, that BMPR2 mutation carriers had more severe hemodynamic impairment than non-carriers and reduced NOx levels were significantly associated with such impairment, despite statistically weak values. There was a negative 12% correlation with mean pulmonary arterial pressure (mPAP; p<0.001) and a 13% correlation with pulmonary vascular resistance (PVR; p<0.001), while positive correlations of 7% and 5% were seen for cardiac output (p=0.02) and cardiac index (p=0.02), respectively.
“This implies that the levels of NOx reflected the degree of endothelial cell apoptosis or obliterative vascular remodelling,” notes the team.
IPAH patients with low NOx levels of 10 µmol/L or below also had a markedly worse survival, with 37.5% of 56 patients with these levels dying over the average follow-up period of 26 months, compared with 10.4% of 48 patients with higher levels.
At this cutoff level, NOx concentration predicted death with a 55.8% sensitivity and 80.8% specificity. This predictive ability was numerically superior to that of cardiac output, brain natriuretic peptide (BNP), mPAP and PVR, the researchers report.
“The cut-off level for NOx suggests more IPAH patients may be identified as being at risk using this biomarker. Although plasma BNP levels are recommended for initial risk stratification and are biomarkers for PAH prognoses, NOx was superior to BNP in predicting outcomes in our study,” say Jing and colleagues.
“NOx may provide an insight into a distinct pathophysiologic process, suggesting that multi-marker strategies can be increasingly used to assess risks and to utilise individual therapies.”
They add that “the development of effective therapeutic strategies using NOx metabolites requires further study and clarification.”
By Lucy Piper
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