Background:
Iron deficiency promotes pulmonary vascular remodeling in pre-clinical models, and is associated with worse outcomes in pulmonary arterial hypertension. However, the consequences of iron deficiency in patients with pulmonary hypertension due to chronic lung disease (Group 3 PH) are unexplored.
Methods:
We studied 122 consecutive Group 3 PH patients from the University of Minnesota Pulmonary Hypertension Repository. Serum soluble transferrin receptor (sTR) levels quantified iron deficiency. We evaluated the relationship between iron deficiency and pulmonary vascular disease, right ventricular (RV) function, exercise capacity, and survival.
Results:
The iron deficient group (<4.8mg/L sTR) had significantly higher mean pulmonary arterial pressure (40±9 mmHg, n=59 vs. 44±13 mmHg, n=61;
p
=.02) and lower pulmonary arterial compliance (2.2±1.2 mL/mmHg, n=52 vs. 1.7±0.8 mL/mmHg, n=55;
p
=.01), but there was no difference in pulmonary vascular resistance. Moreover, there were trends for higher right atrial pressure (7±4 mmHg, n=58 vs. 9±6 mmHg, n=61;
p
=0.08) in iron deficient patients. However, iron deficiency did not significantly alter RV function by echocardiography, 6-minute walk distance, or survival.
Conclusions:
Iron deficiency in Group 3 PH is associated with worse pulmonary vascular disease. This suggests iron deficiency could contribute to pulmonary vascular disease in Group 3 PH, and future studies are needed to determine if iron replacement could be a therapy for this deadly type of PH.
Introduction:
Inflammation plays a mechanistic role in pulmonary arterial hypertension (PAH); however, what triggers inflammation remains unclear.
Hypothesis:
PAH is characterized by gut dysbiosis and barrier dysfunction, leading to an altered burden of circulating microbial metabolic products, promoting disease. We aimed to characterize the gut microbiome and circulating microbial metabolic products in healthy controls and PAH patients.
Methods:
The V4 hypervariable region of the 16S rRNA gene was analyzed from fecal samples of 40 healthy controls and 57 PAH patients. Plasma was analyzed for interleukin (IL)-6, claudin-3, trimethylamine N-oxide (TMAO), short chain fatty acids, and secondary bile acids.
Results:
PAH patients had elevated plasma IL-6 (Fig 1A,
P
=.02), claudin-3, a measure of intestinal permeability (Fig 1B,
P
=.04), and TMAO (Fig 1C,
P
=.04), and reduced taurolithocholic acid (Fig 1D,
P
=.02). Short chain fatty acid levels were not significantly different (data not shown). Principal component analysis (PCOA) of pairwise Bray-Curtis dissimilarity showed distinct microbiome compositions (Fig 1E,
P
<.001). The Shannon diversity index (Fig 1F,
P
<.001) and species richness (Fig 1G,
P
=0.005) were lower in PAH patients. Linear discriminant analysis (LDA) of effect size revealed that PAH patients had increased relative abundances of
Bacteroidetes
and
Proteobacteria
and decreased relative abundances of
Ruminococcaceae
and
Lachnospiraceae
(Fig 1H). There was no difference in gut microbiome richness and Shannon diversity between patients with low, intermediate, and high-risk REVEAL scores (data not shown).
Conclusions:
PAH patients have distinct gut dysbiosis, increased intestinal permeability (claudin-3), and circulating microbial metabolic products. These findings support our hypothesis that microbiome-driven, pro-inflammatory signals may contribute to PAH pathogenesis.
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