The pathogenesis of pulmonary arterial hypertension is closely associated with dysregulated inflammation. Recently, abnormal alterations in gut microbiome composition and function were reported in a pulmonary arterial hypertension experimental animal model. However, it remains unclear whether these alterations are a result or the cause of pulmonary arterial hypertension. The purpose of this study was to investigate whether alterations in the gut microbiome affected the hemodynamics in SU5416/hypoxia rats. We used the SU5416/hypoxia rat model in our study. SU5416/hypoxia rats were treated with a single SU5416 injection (30 mg/kg) and a three‐week hypoxia exposure (10% O₂). Three SU5416/hypoxia rats were treated with a combination of four antibiotics (SU5416/hypoxia + ABx group) for four weeks. Another group was exposed to hypoxia (10% O₂) without the SU5416 treatment, and control rats received no treatment. Fecal samples were collected from each animal, and the gut microbiota composition was analyzed by 16S rRNA sequencing. The antibiotic treatment significantly suppressed the vascular remodeling, right ventricular hypertrophy, and increase in the right ventricular systolic pressure in SU5416/hypoxia rats. 16S rRNA sequencing analysis revealed gut microbiota modification in SU5416/hypoxia + ABx group. The Firmicutes‐to‐Bacteroidetes ratio in SU5416/hypoxia rats was significantly higher than that in control and hypoxia rats. Compared with the control microbiota, 14 bacterial genera, including Bacteroides and Akkermansia, increased, whereas seven bacteria, including Rothia and Prevotellaceae, decreased in abundance in SU5416/hypoxia rats. Antibiotic‐induced modification of the gut microbiota suppresses the development of pulmonary arterial hypertension. Dysbiosis may play a causal role in the development and progression of pulmonary arterial hypertension.

Background: The surgical indication for chronic thromboembolic pulmonary hypertension (CTEPH) has been modified due to recognition of peripheral type CTEPH and changes in surgical methods and skill. Bosentan and sildenafil are used as modern oral therapy (mod Tx) in patients with inoperable CTEPH, although it remains unknown whether they have positive effects on survival. Methods and Results: A total of 202 patients were diagnosed with CTEPH at Chiba University Hospital between 1986 and 2010, 100 of whom underwent pulmonary endarterectomy. Seven medically treated patients with pulmonary vascular resistance (PVR) ≤300dyn·s·cm–5 were regarded as having mild disease. Survival rate was stratified by date of diagnosis (group 1, 1986–1998; group 2, 1999–2004; group 3, 2005–2010), and prognostic factors in the remaining 95 medically treated patients were investigated. Group 3 included the most patients treated with mod Tx (group 1, 9.1%; group 2, 24.2%; group 3, 65.0%) and had significantly better survival than either group 1 or 2 (5-year survival: group 1, 54.6%; group 2, 69.7%; group 3, 87.3%). Patients receiving mod Tx had significantly better survival than those not on mod Tx (5-year survival: 88.9% vs. 60.2%). Multivariate analysis showed that mod Tx, lower PVR, and lack of comorbidity were significant predictors of better outcome. Conclusions: Medically treated patients with CTEPH had a better survival rate, and the use of mod Tx contributed to improved survival. (Circ J 2013; 77: 2110–2117)

Background and objective: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease in some patients, despite improved treatments. Microvasculopathy has been implicated in the poor outcomes of patients with CTEPH. A reduction in the diffusing capacity for carbon monoxide (DL_CO ) was previously suggested to indicate microvasculopathy in CTEPH patients; therefore, we assessed DL_CO /alveolar ventilation (DL_CO /V_A ) as a prognostic and pathophysiological marker in CTEPH.Methods: We performed a retrospective cohort study of 214 CTEPH patients consecutively diagnosed between 1986 and 2011. After exclusion of 24 patients because of missing DL_CO data or severe obstructive impairment, the mortality rates of medically treated patients classified with normal or decreased DL_CO values were compared, and prognostic factors were determined. The relationship between long‐term surgical outcomes and DL_CO /V_A was also investigated.Results: Ninety‐one inoperable patients were treated medically, two of whom underwent balloon pulmonary angioplasty. Ninety‐nine underwent pulmonary endarterectomy. The 5‐year survival rate of medically treated patients was significantly lower in patients with decreased DL_CO /V_A than in those with normal values (61.4% vs 90.4%, P = 0.017). Decreased preoperative DL_CO /V_A was associated with a smaller percent decrease in post‐operative pulmonary vascular resistance, but not with the extent of proximal thrombi; these results may support our hypothesis that DL_CO reflects microvascular involvement.Conclusion: Decreased DL_CO/V_A was associated with poor outcomes of medically treated CTEPH patients; and may be useful for identifying high‐risk patients, potentially leading to earlier and more appropriate interventions.

Recent translational studies highlighted the inhibition of transforming growth factor (TGF)-β signaling as a promising target to treat pulmonary arterial hypertension (PAH). However, it remains unclear whether alterations in TGF-β signaling are consistent between PAH patients and animal models. Therefore, we compared TGF-β signaling in the lungs of PAH patients and rats with experimental PAH induced by monocrotaline (MCT) or SU5416+hypoxia (SuHx). In hereditary PAH (hPAH) patients, there was a moderate increase in both TGFβR2 and pSMAD2/3 protein levels, while these were unaltered in idiopathic PAH (iPAH) patients. Protein levels of TGFβR2 and pSMAD2/3 were locally increased in the pulmonary vasculature of PAH rats under both experimental conditions. Conversely, the protein levels of TGFβR2 and pSMAD2/3 were reduced in SuHx while slightly increased in MCT. mRNA levels of plasminogen activator inhibitor (PAI)-1 were increased only in MCT animals and such an increase was not observed in SuHx rats or in iPAH and hPAH patients. In conclusion, our data demonstrate considerable discrepancies in TGFβ-SMAD signaling between iPAH and hPAH patients, as well as between patients and rats with experimental PAH.