Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling.

Pulmonary hypertension is a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance. There is an unmet medical need for the development of therapeutics focusing on the pulmonary vascular remodeling. Bioactive lipids produced by perivascular inflammatory cells might modulate the vascular remodeling. Here, we show that ω-3 fatty acid-derived epoxides (ω-3 epoxides) released from mast cells by PAF-AH2, an oxidized phospholipid-selective phospholipase A2, negatively regulate pulmonary hypertension. Genetic deletion of Pafah2 in mice accelerate vascular remodeling, resulting in exacerbation of hypoxic pulmonary hypertension. Treatment with ω-3 epoxides suppresses the lung fibroblast activation by inhibiting TGF-ß signaling. In vivo ω-3 epoxides supplementation attenuates the progression of pulmonary hypertension in several animal models. Furthermore, whole-exome sequencing for patients with pulmonary arterial hypertension identifies two candidate pathogenic variants of Pafah2. Our findings support that the PAF-AH2-ω-3 epoxide production axis could be a promising therapeutic target for pulmonary hypertension.

Multicentre randomised controlled trial of balloon pulmonary angioplasty and riociguat in patients with chronic thromboembolic pulmonary hypertension: protocol for the MR BPA study.

INTRODUCTION: Management of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remains a clinical challenge. Currently, medical treatment involving pulmonary vasodilators (such as soluble guanylate-cyclase stimulators) is recommended, primarily for ameliorating symptoms. More recently, balloon pulmonary angioplasty (BPA) has been developed as alternative treatment for inoperable CTEPH. This study aimed to compare the efficacy and safety of BPA and riociguat (a soluble guanylate-cyclase stimulator) as treatments for inoperable CTEPH. METHODS AND ANALYSIS: This study is a multicentre randomised controlled trial. Subjects with inoperable CTEPH were randomised (1:1) into either a BPA or riociguat group, and observed for 12 months after initiation of treatment. The primary endpoint will be the change in mean pulmonary arterial pressure from baseline to 12 months after initiation of treatment. For primary analysis, we will estimate the least square means difference and 95% CI for the change of pulmonary arterial pressure between the groups at 12 months using the analysis of covariance adjusted for allocation factors. ETHICS AND DISSEMINATION: This study and its protocols were approved by the institutional review board of Keio University School of Medicine and each participating institution. Written informed consent was obtained from all participants. Results will be disseminated at medical conferences and in journal publications. TRIAL REGISTRATION NUMBER: University Hospital Medical Information Network Clinical Trial Registry (UMIN000019549); Pre-results.

Adverse events in patients with ulcerative colitis treated with indigo naturalis: a Japanese nationwide survey.

BACKGROUND: Although indigo naturalis (IN) is effective for patients with active ulcerative colitis (UC), IN was associated with adverse events (AEs), including pulmonary arterial hypertension (PAH). Our aim was to evaluate the occurrence of IN-associated AEs and to evaluate any IN dose-effect on AEs. METHODS: A nationwide survey, using questionnaires, was conducted by conducted by the research group funded by the Ministry of Health, Labour and Welfare of Japan, between June 2017 and September 2018. A first questionnaire determined the occurrence of AEs associated with the therapeutic use of IN or herbal medicines containing IN in patients with UC. A second survey identified the clinical characteristics of patients who developed IN-associated critical AEs, namely, liver dysfunction, PAH, and intussusception. RESULTS: Across 337 participating institutions, 49,320 patients with UC were identified, with IN used in 877 (1.8%). AEs were reported in 91 patients (107 events), including liver dysfunction (n = 40), gastrointestinal symptoms (n = 21), headache (n = 13), and PAH (n = 11). No dose-effect relationship between IN and AEs was identified. Liver dysfunction tended to be mild and reversible. Ten cases of intussusception were reported, with 40% of these patients requiring surgical resection. IN-induced PAH was recovered in patients who discontinued to use IN. No IN-associated deaths were reported. CONCLUSIONS: IN-associated AEs were identified among patients with UC, with liver dysfunction often being reversible, while surgical resection was required in a high proportion of patients who developed intussusception. Both healthcare workers and patients should adequately recognize the potential for AEs with the use of IN.

Therapeutic impact of dietary vitamin D supplementation for preventing right ventricular remodeling and improving survival in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH), caused by elevated pulmonary vascular resistance, leads to right heart failure and ultimately death. Vitamin D deficiency can predispose individuals to hypertension and left ventricular dysfunction; however, it remains unknown how serum vitamin D level is related to PH and right ventricular (RV) dysfunction. METHODS: Serum 25-hydroxyvitamin D [25(OH)D] levels were assessed in PH patients for an association with disease severity. To examine whether vitamin D supplementation could prevent the development of pulmonary vascular remodeling and RV dysfunction in PH, a rat model of PH was fed either normal chow or a high vitamin D diet. RESULTS: The majority (95.1%) of PH patients had 25(OH)D levels in the insufficiency range, which is associated with increased mean pulmonary artery pressure, increased pulmonary vascular resistance, and decreased cardiac output in PH patients. Vitamin D supplementation significantly increased serum 25(OH)D levels and improved survival in PH rats. Interestingly, while the supplemented rats retained the typical increases in medial thickness of the muscular pulmonary arteries and RV systolic pressure, RV cardiomyocyte hypertrophy and B-type natriuretic peptide expression was significantly attenuated. CONCLUSIONS: Vitamin D deficiency is frequently seen in patients diagnosed with PH and low serum levels of 25(OH)D are associated with severity of PH and RV dysfunction. Vitamin D supplementation in PH rats improved survival via ameliorating pathological RV hypertrophy. These findings suggest an insufficient intake of vitamin D might potentially accelerate RV dysfunction, leading to a crucial clinical impact of vitamin D supplementation in PH.

Sorafenib is effective in the treatment of pulmonary veno-occlusive disease.

The present study is the first report of the effectiveness of sorafenib in the treatment of pulmonary veno-occlusive disease (PVOD). A 66-year-old woman with PVOD was started on sorafenib. After 3 months of treatment with a maximum dosage of 400 mg/day sorafenib, there was an improvement in the patient's New York Heart Association (NYHA) functional class from IV to III. However, because of severe painful eruptions as a side effect of sorafenib, the patient stopped sorafenib and was started on imatinib instead. This treatment resulted in a worsening of the patient's NYHA class from III to IV, so sorafenib was restarted at a reduced dosage of 300 mg/day. The resumption of sorafenib was associated with clinical improvement, specifically NYHA class from IV to II and hemodynamic amelioration, and tolerable eruptions. In conclusion, sorafenib may be a potential therapeutic strategy for the treatment of PVOD.

A case of vagally mediated idiopathic ventricular fibrillation.

BACKGROUND: A 25-year-old woman experienced three episodes of syncope over the course of 2 years. The attacks all occurred just after she had sat down, and two were accompanied by convulsions. She had no obvious prodromes and no personal or family history of cardiovascular disease. INVESTIGATIONS: Electrocardiography, chest radiography, echocardiography, cerebral and cardiac MRI, electroencephalography, 24 h Holter monitoring, electrophysiological study with drug provocation testing and heart-rate variability analysis. DIAGNOSIS: Vagally mediated ventricular fibrillation initiated by premature ventricular complexes arising from the right ventricular outflow tract. MANAGEMENT: Catheter ablation was performed at the right ventricular outflow tract and an implantable cardioverter-defibrillator was fitted.