Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension

Hiraide, Takahiro; Kataoka, Masaharu; Suzuki, Hisato; Aimi, Yuki; Chiba, Tomohiro; Isobe, Satoshi; Katsumata, Yoshinori; Goto, Shinichi; Kanekura, Kohsuke; Yamada, Yoshitake; Moriyama, Hidenori; Kitakata, Hiroki; Endo, Jin; Yuasa, Shinsuke; Arai, Yasumichi; Hirose, Nobuyoshi; Satoh, Tsuyoshi; Hakamata, Yoji; Sano, Motoaki; Gamou, Shinobu; Kosaki, Kenjiro; Fukuda, Keiichi

doi:10.1016/j.healun.2019.08.022

Cited by 29 publications

(20 citation statements)

References 21 publications

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“…In the presented case, it was also remarkable, that despite an upfront combination pulmonary vasodilating therapy, the PAH was progressive within a relatively short period of time. This supports the theory of a rather progressive character of the pulmonary vascular disease in MD, with considerable poor prognosis particularly in patients carrying the RNF213 mutation (8). Therefore, advanced treatment (i.e., dual/triple combination therapy, or even parenteral treatment with prostacyclin) might be reasonable options.…”

Section: Discussionsupporting

confidence: 77%

Moyamoya disease associated with pediatric pulmonary hypertension—a case report

Krämer¹,

Beer²,

Kaestner³

et al. 2021

Cardiovasc Diagn Ther

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Moyamoya disease (MD) is a rare vaso-occlusive disorder that primarily affects intracranial cerebral arteries. The involvement of extracranial vessels is unusual. However, there are previous reports suggesting MD to be a systemic disorder, causing disease manifestations in vessels of other parts of the body.We report the case of a female patient with MD and multiple episodes of ischemic strokes followed by bypass surgery of cerebral arteries during infancy. Due to corresponding ischemic lesions the girl showed global retardation of psychomotor development and central right sided movement disorder. At the age of 10 years the girl was admitted to our hospital with recurrent syncope. While cranial MRI excluded any newly added ischemic lesions, electrocardiography revealed evidence of right ventricular hypertrophy, and subsequent echocardiography then indicated pulmonary hypertension, which was confirmed by cardiac catheterization.Despite an upfront combination pulmonary vasodilating therapy, the pulmonary vascular disease appeared to be progressive. Genetic analysis showed heterozygous c.12341C>T mutation in the RNF213 gene. This case presentation demonstrates that pulmonary arterial hypertension is a rare comorbidity in patients with MD, especially in patients with genetic predictors such as the RNF213 mutation. Thus, regular echocardiographic screening for early signs of pulmonary arterial hypertension in patients with MD should be part of regular clinical work-up. Early detection and treatment of pulmonary arterial hypertension in MD might help to improve the long-term outcome in the individual patient.

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Section: Discussionsupporting

confidence: 77%

Moyamoya disease associated with pediatric pulmonary hypertension—a case report

Krämer¹,

Beer²,

Kaestner³

et al. 2021

Cardiovasc Diagn Ther

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“…All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 ( BMPR2 ) and one patient with idiopathic PAH had a mutation in ring finger protein 213 ( RNF213 ), which we recently reported as a novel PAH-related gene. 13 , 17 …”

Section: Resultsmentioning

confidence: 99%

Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension

Momoi

Hiraide

Shinya

et al. 2021

Ther Adv Respir Dis

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Background: The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag. Methods: Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan–Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted. Results: Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12–47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients. Conclusion: Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings. The reviews of this paper are available via the supplemental material section.

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“…Pulmonary arterial hypertension (PAH) is a severe pathophysiological syndrome characterized by pulmonary vasoconstriction and structural remodeling of blood vessel walls, which in turn lead to increased vascular resistance and right ventricular dysfunction (1,2). The causes of PAH are complex, with hypoxia being one of the most important factors (3,4).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑153 attenuates hypoxia‑induced excessive proliferation and migration of pulmonary arterial smooth muscle cells by targeting ROCK1 and NFATc3

Zhao

Wang

et al. 2021

Mol Med Rep

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The aim of the present study was to explore the effect of microRNA (miR)-153 on the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) in a hypoxic condition by targeting ρ-associated, coiled-coil-containing protein kinase 1 (ROCK1) and nuclear factor of activated T cells cytoplasmic 3 (NFATc3). The right ventricular systolic pressure, right ventricular hypertrophy index, medial wall thickness and medial wall area were studied at different time-points after rats were exposed to hypoxia. Western blot analysis was used to detect ROCK1 and NFATc3 protein levels. In addition, reverse transcription-quantitative (RT-q) PCR was performed to confirm the mRNA levels of miR-153, ROCK1 and NFATc3 in human (H)PASMCs under hypoxic conditions. Transfected cells were then used to evaluate the effect of miR-153 on cell proliferation and migration abilities. The association between miR-153 and ROCK1 or NFATc3 was identified through double luciferase assays. Hypoxia induced pulmonary vascular remodeling and pulmonary arterial hypertension, which resulted from the abnormal proliferation of HPASMCs. ROCK1 and NFATc3 were the target genes of miR-153 and miR-153 mimic inhibited the protein expressions of ROCK1 and NFATc3 in HPASMCs and further inhibited cell proliferation and migration under hypoxic conditions. By contrast, the miR-153 inhibitor promoted the proliferation and migration of HPASMCs. miR-153 regulated the proliferation and migration of HPASMCs under hypoxia by targeting ROCK1 and NFATc3.

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Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension

Cited by 29 publications

References 21 publications

Moyamoya disease associated with pediatric pulmonary hypertension—a case report

Moyamoya disease associated with pediatric pulmonary hypertension—a case report

Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension

MicroRNA‑153 attenuates hypoxia‑induced excessive proliferation and migration of pulmonary arterial smooth muscle cells by targeting ROCK1 and NFATc3

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