Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia Related to an &lt;i&gt;ACVRL1&lt;/i&gt; Mutation

Yokokawa, Tetsuro; Sugimoto, Koichi; Kimishima, Yusuke; Misaka, Tomofumi; Yoshihisa, Akiomi; Morisaki, Hiroko; Nakazato, Kazuhiko; Ishida, Takafumi; Takeishi, Yasuchika

doi:10.2169/internalmedicine.3625-19

Cited by 12 publications

(6 citation statements)

References 30 publications

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“…Many of these HHT patients have secondary PH, often as a result of high-output cardiac failure secondary to hepatic arteriovenous malformations (AVMs) [8,10,80,82]. A smaller proportion of patients, about 1%, have heritable or primary PH; this is usually seen with the ACVRL1 mutation (HHT type 2) [83][84][85][86]. The coexistence of PAVMs and PH poses a clinical dilemma, as there is a paucity of data examining the evolution of PH following PAVM embolization.…”

Section: Pulmonary Hypertensionmentioning

confidence: 99%

“…In cases where the effect of embolization is uncertain, temporary occlusion of the feeding artery can be performed with a balloon occlusion catheter while monitoring the cardiovascular response, to predict the risk of pulmonary hemodynamic changes prior to embolization [58]. There may also be a role for endothelin-receptor antagonists to mitigate worsening of PH following PAVM embolization in at-risk patients, though further study is needed [86].…”

Section: Pulmonary Hypertensionmentioning

confidence: 99%

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Approach to Pulmonary Arteriovenous Malformations: A Comprehensive Update

Majumdar

McWilliams

2020

JCM

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Pulmonary arteriovenous malformations (PAVMs) are abnormal direct vascular communications between pulmonary arteries and veins which create high-flow right-to-left shunts. They are most frequently congenital, usually in the setting of hereditary hemorrhagic telangiectasia (HHT). PAVMs may be asymptomatic or present with a wide variety of clinical manifestations such as dyspnea, hypoxemia, or chest pain. Even when asymptomatic, presence of PAVMs increases patients’ risk of serious, potentially preventable complications including stroke or brain abscess. Transcatheter embolotherapy is considered the gold standard for treatment of PAVMs. Though previous guidelines have been published regarding the management of PAVMs, several aspects of PAVM screening and management remain debated among the experts, suggesting the need for thorough reexamination of the current literature. The authors of this review present an updated approach to the diagnostic workup and management of PAVMs, with an emphasis on areas of controversy, based on the latest literature and our institutional experience.

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Section: Pulmonary Hypertensionmentioning

confidence: 99%

Section: Pulmonary Hypertensionmentioning

confidence: 99%

Approach to Pulmonary Arteriovenous Malformations: A Comprehensive Update

Majumdar

McWilliams

2020

JCM

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“…It is known that ACVRL1 is one of the genes affected by germline mutations identified in patients with pulmonary arterial hypertension 28 . Germline mutations of ACVRL1 also cause hereditary hemorrhagic telangiectasia, a dominant autosomal vascular dysplasia, and PH is recognized as a severe complication of this disease 40,41 . It has been reported that ACVRL1 mutations in hereditary hemorrhagic telangiectasia led to a loss of function 42,43 .…”

Section: Discussionmentioning

confidence: 99%

Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils

et al. 2021

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Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary arterial remodeling. Clonal somatic mutations including JAK2V617F, the most frequent driver mutation among myeloproliferative neoplasms, have recently been identified in healthy individuals without hematological disorders. Here, we reveal that clonal hematopoiesis with JAK2V617F exacerbates PH and pulmonary arterial remodeling in mice. JAK2V617F-expressing neutrophils specifically accumulate in pulmonary arterial regions, accompanied by increases in neutrophil-derived elastase activity and chemokines in chronic hypoxia-exposed JAK2V617F transgenic (JAK2V617F) mice, as well as recipient mice transplanted with JAK2V617F bone marrow cells. JAK2V617F progressively upregulates Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells peripherally into mature neutrophils of pulmonary arterial regions. JAK2V617F-mediated STAT3 phosphorylation upregulates ALK1-Smad1/5/8 signaling. ALK1/2 inhibition completely prevents the development of PH in JAK2V617F mice. Finally, our prospective clinical study identified JAK2V617F-positive clonal hematopoiesis is more common in PH patients than in healthy subjects. These findings indicate that clonal hematopoiesis with JAK2V617F causally leads to PH development associated with ALK1 upregulation.

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“…Variant p.Arg484Gln impacts a conserved surface-exposed residue located in helix αI of the kinase C-lobe, and encodes a catalytically inactive ALK1 mutant 86 . Mutations in this region are associated with HHT2, an increased incidence of pulmonary arterial hypertension [87][88][89] , and with other ALK family-associated diseases such as brachydactyly type A2 (ALK6) 90,91 and Loeys-Dietz syndrome (ALK5) 92,93 . ACVRL1 p.Arg484Gln has also been identified in HHT2 94 and in childhood-onset pulmonary arterial hypertension 95 .…”

Section: Variants In Acvrl1 and Other Mutation-intolerant Mendelian V...mentioning

confidence: 99%

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

Zhao

Mekbib

Ent

et al. 2023

Preprint

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To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79x10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22x10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a second-hit allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

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Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia Related to an <i>ACVRL1</i> Mutation

Cited by 12 publications

References 30 publications

Approach to Pulmonary Arteriovenous Malformations: A Comprehensive Update

Approach to Pulmonary Arteriovenous Malformations: A Comprehensive Update

Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

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