Treatment of pulmonary hypertension in patients with Hereditary Hemorrhagic Telangiectasia – A case series and systematic review

Abston, Eric; Hon, Stephanie; Rodriguez-Lopez, Josanna; Moll, M.; Lanuti, Michael; Farber, Harrison W.; Wilson, Kevin C.

doi:10.1016/j.pupt.2021.102033

Cited by 6 publications

(4 citation statements)

References 54 publications

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“…Shunting of blood from the hepatic arteries or portal veins to the hepatic veins caused a hyperdynamic state in patients with hepatic AVMs, with the cardiac output (CO) increasing up to threefold (Garcia-Tsao et al, 2000;Chen et al, 2020). Abston et al (Abston et al, 2021) reported that pulmonary vasodilator therapy may be an available treatment to improve hemodynamics in HHT with PAH patients. Because there have been few randomized trials, no standard medical therapies have been recommended for HHT.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Clinical characteristics and genetic analysis of two patients with hereditary hemorrhagic telangiectasia

et al. 2022

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Objective: To analyze the clinical features and genetic characteristics of two patients with hereditary hemorrhagic telangiectasia (HHT) and to review the relevant literature.Methods: The clinical data of two HHT patients admitted to the author’s hospital between April 2019 and February 2022 were retrospectively analyzed. Meanwhile, the genetic analysis was performed with their consent.Results: The first patient was a 62-year-old woman who had been complaining of shortness of breath and fever for 20 days. Her previous medical history included brain abscess drainage and video-assisted thoracoscopic surgery for a pulmonary hemangioma. A right heart catheterization revealed no pulmonary arterial hypertension, and an abdominal enhanced magnetic resonance imaging revealed multiple arteriovenous malformations in the liver. Her ACVRL1 heterozygous variants were discovered through whole-exon gene testing. The second case involved a 47-year-old woman who had been experiencing chest tightness for the past 2 years. Several years ago, she underwent brain abscess drainage and embolization of a pulmonary arteriovenous fistula. Ultrasound revealed generalized hepatic vascular dilation, and enhanced computed tomography revealed numerous pulmonary venous fistulas scattered in both lungs as well as multiple arteriovenous malformations in the liver. Her whole-exon gene testing revealed that she, like her son, had heterozygous ENG variants.Conclusion: HHT patients may experience infection, bleeding, dyspnea, and other symptoms. Imaging is important in disease diagnosis and management because early detection and treatment can prevent major complications and disability or even death.

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Section: Discussionmentioning

confidence: 99%

Case Report: Clinical characteristics and genetic analysis of two patients with hereditary hemorrhagic telangiectasia

et al. 2022

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“…Furthermore, there is an overlap between both diseases, as up to up to 10% of HHT patients show elevated pulmonary arterial pressures that indicate either the presence of Group 1 PAH (1% of HHT patients) or Group 2 PH associated with high output failure due to liver AVMs (more common, 10%) [27,28].Our group previously discovered BMPR2 signaling inhibitors FHIT [8] and LCK [18], and BMPR2 signaling activating drugs FK506 [9] and Enzastaurin [8] by performing a high throughput screen (HTS) of siRNAs as well as FDA approved drugs to identify modifier genes and drugs that activate the BMPR2 pathway. Both screens were performed using the myoblastoma reporter cell line in which the BMP response element (BRE) from the ID1 promotor was linked to Luciferase (BRE-Luc).…”

Section: Discussionmentioning

confidence: 99%

Identifying transcriptomic downstream targets of genes commonly mutated in Hereditary Hemorrhagic Telangiectasia

Ali

Liu

Schimmel

et al. 2022

Preprint

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Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease that causes arteriovenous vascular malformations (AVMs) in different organs, including the lung. Three genes, ENG (endoglin), ACVRL1 (ALK1) and SMAD4, all members of the TGF-β/BMPR2 signaling pathway, are responsible for over 85% of all HHT cases. However, how these loss-of-function gene mutations lead to AVMs formation and what common downstream signaling they target is unknown. Here, using a combination of siRNA-mediated gene silencing, whole transcriptomic RNA sequencing, bioinformatic analysis, transcriptomic-based drug discovery, endothelial cells functional assays and VEGF signaling analysis, and ex vivo precision cut lung slice (PCLS) cultures approach, we uncovered common downstream transcriptomic gene signatures of HHT-casing genes and identified promising drug for HHT. We found the commonly used BMPR2-signaling downstream target ID1 is not a common downstream target of all the three HHT genes knockdown in human pulmonary microvascular endothelial cells (PMVECs). We identified novel common downstream targets of all the three HHT-causing genes that were enriched for HHT-related biological process and signaling pathways. Among those downstream genes, LYVE1, GPNMB, and MC5R were strong downstream targets that could serve as a better common downstream target than ID1. Furthermore, using the common downstream upregulated genes (HHT disease signature) following HHT gene knockdown, we identified a small molecule drug, Brivanib, that reversed the HHT disease signature, and inhibited VEGF-induced ERK1/2 phosphorylation, proliferation, and angiogenesis in PMVECs and inhibited some of the upregulated HHT disease genes in PCLS. Our findings suggest that Brivanib could be an emerging new drug for HHT.

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“…Beyond supportive therapy (e.g., oxygen supplementation, diuretics, and iron replacement), the treatment of PAH in patients with HHT currently involves the use of standard PAH vasodilator therapies, including endothelin receptor antagonists, phosphodiesterase inhibitors, soluble guanylate cyclase stimulators, and prostanoids. Individual studies have reported success, either in normalization of hemodynamic parameters or improvement of functional status, with the use of bosentan, sildenafil, selexipag, epoprostenol, treprostinil, and iloprost 81–87 . One investigation included a cohort of five patients as well as an analysis of 32 subjects across 21 studies, all of whom were patients with HHT and PAH treated with oral or intravenous prostanoids 87 .…”

Section: Pulmonary Arterial Hypertensionmentioning

confidence: 99%

“…Individual studies have reported success, either in normalization of hemodynamic parameters or improvement of functional status, with the use of bosentan, sildenafil, selexipag, epoprostenol, treprostinil, and iloprost. 81 , 82 , 83 , 84 , 85 , 86 , 87 One investigation included a cohort of five patients as well as an analysis of 32 subjects across 21 studies, all of whom were patients with HHT and PAH treated with oral or intravenous prostanoids. 87 Results showed significant improvement in mPAP (65 ± 19 pretreatment vs. 51 ± 16 mmHg posttreatment; p = 0.04) and PVR (12 ± 6 pretreatment vs. 8 ± 4 WUs posttreatment; p = 0.01) following therapy, with no significant difference in survival between those who received oral or intravenous medication.…”

Section: Pulmonary Arterial Hypertensionmentioning

confidence: 99%

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review

Mathavan,

Reddy

et al. 2023

Pulm. circ.

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Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant hereditary disorder characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectasias, and solid organ arteriovenous malformations (AVMs). Pulmonary hypertension (PH) is an increasingly recognized complication in patients with HHT, most often precipitated by high‐output heart failure in the presence of hepatic AVMs as well as pulmonary arterial hypertension in the form of a proliferative vasculopathy. The presence of PH in patients with HHT is associated with significant elevations in rates of morbidity and mortality. Additionally, there is growing recognition of a thromboembolic propensity in this population that increases the risk of chronic thromboembolic PH, posing unique clinical considerations regarding the use of anticoagulation. Patients with HHT are also at risk of PH due to disorders commonly seen in the general population, including left‐sided heart and lung disease. The etiology of PH in HHT is multifaceted and complex; the diagnostic approach and treatment strategies must consider the underlying pathophysiology of HHT. This comprehensive review summarizes current knowledge of PH in HHT, detailing the pathogenesis of known etiologies, diagnostic evaluation, and suggested treatment modalities as well as emerging therapies that may be of future interest.

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Treatment of pulmonary hypertension in patients with Hereditary Hemorrhagic Telangiectasia – A case series and systematic review

Cited by 6 publications

References 54 publications

Case Report: Clinical characteristics and genetic analysis of two patients with hereditary hemorrhagic telangiectasia

Case Report: Clinical characteristics and genetic analysis of two patients with hereditary hemorrhagic telangiectasia

Identifying transcriptomic downstream targets of genes commonly mutated in Hereditary Hemorrhagic Telangiectasia

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review

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