|
1
|
Hao SY, Muhetaer Y, Zheng X, Long YL, Song JQ, Zhong M. Rapid improvement in postpartum pulmonary hypertension associated with hereditary hemorrhagic telangiectasia: A case report and review of literature. World J Clin Cases 2025; 13:98128. [PMID: 40242231 PMCID: PMC11718578 DOI: 10.12998/wjcc.v13.i11.98128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 11/18/2024] [Accepted: 12/10/2024] [Indexed: 12/26/2024] Open
Abstract
BACKGROUND Postpartum pulmonary arterial hypertension (PAH) complicated with hereditary hemorrhagic telangiectasia (HHT) is a rare condition. Diagnosing and treating PAH in patients with HHT can be challenging. To the best of our knowledge, no previous reports have investigated the efficacy of pulmonary vasodilators in improving hemodynamics in postpartum patients with this disease. CASE SUMMARY In this paper, we report a postpartum case of HHT combined with PAH, presenting with worsening dyspnea. Genetic testing revealed that the patient carried a heterozygous variant of activin receptor-like kinase 1. The patient received various treatments, including diuretics, anticoagulants, sildenafil, macitentan, inhalation of nitric oxide, and iloprost. Changes in PaO2/FiO2, pulmonary artery systolic pressure as assessed by echocardiography, and N-terminus pro-brain natriuretic peptide levels suggested that, except for iloprost inhalation, the other treatments appeared to have limited efficacy. CONCLUSION To our knowledge, this is the first report on efficacy of pulmonary vasodilators in postpartum patients with HHT and PAH.
Collapse
Affiliation(s)
- Sheng-Yu Hao
- Department of Critical Care Medicine, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Yaxiaerjiang Muhetaer
- Department of Critical Care Medicine, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Xin Zheng
- Department of Critical Care Medicine, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Yu-Liang Long
- Department of Cardiology, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Jie-Qiong Song
- Department of Critical Care Medicine, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Ming Zhong
- Department of Critical Care Medicine, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| |
Collapse
|
|
2
|
Qin G, Chen S, Huang F, Mo L, Li K. Imaging manifestations of hereditary hemorrhagic telangiectasia with pulmonary arterial hypertension: a case report. Front Cardiovasc Med 2025; 12:1548130. [PMID: 40190465 PMCID: PMC11968766 DOI: 10.3389/fcvm.2025.1548130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/10/2025] [Indexed: 04/09/2025] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder. Pulmonary arterial hypertension (PAH) is an uncommon complication (affecting <1% of HHT patients). Here, we report the clinical and imaging findings of a rare case of HHT complicated by PAH in a 41-year-old woman. The patient experienced recurrent exertional dyspnea for over 1 year, accompanied by chest tightness and pain, coughing, and production of white mucus. Her medical history included recurrent epistaxis and bilateral lower extremity edema. Due to persistent symptoms, she was hospitalized for further evaluation. Imaging revealed multiple dilated, tortuous vessels and arteriovenous fistulas in both lower lung lobes and the liver. Additionally, myocardial edema and fibrosis were observed in the ventricular insertion points, interventricular septum, right ventricular inferior wall and left ventricular free wall. Reduced pulmonary artery peak flow velocity, maximal flow, and mean wall shear stress (mWSS) were noted. Right heart catheterization confirmed pre-capillary PAH, and genetic testing identified an ACVRL1 mutation. Symptomatic supportive care was provided during hospitalization. We discussed the relationship between PAH and HHT as well as the characteristics of both conditions.
Collapse
Affiliation(s)
| | | | | | | | - Kai Li
- Department of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| |
Collapse
|
|
3
|
Selvadurai Y, Le Fevre ER, Mervis J, Fitzgerald DA. Hereditary haemorrhagic telangiectasia: A primer for the paediatrician. Paediatr Respir Rev 2025; 53:30-34. [PMID: 39214822 DOI: 10.1016/j.prrv.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024]
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by small telangiectasias and larger multisystem arteriovenous malformations (AVMs). Common sites of AVMs include in the nose, lungs, brain and liver. These lesions are prone to rupture, leading to complications including recurrent epistaxis and significant haemorrhage. Pulmonary hypertension (PH) can also occur. This review presents an update on the genetics, clinical manifestations, management options, and screening recommendations for children with HHT.
Collapse
Affiliation(s)
- Yoshua Selvadurai
- Department of Surgery, Gosford Hospital, Central Coast Local Health District, Holden Street, Gosford, NSW 2250, Australia
| | - Emily R Le Fevre
- Department of Respiratory Medicine, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia.
| | - Jonathan Mervis
- Heart Centre for Children, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia
| | - Dominic A Fitzgerald
- Department of Respiratory Medicine, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia; Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, New South Wales 2145, Australia
| |
Collapse
|
|
4
|
Jamindar P, Pope M, Gossage J. Long Term Survival of Heritable Pulmonary Arterial Hypertension Associated with Hereditary Hemorrhagic Telangiectasia: A Case Series. J Clin Med 2023; 13:141. [PMID: 38202148 PMCID: PMC10780235 DOI: 10.3390/jcm13010141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/16/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a hereditary disease characterized by recurrent epistaxis, mucocutaneous telangiectasias, and visceral arteriovenous malformations. Multiple genetic mutations have been linked to this rare disease, including ENG, ALK1 (ACVRL1), and MADH4. Pulmonary hypertension is a potential complication of HHT, with the most common phenotypes being World Health Organization (WHO) group 1 heritable pulmonary arterial hypertension (PAH), which is typically associated with ALK1 mutation; WHO group 2 pulmonary hypertension due to high output heart failure from hepatic arteriovenous malformations and/or anemia; and WHO group 2 due to high pulmonary artery wedge pressure. There is scarce evidence to help guide treatment of heritable PAH in HHT, and observational literature suggests that patients with HHT and heritable PAH have a worse prognosis compared to patients with idiopathic PAH. We describe the diagnosis, pulmonary hemodynamics, and detailed treatment courses of three patients with ALK1-associated HHT and PAH, who all exhibited objective clinical improvement with parenteral prostacyclins and oral agents.
Collapse
Affiliation(s)
- Parth Jamindar
- Division of Pulmonary, Critical Care and Sleep Medicine, Augusta University Medical Center, Augusta, GA 30912, USA; (P.J.); (J.G.)
| | - Michael Pope
- Division of Internal Medicine, Augusta University Medical Center, Augusta, GA 30912, USA
| | - James Gossage
- Division of Pulmonary, Critical Care and Sleep Medicine, Augusta University Medical Center, Augusta, GA 30912, USA; (P.J.); (J.G.)
| |
Collapse
|
|
5
|
Niklasson J, Rönnblom A, Lidian A, Thor A. Oral manifestations and dental considerations of patients with hereditary hemorrhagic telangiectasia: a scoping review. Oral Surg Oral Med Oral Pathol Oral Radiol 2023; 136:691-702. [PMID: 37752017 DOI: 10.1016/j.oooo.2023.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/20/2023] [Accepted: 08/05/2023] [Indexed: 09/28/2023]
Abstract
OBJECTIVE We examined the range, nature, and extent of research conducted regarding the oral and dental implications of hereditary hemorrhagic telangiectasia (HHT) to identify gaps in the research and knowledge of the field. STUDY DESIGN We performed a scoping review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews and 2017 Guidance for the Conduct of Joanna Briggs Institute Scoping Reviews. We searched the MEDLINE and Web of Science databases for all full-text articles published in English from December 1946 to October 2022. RESULTS We identified 103 articles describing oral and dental considerations of patients with HHT, primarily case reports. Most reported oral telangiectasias of the tongue, lips, and palate. Many reported management of bleeding and the use or recommendation of prophylactic antibiotics before dental procedures. CONCLUSIONS Oral telangiectasias are commonly found in patients with hereditary hemorrhagic telangiectasia, and dental professionals may be the first to diagnose it in their patients. Early detection and diagnosis are important to prevent potentially fatal outcomes, and prophylactic antibiotics before procedures may be warranted.
Collapse
Affiliation(s)
- Julia Niklasson
- Department of Plastic and Oral and Maxillofacial Surgery, Uppsala University, Uppsala, Sweden.
| | - Anders Rönnblom
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Adnan Lidian
- Department of Otorhinolaryngology and Head and Neck Surgery, Uppsala University, Uppsala, Sweden
| | - Andreas Thor
- Department of Plastic and Oral and Maxillofacial Surgery, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
6
|
Mathavan A, Mathavan A, Reddy R, Jones K, Eagan C, Alnuaimat H, Ataya A. Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review. Pulm Circ 2023; 13:e12301. [PMID: 37868718 PMCID: PMC10585978 DOI: 10.1002/pul2.12301] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/06/2023] [Accepted: 10/09/2023] [Indexed: 10/24/2023] Open
Abstract
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.
Collapse
Affiliation(s)
- Akash Mathavan
- Department of Internal MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Akshay Mathavan
- Department of Internal MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Renuka Reddy
- Division of Pulmonary, Critical Care, and Sleep MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Kirk Jones
- Department of Internal MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Christina Eagan
- Division of Pulmonary, Critical Care, and Sleep MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Hassan Alnuaimat
- Respiratory Institute Pulmonary, Critical Care, and Sleep MedicineCleveland Clinic Abu DhabiAbu DhabiUnited Arab Emirates
| | - Ali Ataya
- Division of Pulmonary, Critical Care, and Sleep MedicineUniversity of FloridaGainesvilleFloridaUSA
| |
Collapse
|
|
7
|
Abston E, Hon S, Rodriguez-Lopez J, Moll M, Lanuti M, Farber HW, Wilson KC. Treatment of pulmonary hypertension in patients with Hereditary Hemorrhagic Telangiectasia - A case series and systematic review. Pulm Pharmacol Ther 2021; 68:102033. [PMID: 33895318 DOI: 10.1016/j.pupt.2021.102033] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/22/2021] [Accepted: 04/12/2021] [Indexed: 11/19/2022]
Abstract
RATIONALE Pulmonary Arterial Hypertension (PAH), a rare complication of HHT is associated with poor outcome. There are no trials to date that have investigated whether pulmonary vasodilator therapy improves hemodynamics or survival in this disease. OBJECTIVE To determine whether pulmonary vasodilator therapy improves survival, exercise capacity, or hemodynamics in HHT patients with pre-capillary PH. METHODS We performed a before-and-after observational study on a multicenter cohort of subjects with HHT-PAH who received intravenous prostanoid therapy. We then conducted a systematic review, searching Medline and EMBASE through December 2019. Studies that enrolled HHT-PAH subjects and reported treatment outcomes were selected. PROSPERO #158179. RESULTS Twenty-one articles were selected. Studies were before-and-after observational studies, case reports, and case series. Among all subjects with HHT-PAH, both mPAP (65 ± 19 pre-treatment vs 51 ± 16 mmHg post-treatment p = 0.04) and PVR (12 ± 6 pre-treatment vs 8 ± 4 WU post-treatment p = 0.01) improved with treatment. The mPAP improved with either oral (57 ± 17 pre-treatment versus 44 ± 13 mmHg post-treatment, p = 0.03) or intravenous (80 ± 15 pre-treatment versus 64 ± 16 mmHg post-treatment, p = 0.017) therapy. PVR also improved with either oral (10 ± 4 pre-treatment versus 6 ± 3 WU post-treatment, p = 0.004) or intravenous (17 ± 5 pre-treatment versus 10 ± 4 WU post-treatment, p = 0.04) therapy. Survival among HHT-PAH patients who received oral or intravenous therapy was not different (p = 0.2). Unadjusted survival among HHT-PAH patients was longer than that of IPAH patients (p = 0.008). There was no difference in side effects among HHT-PAH patient who received oral or intravenous therapy (p = 0.1). CONCLUSION Pulmonary vasodilator therapy is effective in improving hemodynamics of subjects with HHT-PAH and was not associated with increased risk of side effects.
Collapse
Affiliation(s)
- Eric Abston
- Division of Allergy, Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Center for Thoracic Cancers, Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
| | - Stephanie Hon
- Division of Allergy, Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Division of Pulmonary, Critical Care, And Sleep Medicine, Department of Medicine, Tufts Medical Center, Boston, MA, USA
| | - Josanna Rodriguez-Lopez
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Matt Moll
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Michael Lanuti
- Center for Thoracic Cancers, Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Harrison W Farber
- Division of Pulmonary, Critical Care, And Sleep Medicine, Department of Medicine, Tufts Medical Center, Boston, MA, USA
| | - Kevin C Wilson
- Division of Allergy, Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| |
Collapse
|
|
8
|
Zaaijer BM, Duppen N, Willemse BW, Verhagen MV, Roofthooft MT, Timens W, Berger RM, Douwes JM. Pulmonary arterial hypertension associated with pulmonary arteriovenous malformations and pulmonary veno-occlusive disease: A devastating combination. Respir Med Case Rep 2021; 34:101564. [PMID: 34934615 PMCID: PMC8654615 DOI: 10.1016/j.rmcr.2021.101564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 11/22/2021] [Accepted: 11/28/2021] [Indexed: 11/24/2022] Open
Abstract
We describe a case of an adolescent male with the rare combination of pulmonary arterial hypertension (PAH) and pulmonary arteriovenous malformations (PAVM's) without confirmed hereditary hemorrhagic telangiectasia (HHT). The patient showed clinical deterioration on standard vasodilator therapy, leading us to question our initial diagnosis. Post-mortem evaluation confirmed the presence of pulmonary veno-occlusive disease of which no conclusive signs were recognized at diagnostic work-up. This case demonstrates the heterogeneity in the diseases causing PAH and shows that an unexpected treatment response should alert the physician to question the original diagnosis.
Collapse
|
|
9
|
Yokokawa T, Sugimoto K, Kimishima Y, Misaka T, Yoshihisa A, Morisaki H, Yamada O, Nakazato K, Ishida T, Takeishi Y. Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia Related to an ACVRL1 Mutation. Intern Med 2020; 59:221-227. [PMID: 31511490 PMCID: PMC7008044 DOI: 10.2169/internalmedicine.3625-19] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Pulmonary hypertension and hereditary hemorrhagic telangiectasia (HHT) have an association mediated by activin A receptor type II-like 1 (ACVRL1) gene pathogenic variants. A 30-year-old woman was previously admitted to a hospital due to lung hemorrhage, and was diagnosed with pulmonary hypertension, but stopped follow-up visits. At 48 years of age, she was admitted to our hospital and was diagnosed with HHT. Genetic testing revealed an ACVRL1 pathogenic variant. After the initiation of pulmonary vasodilator treatment, the patient's mean pulmonary artery pressure started to decrease from 43 mmHg, declining to 37 mmHg when she was 58 years of age. This is the first report describing the 28-year follow-up of an HHT and pulmonary hypertension patient with an ACVRL1 mutation.
Collapse
Affiliation(s)
- Tetsuro Yokokawa
- Department of Cardiovascular Medicine, Fukushima Medical University, Japan
- Department of Pulmonary Hypertension, Fukushima Medical University, Japan
| | - Koichi Sugimoto
- Department of Cardiovascular Medicine, Fukushima Medical University, Japan
- Department of Pulmonary Hypertension, Fukushima Medical University, Japan
| | - Yusuke Kimishima
- Department of Cardiovascular Medicine, Fukushima Medical University, Japan
| | - Tomofumi Misaka
- Department of Cardiovascular Medicine, Fukushima Medical University, Japan
- Department of Advanced Cardiac Therapeutics, Fukushima Medical University, Japan
| | - Akiomi Yoshihisa
- Department of Cardiovascular Medicine, Fukushima Medical University, Japan
- Department of Advanced Cardiac Therapeutics, Fukushima Medical University, Japan
| | - Hiroko Morisaki
- Department of Medical Genetics, Sakakibara Heart Institute, Japan
| | - Osamu Yamada
- Department of Pathology, National Cerebral and Cardiovascular Center, Japan
| | - Kazuhiko Nakazato
- Department of Cardiovascular Medicine, Fukushima Medical University, Japan
| | - Takafumi Ishida
- Department of Cardiovascular Medicine, Fukushima Medical University, Japan
| | - Yasuchika Takeishi
- Department of Cardiovascular Medicine, Fukushima Medical University, Japan
| |
Collapse
|
|
10
|
Das BB, Chan KC. Syncope in a Child with Pulmonary Hypertension and Positive Gene Tests for Hereditary Hemorrhagic Telangiectasia and Long QT Syndrome. Cardiovasc Hematol Agents Med Chem 2020; 18:70-76. [PMID: 31657683 DOI: 10.2174/1871525717666191028102503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 06/10/2023]
Abstract
We present a 10-year-old boy with syncope who was found to have long-QT syndrome and severe Pulmonary Hypertension (PH) both in the absence of a secondary cause; to our knowledge, this is the first report with this unusual coexistence. His genetic tests were positive for hereditary hemorrhagic telangiectasia and Long QT Syndrome (LQTS) without any family history of PH or LQTS. We demonstrated that digital subtraction pulmonary angiography was more useful compared to CT angiogram to demonstrate pulmonary vascular changes which correlated with a noresponse to acute vasoreactivity testing during right heart catheterization. He has been stable for the last 2 years on Ambrisentan, Sildenafil, and Nadolol without recurrence of symptoms.
Collapse
Affiliation(s)
- Bibhuti B Das
- Department of Pediatric Cardiology, Baylor College of Medicine, Texas Children's Hospital, Austin Specialty Care, Austin, TX 78759, United States
| | - Kak-Chen Chan
- Joe DiMaggio Children's Hospital Heart Institute, Memorial Healthcare System, Hollywood, FL 33021, United States
| |
Collapse
|
|
11
|
Vorselaars VMM, Hosman AE, Westermann CJJ, Snijder RJ, Mager JJ, Goumans MJ, Post MC. Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia. Int J Mol Sci 2018; 19:ijms19103203. [PMID: 30336550 PMCID: PMC6213989 DOI: 10.3390/ijms19103203] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/08/2018] [Accepted: 10/10/2018] [Indexed: 12/20/2022] Open
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for proteins involved in the transforming growth factor-beta (TGF-β) superfamily, a signalling pathway that is essential for angiogenesis. Changes within this pathway can lead to both the proliferative vasculopathy of HPAH and arteriovenous malformations seen in HHT. Clinical signs of the disease combination may not be specific but early diagnosis is important for appropriate treatment. This review describes the molecular mechanism and management of HPAH and HHT.
Collapse
Affiliation(s)
| | - Anna E Hosman
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.
| | | | - Repke J Snijder
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.
| | - Johannes J Mager
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.
| | - Marie-Jose Goumans
- Department of Molecular Cell Biology, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands.
| | - Marco C Post
- Department of Cardiology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.
| |
Collapse
|
|
12
|
Li W, Xiong CM, Gu Q, Wang XT, Cheng XL, Huang L, Yang T, Luo Q, Zhao ZH, Ni XH, Liu ZH, He JG. The clinical characteristics and long-term prognosis of pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia. Pulm Circ 2018; 8:2045894018759918. [PMID: 29480092 PMCID: PMC5888830 DOI: 10.1177/2045894018759918] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a severe complication of hereditary hemorrhagic telangiectasia (HHT); however, little is known about its clinical characteristics and prognosis. Nine newly diagnosed HHT-PAH patients were prospectively recruited between October 2007 and January 2016 and were followed up every half-year. Eighteen idiopathic pulmonary arterial hypertension (IPAH) patients, matched with HHT-PAH patients on mean pulmonary arterial pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, cardiac index, and World Health Organization (WHO) functional class (FC), were recruited. The clinical characteristics of HHT-PAH patients were described and the prognosis of these two cohorts were compared. Of HHT-PAH patients, 55.56% were WHO FC III. Kaplan–Meier survival analysis showed one- and three-year survival rates of HHT-PAH patients were 77.8% and 53.3% respectively, which were worse than matched IPAH patients (log rank: P = 0.047). HHT-PAH patients had higher red cell distribution width (14.88 ± 2.93% versus 13.19 ± 0.83%, P = 0.031), larger right ventricular anteroposterior diameter (34.67 ± 6.67 mm versus 28.56 ± 6.35 mm, P = 0.029), and lower mean corpuscular hemoglobin concentration (317.38 ± 17.71 g/L versus 335.72 ± 14.68 g/L, P = 0.011) than matched IPAH patients. Multivariate Cox proportional hazards regression analyses showed baseline total bilirubin independently predicted the mortality of HHT-PAH after adjusting by age, cardiac index, mixed venous oxygen saturation, or serum uric acid. HHT-PAH patients may have a worse prognosis than matched IPAH patients. Baseline total bilirubin may be a promising predictor for the long-term prognosis in HHT-PAH patients.
Collapse
Affiliation(s)
- Wen Li
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chang-Ming Xiong
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qing Gu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiao-Tong Wang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiao-Ling Cheng
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Huang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Yang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qin Luo
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhi-Hui Zhao
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin-Hai Ni
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhi-Hong Liu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jian-Guo He
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
13
|
Revuz S, Decullier E, Ginon I, Lamblin N, Hatron PY, Kaminsky P, Carette MF, Lacombe P, Simon AC, Rivière S, Harlé JR, Fraisse A, Lavigne C, Leguy-Seguin V, Chaouat A, Khouatra C, Dupuis-Girod S, Hachulla E. Pulmonary hypertension subtypes associated with hereditary haemorrhagic telangiectasia: Haemodynamic profiles and survival probability. PLoS One 2017; 12:e0184227. [PMID: 28981519 PMCID: PMC5628806 DOI: 10.1371/journal.pone.0184227] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 08/21/2017] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Different pulmonary hypertension (PH) mechanisms are associated with hereditary haemorrhagic telangiectasia (HHT). METHODS AND RESULTS We conducted a retrospective study of all suspected cases of PH (echocardiographically estimated systolic pulmonary artery pressure [sPAP] ≥ 40 mmHg) in patients with definite HHT recorded in the French National Reference Centre for HHT database. When right heart catheterization (RHC) was performed, PH cases were confirmed and classified among the PH groups according to the European guidelines. Among 2,598 patients in the database, 110 (4.2%) had suspected PH. Forty-seven of these 110 patients had RHC: 38/47 (81%) had a confirmed diagnosis of PH. The majority of these had isolated post-capillary PH (n = 20). We identified for the first time other haemodynamic profiles: pre-capillary pulmonary arterial hypertension (PAH) cases (n = 3) with slightly raised pulmonary vascular resistances (PVR), and combined post- and pre-capillary PH cases (n = 4). Compared to controls, survival probability was lower in patients with PAH. CONCLUSION This study revealed the diversity of PH mechanisms in HHT. The description of combined post- and pre-capillary PH with/or without high cardiac output (CO) suggests either a continuum between the pre- and post-capillary haemodynamic profiles or a different course in response to high CO.
Collapse
Affiliation(s)
- Sabine Revuz
- Département de Médecine Interne et Immunologie clinique, CHU de Brabois, Vandœuvre-lès-Nancy, France
| | | | - Isabelle Ginon
- Service d’Explorations Cardiologiques, Centre Hospitalier Lyon Sud, Pierre-Bénite, Hospices Civils de Lyon, Lyon, France
| | - Nicolas Lamblin
- Service de Cardiologie, CHRU de Lille, Université de Lille, Lille, France
| | - Pierre-Yves Hatron
- Service de Médecine interne, CHRU de Lille, Université de Lille, Lille, France
| | - Pierre Kaminsky
- Département de Médecine Interne et Immunologie clinique, CHU de Brabois, Vandœuvre-lès-Nancy, France
| | | | - Pascal Lacombe
- Service d’Imagerie diagnostique et interventionnelle, APHP Hôpital Ambroise Paré, Boulogne-Billancourt, France
| | | | - Sophie Rivière
- Service de Médecine interne, CHU Montpellier, Montpellier, France
| | - Jean-Robert Harlé
- Service de Médecine interne, CHU Marseille Hôpital de la Conception, Marseille, France
| | - Alain Fraisse
- Paediatric Cardiology Service, Royal Brompton and Harefield Hospitals Trust, London, United Kingdom
| | - Christian Lavigne
- Service de Médecine interne et Maladies vasculaires, CHU Angers, Angers, France
| | | | - Ari Chaouat
- Département de Pneumologie, CHU de Brabois, Vandœuvre-lès-Nancy, France
| | - Chahera Khouatra
- Service de Pneumologie, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France
| | - Sophie Dupuis-Girod
- Service de Génétique et Centre de Référence pour la Maladie de Rendu-Osler, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France
| | - Eric Hachulla
- Service de Médecine interne, CHRU de Lille, Université de Lille, Lille, France
| |
Collapse
|
|
14
|
Miyake R, Fujino T, Abe K, Hosokawa K, Ohtani K, Morisaki H, Yamada O, Higo T, Ide T. Pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia successfully treated with sildenafil. Int J Cardiol 2016; 214:275-6. [DOI: 10.1016/j.ijcard.2016.03.211] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 03/27/2016] [Indexed: 12/14/2022]
|
|
15
|
Vorselaars VMM, Velthuis S, Snijder RJ, Vos JA, Mager JJ, Post MC. Pulmonary hypertension in hereditary haemorrhagic telangiectasia. World J Cardiol 2015; 7:230-237. [PMID: 26015855 PMCID: PMC4438464 DOI: 10.4330/wjc.v7.i5.230] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 12/26/2014] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disorder characterised by vascular malformations in predominantly the brain, liver and lungs. Pulmonary hypertension (PH) is increasingly recognised as a severe complication of HHT. PH may be categorised into two distinct types in patients with HHT. Post-capillary PH most often results from a high pulmonary blood flow that accompanies the high cardiac output state associated with liver arteriovenous malformations. Less frequently, the HHT-related gene mutations in ENG or ACVRL1 appear to predispose patients with HHT to develop pre-capillary pulmonary arterial hypertension. Differentiation between both forms of PH by right heart catheterisation is essential, since both entities are associated with severe morbidity and mortality with different treatment options. Therefore all HHT patients should be referred to an HHT centre.
Collapse
|
|
16
|
Handa T, Okano Y, Nakanishi N, Morisaki T, Morisaki H, Mishima M. BMPR2 gene mutation in pulmonary arteriovenous malformation and pulmonary hypertension: a case report. Respir Investig 2014; 52:195-198. [PMID: 24853021 DOI: 10.1016/j.resinv.2013.08.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Revised: 07/14/2013] [Accepted: 08/02/2013] [Indexed: 06/03/2023]
Abstract
The transforming growth factor-β superfamily signaling pathway is thought to be involved in the pathogenesis of pulmonary arteriovenous malformation (PAVM). However, the association between bone morphogenetic protein receptor type 2 (BMPR2) gene mutations and PAVM remains unclear. We present a case of concurrent PAVM and pulmonary arterial hypertension (PAH), with a deletion mutation in exon 6 and exon 7 of the BMPR2 gene. Drug treatment for PAH improved the patient's hemodynamics and exercise capacity, but worsened oxygenation. This case suggests that BMPR2 gene mutation may be associated with the complex presentation of PAVM combined with PAH.
Collapse
Affiliation(s)
- Tomohiro Handa
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Yoshiaki Okano
- Department of Internal Medicine, Hanwa Daini Senboku Hospital, Sakai, Japan.
| | - Norifumi Nakanishi
- Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
| | - Takayuki Morisaki
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.
| | - Hiroko Morisaki
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.
| | - Michiaki Mishima
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| |
Collapse
|
|
17
|
Chadha D, Handa A, Kumar A. Pulmonary hypertension in a patient with hereditary haemorrhagic telangiectasia. BMJ Case Rep 2013; 2013:bcr-2012-008352. [PMID: 23378554 DOI: 10.1136/bcr-2012-008352] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
A young male patient reported for evaluation of progressive easy fatigability, accompanied by a recent history of recurrent haemoptysis. His clinical examination was unremarkable except for evidence of pulmonary arterial hypertension (PAH). Routine investigations (haemogram, coagulogram, serological tests for connective tissue disorders and a sputum Ziehl Neelsen stain for acid-fast bacilli) were normal. Two-dimensional echocardiography suggested PAH (pulmonary artery systolic pressure-67 mm Hg), whereas the 64-slice spiral CT pulmonary angiogram showed a dilated main pulmonary artery along with bilateral arteriovenous malformations. Cardiac catheterisation performed subsequently confirmed the presence of PAH. On the basis of the above findings, a diagnosis of hereditary haemorrhagic telangiectasia (HHT) complicated with PAH was made, and the patient was started on oral sildenafil therapy to which he responded well. This rare complication of HHT, which requires a high degree of suspicion for diagnosis, is discussed.
Collapse
Affiliation(s)
- Davinder Chadha
- Department of Cardiology, MH, CTC, Pune, Maharashtra, India.
| | | | | |
Collapse
|
|
18
|
Ikarashi N, Toba K, Kato K, Ozawa T, Oda M, Takayama T, Kobayashi H, Yanagawa T, Hanawa H, Suzuki T, Nakazawa M, Nomoto M, Asami F, Higuchi M, Saito H, Aizawa Y. Erythropoietin, but not asialoerythropoietin or carbamyl-erythropoietin, attenuates monocrotaline-induced pulmonary hypertension in rats. Clin Exp Hypertens 2012; 34:575-81. [PMID: 22559233 DOI: 10.3109/10641963.2012.681728] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Erythropoietin (EPO) has long been utilized for the treatment of renal anemia. The erythropoietin receptor (EPOR) is also expressed in the cardiovascular and central nervous systems in addition to an erythroid lineage, to provide an organoprotective role against several types of cellular stress. Pulmonary hypertension (PH) is a poor prognostic disease caused by primary and secondary pulmonary vascular injury. We observed the effects of EPO derivatives on monocrotaline-induced PH in rats on the supposition that EPO may protect small arteries from injury. Asialoerythropoietin (AEPO) lacks sialic acids in the termini of carbohydrate chains that results in rapid clearance from blood. Carbamyl-erythropoietin (CEPO) interacts with EPOR/βc heterodimers, but not with EPOR homodimers expressed in erythroid cells. Monocrotaline-injected rats were treated with continuous intravenous injection of 2500 ng/kg/day of EPO, AEPO, or CEPO for 21 days, and lung histology, cardiac function, and mRNA expression in the lungs were examined. Wall thickening of small arteries in the lungs and PH were improved by administration of EPO, but not by its non-hematopoietic derivatives, AEPO, or CEPO. Erythropoietin administration increased mRNA expression of the anti-apoptotic molecule, Bcl-xL, and maintained expression of the CD31 antigen. We conclude that lungs may express EPOR homoreceptors, but not heteroreceptors. Adequate serum erythropoietin levels may be essential for pulmonary protective effects.
Collapse
Affiliation(s)
- Noboru Ikarashi
- Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Huang ZW, Fan ZX, Sun JT, Li WM, Gao YQ, Quan YH, Geng YM, Niu YY, Wu BX. The short- and medium-term results of transcatheter closure of atrial septal defect with severe pulmonary arterial hypertension. Heart Vessels 2011; 27:603-9. [DOI: 10.1007/s00380-011-0187-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Accepted: 08/12/2011] [Indexed: 11/24/2022]
|