Case Studies in Hereditary Hemorrhagic Telangiectasia: Heritable Pulmonary Arterial Hypertension and High- Output Heart Failure

Transcription

1 PH GRAND ROUNDS Case Studies in Hereditary Hemorrhagic Telangiectasia: Heritable Pulmonary Arterial Hypertension and High- Output Heart Failure Section Editor Deborah J. Levine, MD Shweta Sood, MD, MS Fellow Division of Pulmonary and Critical Care Medicine Washington University in St. Louis St. Louis, MO Murali M Chakinala, MD, FCCP Professor of Medicine Division of Pulmonary and Critical Care Medicine Washington University School of Medicine St. Louis, MO Hereditary hemorrhagic telangiectasia (HHT) can lead to pulmonary hypertension (PH) and heart failure in 1 of 2 ways, which is vital to recognize and distinguish. More commonly, HHT patients develop a form of high-output heart failure (HOHF) and resultant mild PH. Less commonly, patients with HHT can develop a form of heritable pulmonary arterial hypertension (HPAH) and subsequent right-sided heart failure (RHF). Accurate diagnosis is crucial, as the management of these 2 clinical entities is different. We spotlight 2 HHT cases to illustrate the diagnosis and treatment of HPAH in contrast to HOHF. CASE 1 Presentation and Evaluation: JW is a 64-year-old woman with HHT who presents with episodic dyspnea and abdominal fullness. She reports chronic daily epistaxis for several years, and her history is notable for iron deficiency anemia requiring both oral and intravenous (IV) iron therapy. She is a lifelong nonsmoker with no history of heavy alcohol use or illicit drug use. She has a family history of recurrent epistaxis in her mother, maternal aunt, maternal niece, and both her sons. Her physical examination is remarkable for several mucocutaneous telangiectasias on the lip and tongue, a hyperdynamic precordium with a II/VI systolic ejection murmur heard along the left sternal border, bruits in the right upper quadrant of the abdomen, and small punctate telangiectasias on the hand and chest. JW s labs are noteworthy for hemoglobin of 9.9, hematocrit of 33.5, and platelets of 200,000. Recent esophagogastroduodenoscopy (EGD) found several gastrointestinal (GI) telangiectasias that were treated by argon plasma coagulation. Chest computed tomography (CT) reveals 2 pulmonary arteriovenous malformations (PAVMs), cardiomegaly with dilation of all 4 chambers, and a dilated pulmonary artery (PA) (Figure 1A). The PAVMs Figure 1: JW s chest, abdominal imaging. (A) Chest CT angiogram with dilated pulmonary artery (*) resulting from chronic high-flow and mild PH. (B) Abdominal MRI displaying the extensive AVMs (arrows). (C) Abdominal MRI again highlighting the extensive AVMs and the increased liver volume (arrows). Key Words arteriovenous malformation, heritable pulmonary arterial hypertension, hereditary hemorrhagic telangiectasia, high-output heart failure, right heart failure Correspondence: chakinalam@wustl.edu Advances in Pulmonary Hypertension Volume 16, Number 1;

2 undergoes a right heart catheterization (RHC), which reveals elevated cardiac output (CO) and cardiac index (CI) with minimal increases in PA pressure (PAP) and pulmonary artery wedge pressure (PAWP) (Table 2). Diagnosis: The patient is diagnosed with HOHF and mild PH secondary to liver AVMs and chronic anemia. Figure 2: JW s echocardiography. (A-B) Four-chamber views show significant LV and LA enlargement, respectively, in the setting of HOHF and before bevacizumab therapy. Corresponding right-sided chambers are also significantly dilated (*). (C-D) Four-chamber view 15 months after beginning bevacizumab illustrates significant reduction in LA size, as well as marked reduction in the dimensions of right-sided chambers. See Table 1 for quantifiable differences between studies. are small (feeding arteries <3 mm) and do not require embolization. In addition, an abdominal CT shows innumerable hepatic AVMs (HAVMs) with marked dilatation and tortuosity of celiac and hepatic arteries (Figure 1B). Abdominal magnetic resonance imaging (MRI) confirms the presence of multiple arteriovenous malformations (AVMs) and hepatomegaly with a total liver volume of 1882 ml (normal, ml) (Figure 1C). 1 On transthoracic echocardiogram (TTE), the left ventricle (LV) is enlarged but has normal function, while the right ventricle s (RV) size and function appear normal and pulmonary artery systolic pressure (PASP) is 35 mm Hg (Figures 2A, 2B and Table 1). She Treatment and Response: Over the next 2 years, JW is aggressively treated with multiple interventions. The epistaxis improves with nasal hygiene, cauterizations, and tranexamic acid (TxA). Her chronic iron deficiency anemia requires multiple iron infusions and several blood transfusions to maintain ferritin above 50 ng/ml and hemoglobin consistently above 10 g/ dl. She is also treated with bevacizumab: 5 mg/kg doses every 2 weeks for 6 treatments, followed by monthly for 3 treatments, and then every other month. Her dyspnea and abdominal fullness improved and she required less frequent IV iron therapy and no further transfusions. After 9 months of bevacizumab, RHC showed significant reduction in CI (Table 2) and 6-minute walk distance (6MWD) increased from 470 to 565 meters. Fifteen months after beginning bevacizumab, indices from echocardiography confirm improvement in her hyperdynamic state with decreased LV Table 1. Transthoracic Echocardiogram Results for Case 1, Before and After Bevacizumab TTE Prebevacizumab 15 months after starting bevacizumab LVEDVI LVEF (%) LAVI E/e RV Diameter TAPSE Tricuspid Regurgitation PASP (mm Hg) LVOT TVI N/A 3.5 Mild Mild Table 2. Right Heart Catheterization Results for Case 1, Before and After Bevacizumab PAP (mean) RAP PAWP CO/CI PVR (Wood units) Baseline 40/20 (27) /8.5 (TD) months after starting bevacizumab 29/15 (20) /5.0 (TD) Advances in Pulmonary Hypertension Volume 16, Number 1; 2017

3 end-diastolic volume index (LVED- VI), left atrial volume index (LAVI), and LV outflow tract s time-velocity integral (VTI), signifying a decrease in her stroke volume (Figures 2C, 2D and Table 1). Six-minute walk distance remains excellent at 520 meters. Her long-term prognosis has improved considerably. CASE 2 Presentation and Evaluation: JS is a 54-year-old woman who presents to the HHT center after chest imaging detected PAVMs. She also reports chronic daily epistaxis, fatigue, and intermittent palpitations. She denies any history of blood transfusions or iron therapy. She is a nonsmoker and denies alcohol or illicit drug use. Her family history is relevant for recurrent epistaxis in her father and paternal uncle. On examination, she has a lower lip telangiectasia and an abdominal bruit. Her labs are unremarkable. CT angiogram shows multiple PAVMs (Figures 3A, 3B) and innumerable HAVMs with dilated celiac and hepatic arteries. Additionally, she has a right paraspinous AVM (Figure 3C) and a right renal sinus AVM (Figure 3D). EGD shows no GI telangiectasias. TTE shows normal LV and RV size and function with normal ejection fraction, a PASP of 35 mm Hg (Figures 4A, 4B and Table 3). Due to her HAVMs, RHC is performed and reveals normal PA pressures and a borderline high-output state (Table 4). Figure 3: JS s chest, abdominal imaging. (A) Bilateral PAVMs are visible. (B) Maximum intensity projection highlights the feeding artery (larger arrow) and draining vein (smaller arrow) to a left lower lobe AVM. (C) Paraspinous AVM is noted but no intervention undertaken (yellow arrows). (D) Renal artery AVM seen in the renal hilus (red arrow). Initial Assessment and Management: JS meets all 4 Curacao clinical criteria for HHT (ie, family history, spontaneous/recurrent epistaxis, mucocutaneous telangiectasias, and visceral AVMs). Furthermore, genetic testing reveals a mutation in the gene for activin receptor-like kinase 1 (ACVRL1). In addition to genetic counseling, she undergoes nasal cauterization. She has successful embolizations for both her pulmonary and renal AVMs. Her paraspinous AVM is monitored but not intervened upon due to its proximity to spinal artery. She receives IV iron therapy. Seven Years Later: JS presents with dyspnea, exertional chest tightness, abdominal fullness, and decreased oral intake. Examination now reveals elevated jugular venous pressure, trace lower extremity edema, and parasternal lift. B-type natriuretic peptide (BNP) is TTE shows markedly dilated RV with severely depressed global RV systolic function, dilated right atrium (RA), Table 3. Transthoracic Echocardiogram for Case 2 TTE LVEDVI LVEF (%) LAVI E/e RV Diameter TAPSE Tricuspid Regurgitation PASP (mm Hg) Mild Severe LVOT TVI Table 4. Right Heart Catheterization Results for Case 2, Initial Visit (2009) and During Hospitalization (2016) RHC PAP (mean) RAP PAWP TPG CO/CI PA Sat /10 (17) /4.6 (TD) 6.8/4.6 (Fick) /37 (54) /3.4 (TD) 5.5/3.4 (Fick) PVR (Wood units) 79% % 9.1 Advances in Pulmonary Hypertension Volume 16, Number 1;

4 Table 5. Differences Between HPAH and HOHF HPAH (Group 1) HOHF (Group 2) Frequency Rare More common Age of onset Younger patients (<40 years) Older patients (>40 years) Mimics IPAH Left-sided heart failure Pathogenesis Proliferative arteriopathy Shunting through large AVMs Pathophysiology Unique physical findings TTE findings Increased PVR Increased PAP RV hypertrophy RV failure Prominent second heart sound (S2) RV heave Hepatic congestion Lower extremity edema Enlarged RV size Diminished RV function Elevated PASP Normal or low CO Liver AVM Left-to-right shunting Increased preload Increased LV work Left heart failure PH RV failure Bounding pulses Wide pulse pressure RUQ abdominal bruits Hepatomegaly Enlarged LV Left atrial dilation RV size and function normal Increased CO and SV Hemodynamics: PAP PAWP CO/CI PVR Left atrium Treatment Significantly elevated Normal Low normal Elevated LA size normal LAP normal Diuretics Oxygen (without aggravating epistaxis) Pulmonary vasodilators Lung transplant? Borderline mildly elevated Normal elevated High Normal mildly elevated (<4 W units) LA size enlarged LAP increased Diuretics, LV afterload (if tolerated) Iron repletion Bevacizumab Liver transplant (for refractory HOHF) severe tricuspid regurgitation (TR) and PASP of 85 mm Hg (Figures 4C, 4D and Table 3). Given her decompensated state, the patient undergoes RHC (Table 4). Diagnosis: The patient is diagnosed with heritable PAH related to ACVRL1 mutation, modified World Health Organization functional class IIIB. Treatment and Response: She is diuresed and started on an endothelin receptor antagonist, ambrisentan, during her hospitalization. Soon after discharge, she is also started on inhaled treprostinil, which is considered to carry fewer challenges and side effects than a parenteral prostacyclin analog (eg, hypotension, bleeding, and risk of bloodstream infection). Four months later, she reports significant improvement in her symptoms to (modified) functional class II and exertional capacity by an improved 6MWD. Patient was lost to follow-up as she sought care at an HHT center of excellence closer to her home. Discussion: HHT is a hereditary multiorgan condition that is transmitted through an autosomal dominant inheritance pattern and affects between 1 in 5000 to 1 in 8000 of the population. 2 Diagnosis is made by satisfying at least 3 of 4 Curacao clinical criteria: family history (ie, affected first-degree relative), spontaneous and recurrent epistaxis, mucocutaneous telangiectasias (customarily affecting the lips, tongue, palate, pinna of ears, and hands), visceral AVMs (including lungs, liver, brain, GI tract, and spinal cord), or by identification of a causative genetic mutation in one of the known HHT genes. 3 Prior studies suggest nearly 90% of HHT patients have epistaxis and 50% to 80% present with mucocutaneous telangiectasias. Additionally, 5% to 15% of HHT patients have cerebral AVMs, 15% to 30% have macroscopic PAVMs, 13% to 45% have GI telangiectasias, and 8% to 31% have liver AVMs. 4,5 Likelihood of manifestations varies by the age of any affected individual. HHT is caused by genetic mutations primarily in 1 of 2 genes: endoglin (ENG) and ACVRL1. Both genes encode cell receptors involved in the TGF-beta signaling pathway and mutations disrupt angiogenesis homeostasis. 6,7 HHT is subdivided into type 1 and 2. 8 HHT type 1 patients have ENG mutations and are more likely to have cerebral and pulmonary AVMs, 2 while HHT type 2 patients have ACVRL1 mutations and are more likely to have HAVMs. Less commonly, SMAD4 mutations lead to an overlap syndrome that has features of HHT and juvenile polyposis. Pulmonary hypertension is a relatively rare complication of HHT. Due to the lack of prospective screening studies and a heavy reliance on echocardiography, the true prevalence of PH in HHT is 10 Advances in Pulmonary Hypertension Volume 16, Number 1; 2017

5 Figure 4: JS s echocardiography. (A, B) Four-chamber and parasternal long-axis views of initial echocardiogram with only mild left atrial enlargement, while remaining chambers were normal in size. Dimensions of LV > RV and LA > RA, respectively. (C, D) Four-chamber and parasternal long-axis views 7 years later reveal marked interval increase in RV and RA, which are now bigger then corresponding left-sided chambers. unknown. Similar to systemic sclerosis, sickle cell disease, end-stage renal disease, or cirrhosis, PH can develop in HHT by more than one mechanism and requires thorough evaluation when suspected (Table 5). Recently published experience highlights the impact that PH has on mortality in HHT. 9,10 Some ACVRL1 mutations, and possibly ENG mutations, are linked to the development of a proliferative arteriopathy in the pulmonary circulation, similar to idiopathic pulmonary arterial hypertension (IPAH) and pulmonary arterial hypertension (PAH) due to bone morphogenetic protein receptor 2 (BMPR2) mutations. This form of PH is classified as Group 1 PH, HPAH in patients with concomitant HHT diagnosis (Case 2). 11 Patients with ACVRL1 mutations often manifest PAH before HHT is apparent and earlier in life than HPAH patients with BMPR2 mutations. 12 Therefore, the diagnosis of IPAH or HPAH in young adults or children should at least make one consider an underlying HHT mutation, especially if epistaxis is a notable complaint or if a visceral AVM is detected in the lung, liver, or brain. Interestingly, Girard and colleagues also identified a relatively higher frequency of mutations in exon 10 of the ACVRL1 gene in HHT-PAH cases. More commonly, PH develops in HHT as a late manifestation of left-sided dysfunction (Case 1), which results from extensive HAVMs. Similar to endstage renal disease patients who develop PH from an overgrown artificial arteriovenous fistula, HAVMs shunt blood left to right, thus chronically increasing cardiac preload. This abnormal physiology eventually overwhelms myocardial capacity and workload with ensuing HOHF and increased left-sided filling pressures. The combination of elevated left-sided filling pressures, increased cardiac output, and possible abnormal pulmonary vascular response (due to ACVRL1 or ENG mutations) leads to PH and eventually RHF. Because PH develops as a consequence of left-sided dysfunction, this more common form of PH in HHT best fits into Group 2 PH or PH owing to left heart dysfunction. In a recent study, 45% of patients with HHT were diagnosed with PH. HHT patients with PH had a higher likelihood of having visceral AVMs and a higher mortality rate compared to HHT patients without PH. 5 Furthermore, HHT patients who develop PH tend to present earlier than PH patients without HHT. 12 In addition to the customary diagnostic studies performed in any individual with unexplained or severe PH (eg, ventilation-perfusion scanning, pulmonary function testing), additional noninvasive evaluations are warranted when PH is suspected in the context of HHT (Table 5). Laboratory evaluation should include the complete blood count (CBC), red blood cell indices (MCV and RDW), and comprehensive iron studies, due to the increased risk for iron deficiency from chronic epistaxis and/or GI bleeding. In addition, chest CT angiogram should be performed to look for PAVMs, if the bubble echocardiogram suggests transpulmonary communications. Importantly, careful imaging of the liver, either by ultrasound, abdominal CT, or MRI, must be performed to assess the burden of HAVMs. Ultimately, RHC is crucial for confirming a PH diagnosis, distinguishing between the types of PH, and providing prognostic information in either type of PH found in HHT. The most distinguishing hemodynamic feature is the pulmonary vascular resistance (PVR), which is significantly elevated in HPAH and emblematic of the proliferative arteriopathy. Meanwhile, the PVR in HOHF will either be normal or at most only mildly elevated (ie, <4 Wood units). The treatment approach of Group 1 (PAH) and Group 2 (HOHF) PH in HHT should first include basic heart failure management. Diuretics help immensely by optimizing volume status and minimizing exertional symptoms. LV afterload reduction may be helpful only when LV systolic function is depressed in the late stages of HOHF, but caution must be exercised due to borderline systemic pressures from significant burden of left-to-right shunts. General treatment for HHT hinges on controlling epistaxis, treating underlying visceral AVMs (pulmonary or brain either to provide symptomatic relief or prevent complications), and addressing comorbidities such as anemia and arrhythmias. Atrial tachyarrhythmias should be aggressively abolished, as loss of atrioventricular synchrony can have profound impact with this already com- Advances in Pulmonary Hypertension Volume 16, Number 1;

6 plex pathophysiology. Supplemental oxygen should be used judiciously to correct hypoxemia from mechanisms other than anatomic shunts (eg, PAVMs, patent foramen ovale), as continuous oxygen delivery can aggravate epistaxis. Lastly, oral and/or intravenous iron replacement and possibly transfusions should be administered to avoid significant anemia (ie, <10 g/dl), which further fuels the high-output state and/or compromises peripheral oxygen delivery. Beyond these basic steps, management of HOHF and Group 2 PH in HHT has evolved separately over the last decade. The anti-angiogenic effect of bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF) signaling, has been exploited to reduce HHT-related epistaxis and GI bleeding as well as decrease burden of HAVMs and the degree of left-to-right shunting, which in turn improves HOHF (shown in Case 1). 13 In one prospective study of 25 HHT patients with HOHF, bevacizumab dosed 5 mg/kg every 2 weeks for 6 treatments led to significant improvement in hemodynamics and epistaxis with an acceptable safety profile. In spite of this promising early experience, many questions over bevacizumab still abound, including when to initiate treatment and how long someone should be treated, as the effect of bevacizumab on AVMs and telangiectasias wanes over time. Other treatment options include HAVM embolization (if a small number of AVMs) and liver transplantation (if liver is occupied by multiple AVMs) However, HAVM embolization is controversial and rarely attempted due to concerns of hepatic or biliary necrosis. Liver transplantation is reserved for refractory cases and has excellent long-term results. Treatment of HPAH in HHT diverges from HOHF and Group 2 PH by the use of pulmonary vasodilators. Bosentan, sildenafil, inhaled iloprost, and IV epoprostenol have all been used with varying degrees of success. 10,17-20 However, PH medications can be challenging in this population and have the potential to worsen HHT-related bleeding. 10 Phosphodiesterase type-5 inhibitors and the prostacyclin analogs through inhibition of platelet aggregation can promote bleeding from existing sites. Furthermore, pulmonary vasodilators increase blood flow through the vascular lesions of HHT, thus increasing the risk of bleeding. One additional challenging aspect is the approach to PAVMs in the setting of severe HPAH. While embolization of PAVMs usually has negligible hemodynamic effects, this may not be assumed for the unique situation of HPAH with severely elevated PVR and sizable PAVMs. 21 In this rare situation, embolization of a large PAVM or multiple smaller PAVMs may lead to further increase in the PVR and hemodynamic instability due to acute worsening of RV function. Timing and sequence of interventions (ie, initiation of pulmonary vasodilators and embolization) in these dicey situations is unclear but should warrant multidisciplinary input and the availability of advanced therapies, including IV prostacyclin analogs, inotropic support, and even extracorporeal life support. Overall prognosis of patients with HPAH in HHT is guarded, and mortality may be worse than other forms of HPAH and IPAH. 12 Accordingly, these rare and tough cases of HPAH should be managed closely and jointly by centers with expertise in PAH and HHT. Conclusion: PH may be encountered in HHT not infrequently and emerging evidence illustrates that PH portends a worse prognosis. Importantly, PH develops by 1 of 2 main mechanisms, with HOHF and Group 2 PH being much more common than HPAH (Group 1 PH). While basic heart failure management is similar for both entities, unique treatment options have emerged for both entities and should be considered after careful characterization of hemodynamics by RHC and with the input of an HHT expert. Teaching Points 1. HHT can be diagnosed by satisfying at least 3 of 4 Curacao clinical criteria: family history, spontaneous and recurrent epistaxis, mucocutaneous telangiectasias, visceral AVMs. 2. HHT patients often develop HAVMs that lead to HOHF and mild PH, which is considered Group 2 PH. 3. Less commonly, HHT patients can develop severe HPAH, which is a subtype of Group 1 PH. 4. Mutations in ACVRL1 are associated with both forms of PH in HHT. 5. Accurate diagnosis is crucial and requires RHC, as management differs for these 2 entities; but either type of PH is associated with a worse prognosis in HHT. 6. Treatment approach for Group 1 (PAH) and Group 2 (HOHF) PH should initially center on basic heart failure management while minimizing HHT-related bleeding, anemia, and iron deficiency. 7. Treatment of HOHF is evolving to using anti-angiogenic agents, while pulmonary vasodilators must be used carefully in HPAH due to potential for aggravating bleeding; these challenging cases are best managed in conjunction with an HHT expert. References 1. Heinemann A, Wischhusen F, Püschel K, Rogiers X. Standard liver volume in the Caucasian population. Liver Transpl Surg. 1999;5(5): Faughnan ME, Granton JT, Young LH. The pulmonary vascular complications of hereditary haemorrhagic telangiectasia. Eur Respir J. 2009;33(5): Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91(1): te Veldhuis EC, te Veldhuis AH, van Dijk FS, et al. Rendu-Osler-Weber disease: update of medical and dental considerations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105(2):e38-e Sopeña B, Pérez-Rodriguez MT, Portela D, Rivera A, Freire M, Martinez-Vázquez C. High prevalence of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. Eur J Intern Med. 2013;24(3):e30-e Rigelsky CM, Jennings C, Lehtonen R, Minai OA, Eng C, Aldred MA. BMPR2 mutation in a patient with pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia. Am J Med Genet A. 2008;146A(19): Eyries M, Coulet F, Girerd B, et al. ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Clin Genet. 2012;82(2): Battaile JT, Ochoa CD. Distinct Forms of 12 Advances in Pulmonary Hypertension Volume 16, Number 1; 2017

7 Pulmonary Hypertension Complicate Hereditary Hemorrhagic Telangiectasia. Adv Pulm Hypertens. 2015;14(3): Chizinga M, Rudkovskaia AA, Henderson K, et al. Pulmonary Hypertension Prevalence and Prognosis in a Cohort of Patients with Hereditary Hemorrhagic Telangiectasia Undergoing Embolization of pavms. Am J Respir Crit Care Med Apr 4. [Epub ahead of print] 10. Lyle MA, Fenstad ER, McGoon MD, et al. Pulmonary Hypertension in Hereditary Hemorrhagic Telangiectasia. Chest. 2016;149(2): Trembath RC, Thomson JR, Machado RD, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001;345(5): Girerd B, Montani D, Coulet F, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010;181(8): Dupuis-Girod S, Ginon I, Saurin JC, et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA. 2012;307(9): Trotter JF, Suhocki PV, Lina JR, Martin LW, Parrish JL, Swantkowski T. Hereditary hemorrhagic telangiectasia causing high output cardiac failure: treatment with transcatheter embolization. Am J Gastroenterol. 1998;93(9): Le Corre F, Golkar B, Tessier C, Kavafyan J, Marty J. Liver transplantation for hepatic arteriovenous malformation with high-output cardiac failure in hereditary hemorrhagic telangiectasia: hemodynamic study. J Clin Anesth. 2000;12(4): Dupuis-Girod S, Chesnais AL, Ginon I, et al. Long-term outcome of patients with hereditary hemorrhagic telangiectasia and severe hepatic involvement after orthotopic liver transplantation: a single-center study. Liver Transpl. 2010;16(3): Miyake R, Fujino T, Abe K, et al. Pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia successfully treated with sildenafil. Int J Cardiol. 2016;214: Chang SA, Jang SY, Ki CS, Kang IS, Kim DK. Successful bosentan therapy for pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia. Heart Vessels. 2011;26(2): Minai OA, Rigelsky C, Eng C, Arroliga AC, Stoller JK. Long-term outcome in a patient with pulmonary hypertension and hereditary hemorrhagic telangiectasia. Chest. 2007;131(4): Ishiwata T, Terada J, Tanabe N, et al. Pulmonary arterial hypertension as the first manifestation in a patient with hereditary hemorrhagic telangiectasia. Intern Med. 2014;53(20): Shovlin CL, Tighe HC, Davies RJ, Gibbs JS, Jackson JE. Embolisation of pulmonary arteriovenous malformations: no consistent effect on pulmonary artery pressure. Eur Respir J. 2008;32(1): Advances in Pulmonary Hypertension Volume 16, Number 1;