Pulmonary vascular manifestations of hereditary haemorrhagic telangiectasia

Abstract

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant, multisystem disorder that manifests with a spectrum of disease including cardiopulmonary complications. HHT is characterised by aberrant signalling via the transforming growth factor β (TGFβ) pathway, with loss of vascular integrity, angiogenesis and vascular dysplasia. The disease has an estimated prevalence of 1 in 5000 persons and the penetrance increases with increasing age. HHT commonly presents with epistaxis and telangiectasia, while visceral arteriovenous malformations are not uncommon. Mutations in the ENG, ACVRL1 and MADH4 genes account for 97% of all HHT cases, and it is recommended that genetic tests are used in combination with the clinical Curaçao criteria to confirm the diagnosis. HHT can be complicated by significant pulmonary vascular disease including pulmonary arteriovenous malformations, pulmonary arterial hypertension and high output cardiac failure. These are associated with substantial morbidity and mortality and therefore timely diagnosis is important to mitigate complications and optimise preventative strategies. This article outlines important advances in our understanding of the pathobiology of HHT and current recommendations regarding the diagnosis and screening of HHT with a specific focus on adult patients with pulmonary vascular disease. Important therapeutic advances, novel therapies on the horizon and unmet needs are also explored.

Keywords: bevacizumab; hereditary haemorrhagic telangiectasia; pulmonary arterial hypertension; pulmonary vascular disease.

Figure 1

Molecular pathways in HHT. Figure 1 outlines important ligands, receptors and intracellular signalling molecules which are implicated in the pathobiology of HHT. BMP9 ligands, which are encoded by GDF2, bind to cell surface receptors such as endoglin. Endoglin acts as an auxiliary receptor and promotes signalling via ALK1. This promotes phosphorylation of SMAD 1/5/8, which forms a complex with SMAD 4 (encoded by MADH4) and translocates to the nucleus to modify gene expression. Abbreviations: BMP9: bone morphogenetic protein‐9, ALK1: activin receptor‐like kinase‐1, SMAD: suppressors of mothers against decapentaplegic 4, GDF2: Growth differentiation factor 2. Created with Biorender. com.

Figure 2

Pulmonary vascular complications. Figure 2 outlines important pulmonary vascular complications in HHT, which are described in greater detail in the manuscript. Abbreviations: TTCE: Transthoracic contrast echocardiogram, Echo: echocardiogram, RHC: right heart catheterisation, PAH: pulmonary arterial hypertension, HOCF: high output cardiac failure, AVMs: arteriovenous malformation, Liver VMs: liver vascular malformations, OLT: orthotopic liver transplantations. Created with Biorender. com.

Figure 3

Illustrates echocardiographic, CT and pulmonary angiogram features of PAVMs in subjects with HHT. Figure 3A: Apical 4‐chamber view from patient with newly‐diagnosed HHT with an endoglin mutation, following agitated saline injection, demonstrating opacification of right‐sided chambers. Figure 3B: Moderate number of bubbles seen in the left heart after 4 cardiac cycles, consistent with an intrapulmonary shunt. Figure 3C: High Resolution CT from the same patient demonstrating small right middle and left lower lobe PAVMs (arrows). The patient was referred for consideration of PAVM embolization. Figure 3D: Pulmonary angiogram of large left lower lobe PAVM in an 18‐year‐old with known HHT and endoglin mutation, pre‐ and post‐embolization with multiple microvascular plugs. Figures E‐G: CT pulmonary angiogram images of a 34‐year‐old with known HHT with ACRVL1 mutation who developed exertional dyspnoea over the period of 1 year. Figure 3E: Dilated main pulmonary artery. Figure 3F: Dilated right heart chambers with a non‐dilated left atrium. Figure 3G. Right lower lobe PAVM (arrow). Subsequent right heart catheterisation demonstrated pre‐capillary pulmonary hypertension with mean right atrial pressure 9 mmHg, mean pulmonary arterial pressure 60 mmHg, pulmonary arterial wedge pressure 10 mmHg, cardiac output 4.9 L/min, cardiac index 2.7 L/min/m² and pulmonary vascular resistance of 10.2 WU. The patient responded to dual oral combination therapy with the subsequent addition of an IP prostacyclin receptor agonist. The PAVM was subsequently closed with no evidence of cardiovascular deterioration. Abbreviations: RV, right ventricle; RA, right atrium; LV, left ventricle; LA, left atrium; AA, ascending aorta; PA, pulmonary artery; DA, descending aorta; PV, pulmonary vein; PAVM, pulmonary arteriovenous malformation.

Figure 4

Describes a case of HOCF associated with liver VMs and severe anaemia. Figure 4A: CT demonstrating a dilated main pulmonary artery. Figure 4B: CT image shows mild dilatation of the right ventricle. Figure 4C: CT demonstrates bi‐atrial enlargement and shows a right effusion (transudate). Figure 4D: CT demonstrates evidence of multiple hepatic vascular malformations. Figure 4E: Echocardiogram apical 4‐chamber view shows bi‐atrial and right ventricular dilatation. Figure 4F: Images from capsule endoscopy demonstrate multiple small bowel angioectasia. Figure 4F‐H: illustrate significant improvements in NT‐proBNP, haemaglobin and incremental shuttle walking distance following initiation of bevacizumab (red arrow). Abbreviations: RV, right ventricle; RA, right atrium; LV, left ventricle; LA, left atrium; SVC, superior vena cava; AA, ascending aorta; PA, pulmonary artery; DA, descending aorta; ISWD, incremental shuttle walking distance.

Figure 5

A case of PAH‐HHT and recurrent gastrointestinal bleeds which responded to bevacizumab. Figure 5A: CT thorax demonstrating a dilated right heart with compression of the intraventricular septum and left ventricular cavity in a patient with PAH‐HHT. Figure 5B highlights the reverse Potts shunt (red arrow) and dilated pulmonary artery. Figure C illustrates a rise in haemoglobin following the initiation of bevacizumab, with subsequent stabilisation. Abbreviations: RV, right ventricle; RA, right atrium; LV, left ventricle; PA, pulmonary artery.