Hereditary haemorrhagic telangiectasia: novel cardiopulmonary insights

Abstract

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber (ROW) syndrome, is a genetic vascular disorder. The estimated worldwide prevalence is at least one in 5000 individuals, however large regional variance exists. HHT is characterised by abnormal direct artery-to-vein communications. These abnormal vascular structures range from small telangiectasia (dilated microvessels in skin and mucous membranes) to large arteriovenous malformations (AVMs) which occur predominantly in the liver, brain and lungs, but can theoretically grow in every organ. These AVMs cause shunting and carry the risk for paradoxical embolism and haemorrhage and are therefore associated with significant morbidity and potential severe complications. If untreated, life expectancy is significantly lower in HHT patients compared to their partners, but prevention of HHT complications with screening programs could improve life expectancy. HHT has an autosomal dominant pattern of inheritance with two main subtypes (including over 80% of all HHT patients); HHT type 1 (HHT1) and HHT type 2 (HHT2). HHT1 results from mutations in the ENG gene encoding the protein endoglin and HHT2 results from mutations in the activin receptor-like kinase (ACVRL1) gene, encoding the protein ALK-1. A third and more rare disease-causing mutation has been found in the SMAD4 gene, causing a combination of the juvenile polyposis syndrome and HHT. This thesis focuses on the different clinical aspects of HHT. Both new insights on the diagnostic use of transthoracic contrast echocardiography (TTCE) and disease associations are described. The main conclusions will be described below. (I) There is a good reproducibility of pulmonary right-to-left shunt (RLS) quantification using TTCE. (II) Growth of pulmonary RLS can be found in all HHT patients, therefore follow-up is important. However, in the subgroup of patients without pulmonary RLS at baseline, no treatable PAVMs were found at five years follow-up. (III) The presence of aortopathy is significantly increased in SMAD4 mutation carriers compared to the ENG and ACVRL carriers and non-HHT subjects. (IV) The prevalence of pulmonary hypertension (PH) is increased in HHT compared to HHT negative controls. This increase is most prominent in HHT type 2 and mainly results from the high cardiac output state associated with liver AVMs. Hereditary pulmonary arterial hypertension was rare in our cohort of HHT patients. However, since the prognosis of this disease combination is very poor, early recognition is important. (V) Percutaneous closure of the left atrial appendage may provide an alternative strategy to oral anticoagulation in HHT patients with atrial fibrillation induced high stroke risk. In conclusion, all the aspects mentioned above show the complexity of HHT, the inhomogeneity of the population and the need for multidisciplinary and specialised care. Clinicians should be aware of the possibility of different and potentially severe complications depending on HHT type. Echocardiography should be used to screen for PAVMs, is important for the follow-up of small pulmonary RLS and can be used to screen for othercomplications such as PH and aortic dilation.