Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disease associated with mutations in genes encoding proteins of the transforming growth factor β (TGF-β) family, i.e. endoglin (ENG), activin receptor A (ACVRL1), and SMAD 4 (small mother against decapentaplegic 4). Mutations in any of these genes lead to the onset of arteriovenous malformations (AVMs). The clinical consequences of this syndrome are primarily AVM-associated complications.

Major cardiovascular consequences occur in the more advanced stages, but their prevalence is low. Most HHT patients are asymptomatic, and ischemic heart disease has a significantly lower prevalence than in the general population. The limited sample size of studies currently published in the literature makes it difficult to characterize any subclinical cardiovascular alterations in asymptomatic HHT subjects.

Alterations in TGF-β family proteins likely result in a protective effect on the coronary circulation against atherosclerosis. A thorough understanding of the potential protective factors against coronary artery disease, underlying HHT alterations, may allow the development of gene therapy models inspired by the HHT phenotype. Some manifestations of extracellular matrix remodelling at the tissue level (i.e. myocardial and valvular) may be more prevalent in HHT patients than in the general population. Finally, any subclinical alterations in cardiac function related to chronic anaemia and possible iron overload due to iron replacement therapy are not yet known.

Primary objective of the study will be to perform a complete echocardiographic characterization, using new imaging methods aimed at identifying even subclinical dysfunctions of cardiac mechanics, including a phenotyping of the morphology and function of the valvular systems, as well as paradoxical shunts.

Secondary objectives of the study will be: 1) To verify whether there are echocardiographic differences, related to extracellular matrix remodelling, in addition to the presence of shunts, between the various HHT genotypes and to identify any genotype-phenotype correlations. 2)To verify the impact of chronic anaemia and iron supplementation on cardiac mechanics in relation to possible genotype-phenotype interactions.

About study methodology, collection and analysis of clinical and echocardiographic data will be obtained from routine cardiac assessments performed as part of the HHT clinical-care pathway.

Inclusion Criteria:

• Patients > 10 years of age with a genetic diagnosis, i.e. a pathogenic mutation in the endoglin (ENG), activin receptor A (ACVRL1) or small mother against decapentaplegic (SMAD4) gene, and/or a clinically confirmed diagnosis of hereditary hemorrhagic teleangectasia (HHT) according to the Curaçao criteria
• Signed informed consent

Exclusion Criteria:

• Patients whose echocardiographic images are of suboptimal quality and cannot be adequately analysed.
• No signed informed consent

380 patients will be enrolled, approximately 30 of whom are between the ages of 10 and 18. These patients currently undergo echocardiography with bubble test for pulmonary arteriovenous malformation (AVM) screening, as part of the hereditary haemorrhagic telangiectasia (HHT) clinical care pathway and therefore as part of standard clinical practice. Pregnant women and paediatric patients (aged 10 and older) will constitute subgroups and will be analysed separately.