Pulmonary Hypertension in a Large Cohort with Hereditary Hemorrhagic Telangiectasia

Abstract

Background: Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations in the brain, liver, and lungs. Pulmonary hypertension (PH) is increasingly recognized as a severe complication of HHT. However, there are no studies describing the prevalence of PH in HHT compared to HHT-negative controls. Objective: To assess the estimated prevalence of PH in patients with HHT compared to HHT-negative controls. Methods: All consecutive subjects screened for HHT with available genetic testing and echocardiography-based peak tricuspid regurgitation velocity (TRV) measurement were included. Increased-probability PH was defined as a TRV >2.8 m/s. Results: In 578 subjects, both echocardiography and genetic testing were available. A reliable TRV was measured in 383 (66.3%), of whom 127 had HHT type 1 (HHT1), 150 had HHT type 2 (HHT2), and 106 were HHT-negative controls, with a mean TRV of 2.3 ± 0.4, 2.4 ± 0.5, and 2.2 ± 0.3 m/s, respectively (p = 0.008 and p < 0.001 vs. controls). Increased-probability PH was found in 42 subjects (8.7% in HHT1, 18.0% in HHT2, and 3.8% in HHT-negative controls). HHT2 and hepatic arteriovenous malformations (HAVMs) were the most important predictors for increased-probability PH (odds ratio 5.6, p = 0.002, and odds ratio 11.3, p < 0.001, respectively). Heritable pulmonary arterial hypertension (HPAH) was diagnosed in 2 patients (0.7%) and only found in HHT2 (1.3%). Conclusion: The estimated prevalence of PH is higher in HHT patients compared to HHT-negative controls. This increase is especially present in HHT2 and mainly associated with the presence of HAVMs. HPAH appears to be rare in HHT patients and was only diagnosed in HHT2.

TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

“…Mutations in the type I receptor ALK1 and co-receptor endoglin are found in hereditary hemorrhagic telangiectasia (HHT)-associated PAH [ 35 , 36 ]. The increased prevalence of (h)PAH in HHT1 and HHT2 could be explained by the involvement of arteriovenous malformations, caused by ALK1 and ENG mutations, in the pathophysiology in both diseases [ 97 , 98 , 99 ]. Interestingly, in idiopathic PAH (iPAH) mRNA and protein levels of ALK1 and endoglin are specifically increased in ECs, leading to enhanced Smad1/5 phosphorylation (pSmad1/5) when stimulated with TGF-β, indicating a disturbed TGF-β/BMP balance [ 19 ].…”

Life expectancy and comorbidities in patients with hereditary hemorrhagic telangiectasia

“…Other studies estimated that the prevalence of pulmonary hypertension in patients with HHT to be up to 21%. 45,46 Unfortunately, pressure estimations and gradients calculated with the transthoracic echocardiography may be inaccurate. 47 Right heart catheterization might be necessary to confirm pulmonary hypertension.…”

Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia

“…Furthermore, all other forms of PH, not related to HHT, could exist in HHT patients as well. The overall occurrence of echocardiographic-based suspected PH in unselected HHT patients is found between 4% and 20% [ 45 , 54 , 56 , 81 ]. We previously described that RHC is indispensable in symptomatic cases since subclassification of PH is based on invasive measurement of haemodynamics.…”

“…We previously described that RHC is indispensable in symptomatic cases since subclassification of PH is based on invasive measurement of haemodynamics. Vorselaars et al described that age, hepatic AVMs and the ACVRL1 mutation are predictors for an increased TRV in HHT patients [ 54 ].…”