Different forms of pulmonary hypertension in a family with clinical and genetic evidence for hereditary hemorrhagic teleangectasia type 2.

Hereditary hemorrhagic telangiectasia (HTT) is an autosomal dominant disease, most frequently caused by a mutation in either ENG or ACVRL1, which can be associated with pulmonary arterial hypertension (PAH). In this report, we describe a new unpublished ACVRL1 mutation segregating in three members of the same family, showing three different types of pulmonary hypertension (PH) in the absence of BMPR2 mutations. The first patient has a form of heritable PAH (HPAH) in the absence of hepatic arteriovenous malformations (AVMs); the second one has a severe form of portopulmonary hypertension (PoPAH) associated with multiple hepatic AVMs; the third one has hepatopulmonary syndrome (HPS) with numerous hepatic arteriovenous fistulas and a form of post-capillary PH due to high cardiac output. In summary, a single mutation in the ACVRL1 gene can be associated, in the same family, with an extreme phenotypic variability regarding not only the clinical presentation of HHT but also the type of PH in the absence of BMPR2 mutations. More studies are needed to evaluate if this variability can be explained by the presence of additional variants in other genes relevant for the pathogenesis of HHT.

Prognostic stratification of patients with chronic systolic heart failure using biomarkers and Doppler echocardiography.

AIMS: To verify whether a combined assessment of left-ventricular filling pattern at Doppler echocardiography, plasma levels of brain natriuretic peptide (BNP) and high-sensitive troponin I (hsTnI) improves prognostic stratification in patients with chronic systolic heart failure. METHODS: Three predictors of prognosis were evaluated in 200 consecutive outpatients with heart failure and left-ventricular ejection fraction 35% or less: left-ventricular filling pattern at Doppler echocardiography, BNP plasma levels and hsTnI plasma levels. RESULTS: During a median follow-up period of 44 months, 15 deaths, two urgent cardiac transplantations, two episodes of ventricular fibrillation and 50 heart failure hospitalizations were observed. The end point of survival analysis was the composite of hard events and hospitalization for acute heart failure. At univariable analysis, the E-wave deceleration time at Doppler echocardiography and BNP plasma level on a continuous log-scale were significantly associated with event-free survival, whereas hsTnI plasma level was not statistically significant. A hierarchical multivariable analysis was performed including a restrictive left-ventricular filling pattern at Doppler as the first prognostic indicator; the subsequent addition of BNP plasma levels above 138  pg/ml (median value) and hsTnI above 0.018  ng/ml (median value) did not further improve prognostic stratification. CONCLUSION: A restrictive left-ventricular filling pattern at Doppler echocardiography is the most important prognostic indicator in chronic heart failure patients. Plasma levels of BNP and hsTnI do not provide additional relevant information to identify patients at higher risk of cardiovascular outcomes.