No abstract

Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is caused by mutations in genes involved in the transforming growth factor beta (TGF-β) signaling pathway (ENG, ACVRL1, and SMAD4). Yet, approximately 15% of individuals with clinical features of HHT do not have mutations in these genes, suggesting that there are undiscovered mutations in other genes for HHT and possibly vascular disorders with overlapping phenotypes. The genetic etiology for 191 unrelated individuals clinically suspected to have HHT was investigated with the use of exome and Sanger sequencing; these individuals had no mutations in ENG, ACVRL1, and SMAD4. Mutations in BMP9 (also known as GDF2) were identified in three unrelated probands. These three individuals had epistaxis and dermal lesions that were described as telangiectases but whose location and appearance resembled lesions described in some individuals with RASA1-related disorders (capillary malformation-arteriovenous malformation syndrome). Analyses of the variant proteins suggested that mutations negatively affect protein processing and/or function, and a bmp9-deficient zebrafish model demonstrated that BMP9 is involved in angiogenesis. These data confirm a genetic cause of a vascular-anomaly syndrome that has phenotypic overlap with HHT.

Liver transplant (LT) candidates today are older, have greater medical severity of illness, and have more cardiovascular comorbidities than ever before. In addition, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Cirrhotic cardiomyopathy, a condition characterized by increased cardiac output and a reduced ventricular response to stress, is present in up to 30% of patients with cirrhosis, thus challenging perioperative management. Current noninvasive tests that assess for subclinical coronary and myocardial disease have low sensitivity, and altered hemodynamics during the LT surgery can unmask latent cardiovascular disease either intraoperatively or in the immediate postoperative period. Therefore, this review, assembled by a group of multidisciplinary experts in the field and endorsed by the American Society of Transplantation Liver and Intestine and Thoracic and Critical Care Communities of Practice, provides a critical assessment of the diagnosis of cardiac and pulmonary vascular disease and interventions aimed at managing these conditions in LT candidates. Key points and practice-based recommendations for the diagnosis and management of cardiac and pulmonary vascular disease in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.

Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension associated with portal hypertension with or without evidence of an underlying liver disease. Despite the potential for curing PoPH with liver transplantation, the presence of moderate or severe PoPH is associated with increased morbidity and mortality and is, therefore, a contraindication to transplantation. Previous studies have predominantly used intravenous epoprostenol for treatment in order to qualify patients for liver transplantation. In this retrospective case series, we describe the clinical course of 11 patients whom we successfully treated (predominantly with oral sildenafil and subcutaneous treprostinil) in order to qualify them for liver transplantation. The mean pulmonary artery pressure significantly improved from 44 to 32.9 mm Hg, and the pulmonary vascular resistance decreased from 431 to 173 dyn second cm À5 . There were significant improvements in the cardiac output and the transpulmonary gradient with these therapies as well. All 11 patients subsequently received liver transplants with a 0% mortality rate to date; the duration of follow-up ranged from 7 to 60 months. After transplantation, 7 of the 11 patients (64%) were off all pulmonary vasodilators, and only 2 patients required transiently increased doses of prostacyclins. In conclusion, an aggressive approach to the treatment of PoPH with sildenafil and/or treprostinil and subsequent liver transplantation may be curative for PoPH in some patients. Liver Transpl 18:686-695, 2012. V C 2012 AASLD.Received September 23, 2011; accepted February 2, 2012.Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension associated with portal hypertension with or without evidence of an underlying liver disease. It is defined as a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg, a pulmonary vascular resistance (PVR) greater than