Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output.

CONTEXT: The only treatment available to restore normal cardiac output in patients with hereditary hemorrhagic telangiectasia (HHT) and cardiac failure is liver transplant. Anti-vascular endothelial growth factor treatments such as bevacizumab may be an effective treatment. OBJECTIVES: To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and quality of life. DESIGN, SETTING, AND PATIENTS: Single-center, phase 2 trial with national recruitment from the French HHT Network. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT. INTERVENTION: Bevacizumab, 5 mg per kg, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed up for 6 months after the beginning of the treatment. MAIN OUTCOME MEASURE: Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography. RESULTS: A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for reread, there was a response in 20 of 24 patients with normalization of cardiac index (complete response [CR]) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m(2) (range, 4.1-6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m(2) (range, 2.9-5.2; P < .001). Median cardiac index at 6 months was significantly lower than before treatment (4.1 L/min/m(2); range, 3.0-5.1). Among 23 patients with available data at 6 months, we observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 minutes per month (range, 0-947) at inclusion, had significantly decreased at 3 months (134 minutes; range, 0-656) and 6 months (43 minutes; range, 0-310) (P = .008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated. CONCLUSION: In this preliminary study of patients with HHT associated with severe hepatic vascular malformations and high cardiac output, administration of bevacizumab was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00843440.

Long-term outcome of patients with hereditary hemorrhagic telangiectasia and severe hepatic involvement after orthotopic liver transplantation: a single-center study.

Hepatic involvement occurs in up to 74% of patients with hereditary hemorrhagic telangiectasia (HHT) and is characterized by a spectrum of arteriovenous malformations. Three different types of intrahepatic shunting may be present: hepatic artery to hepatic veins, hepatic artery to portal vein, and portal vein to hepatic vein. Hepatic involvement in HHT may lead to biliary ischemia, portal hypertension, or high-output cardiac failure (HOCF). Orthotopic liver transplantation (OLT) has been proposed as the only definitive curative treatment. The aim of this study was to evaluate the long-term outcome of patients with hepatic involvement due to HHT after OLT with respect to mortality, cardiac and hepatic status, epistaxis, and quality of life. Patients with HHT and severe hepatic vascular malformations who underwent OLT in the Lyon Liver Transplant Unit (LLTU) from 1993 to 2007 were followed at the LLTU and the French Reference Center for HHT. Quality of life was evaluated with the Short Form 36 questionnaire. There were 13 patients who fulfilled the entry criteria of the study (12 women and 1 man). The mean age at the time of OLT was 51.8 years (range = 33-65 years). Indications for OLT were cardiac failure (n = 9), biliary necrosis (n = 2), both cardiac failure and biliary necrosis (n = 1), and hemobilia (n = 1). The mean duration of follow-up was 109 months (range = 1-200 months). Twelve patients (92.3%) are still alive. For the 9 patients with HOCF, the mean cardiac index decreased from 5.4 L/minute/m(2) before OLT to 3.0 L/minute/m(2) after OLT. No severe hepatic complications were observed after OLT. Nine of the surviving patients (75%) experienced dramatic improvements in epistaxis and quality of life, including an ability to undertake more physical activity. In conclusion, OLT is an important therapeutic option for patients with HHT who have severe hepatic involvement. In the reported cohort, the mortality after OLT for this indication was low.

Pulmonary hypertension subtypes associated with hereditary haemorrhagic telangiectasia: Haemodynamic profiles and survival probability.

BACKGROUND: Different pulmonary hypertension (PH) mechanisms are associated with hereditary haemorrhagic telangiectasia (HHT). METHODS AND RESULTS: We conducted a retrospective study of all suspected cases of PH (echocardiographically estimated systolic pulmonary artery pressure [sPAP] ≥ 40 mmHg) in patients with definite HHT recorded in the French National Reference Centre for HHT database. When right heart catheterization (RHC) was performed, PH cases were confirmed and classified among the PH groups according to the European guidelines. Among 2,598 patients in the database, 110 (4.2%) had suspected PH. Forty-seven of these 110 patients had RHC: 38/47 (81%) had a confirmed diagnosis of PH. The majority of these had isolated post-capillary PH (n = 20). We identified for the first time other haemodynamic profiles: pre-capillary pulmonary arterial hypertension (PAH) cases (n = 3) with slightly raised pulmonary vascular resistances (PVR), and combined post- and pre-capillary PH cases (n = 4). Compared to controls, survival probability was lower in patients with PAH. CONCLUSION: This study revealed the diversity of PH mechanisms in HHT. The description of combined post- and pre-capillary PH with/or without high cardiac output (CO) suggests either a continuum between the pre- and post-capillary haemodynamic profiles or a different course in response to high CO.

Evolution of spontaneous atherosclerotic plaque rupture with medical therapy: long-term follow-up with intravascular ultrasound.

BACKGROUND: Ruptured coronary atheromatous plaque is generally considered to involve a high risk of subsequent clinical events. Few data are available on the natural evolution of non-culprit-lesion ruptured plaque. We therefore used serial intravascular ultrasound (IVUS) to study how such lesions, detected in the context of a first acute coronary syndrome with elevated troponin I levels, develop. METHODS AND RESULTS: Fourteen patients with 28 distinct plaque ruptures (2+/-1 per patient) without significant associated stenosis (minimal lumen cross-sectional area >4 mm2) were included and systematically treated with 40 mg statin and antiplatelet agent (clopidogrel and aspirin for > or =9 months). Mean clinical and IVUS follow-up was 22+/-13 months (median, 22 months). No clinical event related to the lesion under study occurred. On final IVUS examination, half (14 of 28) of the ruptured plaques had healed, and the degree of stenosis tended to diminish (stenosis, 22+/-17% versus 29+/-17% at baseline; P=0.056). No healing-prediction criterion could be identified. CONCLUSIONS: Nearly 2 years of follow-up found that spontaneous coronary atheromatous plaque rupture without significant stenosis detected on first acute coronary syndrome healed without significant plaque modification in 50% of cases with medical therapy.

Dose - response relationship of bevacizumab in hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder associated with epistaxis and hepatic shunts, is responsible for high-output cardiac failure in rare cases. Bevacizumab, which targets vascular endothelial growth factor, was shown to decrease both cardiac index (CI) and epistaxis duration in HHT patients with severe liver involvement. The relationship between its serum concentration and change in both CI and epistaxis duration was investigated to design the bevacizumab maintenance dosing regimen of future therapeutic studies. Twenty-five HHT patients with dyspnea and high CI were included in a prospective non-comparative study. They received bevacizumab at a dose of 5 mg/kg per infusion every 14 days for a total of 6 injections. The relationships between bevacizumab serum concentration and both CI and epistaxis duration were described using transit compartments and direct inhibition pharmacokinetic-pharmacodynamic models. The performances of different maintenance regimens were evaluated using simulation. Infusions every 3, 2 and one months were predicted to maintain 41%, 45% and 50% of patients with CI <4 L/min/m(2) at 24 months, respectively. The fraction of patients with <20 min epistaxis per month was predicted to be 34%, 43% and 60%, with infusion every 3, 2 or one months, respectively. Simulations of the effects of different maintenance dosing regimens predict that monthly 5 mg/kg infusions of bevacizumab should allow sustained control of both cardiac index and epistaxis.

[Diagnosis of systolic heart failure]. / Diagnostic de l'insuffisance cardiaque systolique.

Most of patients with heart failure present a left ventricular systolic dysfunction usually, if not always, associated with a diastolic dysfunction. Clinical manifestations and physical examination allows a presumed diagnosis. Some signs guide toward a systolic heart failure: deviation of cardiac impulse, protodiastolic gallop, functional mitral insufficiency, radiological cardiomegaly associated with signs of postcapillary hypertension, anterior Q wave or complete left bundle branch block. Bed-side dosage of B-type natriuretic peptide is useful to make or exclude the diagnosis of heart failure in patients with acute dyspnea from various causes. Doppler echocardiography is essential to confirm the left ventricular systolic dysfunction and its mechanism: ischemic, valvular or myocardial. The value of shortening fraction is better than eye evaluation. Coronary angiography is indicated when the mechanism of heart failure is unclear and if the patient is relevant to revascularization.

Hereditary hemorrhagic telangiectasia, liver vascular malformations and cardiac consequences.

BACKGROUND: HHT patients with liver vascular malformations (VMs) may develop high-output cardiac failure requiring liver transplant in few cases. OBJECTIVE: Our aim is to show that echocardiography is a good tool to evaluate the severity of hepatic vascular malformations in HHT and can improve medical management in HHT patients. METHODS: The study is a cross-sectional study of cardiac parameters in HHT patients with dyspnea in a single referral center. All HHT patients with dyspnea, consecutively seen at HHT reference center in Lyon between May 2007 and November 2009 were included and had hepatic vascular Ultrasound and Echocardiography. Echocardiographic measures included cardiac output (CO) and index (CI), left ventricle (LV) filling pressures, and pulmonary artery pressure. Then, patients were classified in 4 groups according to the severity: group 1 (normal values), group 2 with isolated high CI, group 3 with high CI and increased LV-filling pressures and group 4 with increased LV-filling pressures and pulmonary hypertension. RESULTS: Fifty-two HHT-patients were analyzed. Eight patients were in group 1, 25 in group 2, 6 in group 3 and 13 in group 4. Age, NYHA class dyspnea, edema, atrial fibrillation, hepatic artery diameter, and BNP (brain natriuretic peptide) levels significantly increased from groups 1 to 4 as well as left atrial area, and presence of mitral regurgitation. Patients with associated pulmonary VMs (n=11) did not show any clinical or echocardiographic differences. CONCLUSION: Performing echocardiography in HHT patients with dyspnea allowed us to better understand the physiological processes of high-CO failure complicating liver vascular malformations and may improve follow-up of patients and treatment decisions.