Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study

center dot Exposure to bosentan was lower in paediatric pulmonary arterial hypertension (PAH) patients treated with the marketed adult formulation at a dose of about 2 mg kg-1 when compared with adult PAH patients. center dot In healthy adult subjects, bosentan pharmacokinetics are less than dose-proportional at doses of >= 500 mg. WHAT THIS STUDY ADDS center dot The pharmacokinetics of a new paediatric bosentan formulation were characterized in paediatric PAH patients. center dot The level of exposure to bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing. center dot In paediatric PAH patients, nondose-proportional pharmacokinetics of bosentan occur at lower doses when compared with healthy adult subjects. AIM To show equivalent bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation. METHODS Thirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with bosentan 2 mg kg-1 b.i.d. and then for 8 weeks with 4 mg kg-1 b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent's and clinician's Global Clinical Impression scales. RESULTS Comparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration-time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg-1 were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in bosentan-naive patients, whereas the rare worsenings occurred in patients already on bosentan prior to study initiation. The paediatric formulation was well accepted and bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported. CONCLUSIONS Exposure to bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit-risk profile for bosentan at 2 mg kg-1 b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerate

Atrial Fibrillation Mechanisms and Implications for Catheter Ablation

AF is a heterogeneous rhythm disorder that is related to a wide spectrum of etiologies and has broad clinical presentations. Mechanisms underlying AF are complex and remain incompletely understood despite extensive research. They associate interactions between triggers, substrate and modulators including ionic and anatomic remodeling, genetic predisposition and neuro-humoral contributors. The pulmonary veins play a key role in the pathogenesis of AF and their isolation is associated to high rates of AF freedom in patients with paroxysmal AF. However, ablation of persistent AF remains less effective, mainly limited by the difficulty to identify the sources sustaining AF. Many theories were advanced to explain the perpetuation of this form of AF, ranging from a single localized focal and reentrant source to diffuse bi-atrial multiple wavelets. Translating these mechanisms to the clinical practice remains challenging and limited by the spatio-temporal resolution of the mapping techniques. AF is driven by focal or reentrant activities that are initially clustered in a relatively limited atrial surface then disseminate everywhere in both atria. Evidence for structural remodeling, mainly represented by atrial fibrosis suggests that reentrant activities using anatomical substrate are the key mechanism sustaining AF. These reentries can be endocardial, epicardial, and intramural which makes them less accessible for mapping and for ablation. Subsequently, early interventions before irreversible remodeling are of major importance. Circumferential pulmonary vein isolation remains the cornerstone of the treatment of AF, regardless of the AF form and of the AF duration. No ablation strategy consistently demonstrated superiority to pulmonary vein isolation in preventing long term recurrences of atrial arrhythmias. Further research that allows accurate identification of the mechanisms underlying AF and efficient ablation should improve the results of PsAF ablation

0386: Prevalence, characteristics and prognosis of moderate to severe tricuspid regurgitation in patients with precapillary pulmonary hypertension

BackgroundOur study aim to characterize clinical, biological, echocardio-graphic and hemodynamic parameters related with severity of TR and if TR is associated with higher risk of acute right ventricular heart failure (ARVHF) or death in PPH patiens.MethodsWe reviewed data from 116 stable patients referred to the French pulmonary hypertension referral center. All patients had right heart catheterization with mean pulmonary pressure (mPAP)>25mmHg, with pulmonary wedge pressure<15mmHg and pulmonary vascular resistance (PVR)>3 WU. On echo-cardiography, severity of TR was determined from 2-dimensional and Doppler color flow image in the apical 4-chamber view. Patients were divided in two groups according to the severity of TR (TR<grade 3 and TR≥grade 3).Results37 (32%) patients have TR grade≥3. Compared with patients TR<grade 3, no difference were observed in gender, NYHA class, and 6-minute walk distance. On RCH, both groups had similar mPAP, cardiac index, right atrial mean pressure and pulmonary vascular resistance. On echocardiography, Patients with TR grade≥3 have higher right atrial volume (57 (45-70) vs 36 (32-40)mL/m2, p<0.001), higher end-diastolic right ventricular area (16 (14-17) vs 14 (13-15)cm2/m2, p=0.04), higher end-systolic right ventricular area (12 (10-14) vs 10 (9-11)cm2/m2, p=0.01), and higher BNP level (248 (141-355) vs 102 (59-144)pg/mL, p=0.003). There were no difference in tricuspid annular plane systolic excursion nor in tricuspid S’ velocity. During a median follow up of 17 months, death or ARVHF was observed in 14% of patients with TR grade≥3 and 7% of patients with TR grade<3 with no statistical difference.ConclusionPPH patients with TR grade≥3 have higher right atrial volume, end-diastolic and end-systolic right ventricular area and BNP level compared with patients with TR<grade 3. There was more numerous major events in follow up in this group, without statistical difference

181 Identification of electrophysiological substrate for ventricular arrhythmias in patients with repaired tetralogy of Fallot

IntroductionPatients with repaired tetralogy of Fallot (TOF) represent a new category of patients referred to electrophysiology laboratory for ventricular arrhythmia (VA) mapping and ablation. Different anatomical regions have been identified as potentially responsible for reentry: ventricular septal defect (VSD) patch, surgical incisions, right ventricular outflow tract (RVOT) patch. We aimed to investigate electrophysiological substrate responsible for potential VA in patients with repaired TOF.MethodsAll patients with repaired TOF referred to the CHU de Bordeaux for VA evaluation from January 2008 to april 2010 underwent right ventricular (RV) 3D mapping. Sinus activation and voltage mapping was then performed before VA induction ± ablation.Results7 patients (4 male, 42,5±12 years old) underwent RV mapping during VA evaluation. Surgical repair of TOF had been realized 36±11 years before the procedure. All patients displayed a right bundle branch block on 12 lead electrocardiogram.Sinus rhythm RV activation begins in all patients in the septum and then activates the RV centrifugally with a zone of slow conduction with a double potential (100±30ms) going from the tricuspid annulus (TA) to the RVOT. Voltage maps (figure) show systematically the same pattern of a zone of low voltage (< 1.5mV) due to the VSD repair close to the RVOT scar area. This area fits with the slow conduction area. In the 2 patients with sustained ventricular tachycardia (VT), critical isthmus was located in this area.ConclusionsSpecific activation and voltage pattern was found in these Fallot patients. In the 2 patients with sustained VT, the critical isthmus was found between VSD repair patch and RVOT scar

Chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism and a major cause of chronic PH leading to right heart failure and death. Lung ventilation/perfusion scintigraphy is the screening test of choice; a normal scan rules out CTEPH. In the case of an abnormal perfusion scan, a high-quality pulmonary angiogram is necessary to confirm and define the pulmonary vascular involvement and prior to making a treatment decision. PH is confirmed with right heart catheterisation, which is also necessary for treatment determination. In addition to chronic anticoagulation therapy, each patient with CTEPH should receive treatment assessment starting with evaluation for pulmonary endarterectomy, which is the guideline recommended treatment. For technically inoperable cases, PH-targeted medical therapy is recommended (currently riociguat based on the CHEST studies), and balloon pulmonary angioplasty should be considered at a centre experienced with this challenging but potentially effective and complementary intervention.status: publishe

Sudden Cardiac Arrest: ECG Repolarization After Resuscitation.

International audienceSudden Cardiac Arrest and ECG Repolarization. Introduction: Early repolarization (ERep) abnormalities on electrocardiogram (ECG) are common immediately following cardiac arrest. We characterized and correlated electrocardiographic repolarization abnormalities immediately after cardiac arrest with acute coronary angiography. Methods and Results: We studied 225 consecutive patients presenting with out-of-hospital cardiac arrest. All these patients had successful cardiopulmonary resuscitation and acute coronary angiography. The first ECG recorded after successful resuscitation was analyzed by two independent cardiologists. Patients were categorized according to their repolarization pattern. Pattern 1: No ST segment elevation or ERep. Pattern 2: ST segment elevation without ERep. Pattern 3: ST segment elevation and ERep. Pattern 4: ERep only. Patterns 1, 2, 3, and 4 were found in 112 (50%), 74 (33%), 19 (8%), and 20 (9%) patients, respectively. Cardiac arrest was due to acute myocardial ischemia in 45%, 82%, 39%, and 15% of patients in groups 1, 2, 3 and 4, respectively (P < 0.0001). Sensitivity and specificity of pattern 2 was 50% and 88%, respectively, for acute coronary lesion, whereas isolated ERep pattern occurred in 9% of cases and was associated with a nonischemic event (80%). Among 65 patients (29%) who survived, 7% of patients with pattern 1, 13% with pattern 2, 60% with pattern 3, and 88% with pattern 4 exhibited ERep on ECG during the follow-up. Conclusion: In the context of cardiac resuscitation, an ECG with ST elevation favors acute myocardial infarction, whereas the presence of ERep is a marker of a nonischemic event and future ERep syndrome. (J Cardiovasc Electrophysiol, Vol. 22, pp. 131-136, February 2011)

Caractéristiques et suivi prospectif sur deux ans des enfants atteints d'hypertension artérielle pulmonaire

BACKGROUND: Limited data are available describing paediatric pulmonary arterial hypertension. AIMS: To characterize the epidemiology, management and impact on quality of life and outcome of paediatric pulmonary arterial hypertension, excluding persistent pulmonary hypertension of the newborn and pulmonary arterial hypertension caused by congenital heart disease. METHODS: In this multicentre study, children with pulmonary arterial hypertension were included and followed prospectively for two years at 21 referral centres in France. WHO functional class, 6-minute walk distance and quality of life (CHQ-PF50 questionnaire) were evaluated. RESULTS: Fifty children were included with a mean age of 8.9 +/- 5.4 years from May 2005 until June 2006. The estimated prevalence for pulmonary arterial hypertension was 3.7 cases/million. Patients had idiopathic pulmonary arterial hypertension (60%), familial pulmonary arterial hypertension (10%), pulmonary arterial hypertension associated with, but not caused by, congenital heart disease (24%), pulmonary arterial hypertension associated with connective tissue disease (4%) or portal hypertension (2%). During follow-up, the combination of pulmonary arterial hypertension-specific therapies was increasingly prescribed (44% patients versus 22% at inclusion). Patients remained stable regarding clinical status, 6-minute walk distance and quality of life. Survival estimates after one and two years were 86% (95% CI 76, 96) and 82% (95% CI 71, 93), respectively. CONCLUSIONS: In children, idiopathic/familial pulmonary arterial hypertension accounts for the majority of cases. A specific pulmonary arterial hypertension group in conjunction with congenital heart disease can be identified that resembles patients with idiopathic pulmonary arterial hypertension. Combined pulmonary arterial hypertension-specific therapies may have contributed to disease stability and favourable survival