Alain Fraisse

Clinical Outcomes of Pulmonary Arterial Hypertension in Patients Carrying an ACVRL1 (ALK1) Mutation

RATIONALEnActivin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a cause of hereditary hemorrhagic telangiectasia (HHT) and/or heritable pulmonary arterial hypertension (PAH).nnnOBJECTIVESnTo describe the characteristics of patients with PAH carrying an ACVRL1 mutation.nnnMETHODSnWe reviewed clinical, functional, and hemodynamic characteristics of 32 patients with PAH carrying an ACVRL1 mutation, corresponding to 9 patients from the French PAH Network and 23 from literature analysis. These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation). Distribution of mutations in the ACVRL1 gene in patients with PAH was compared with the HHT Mutation Database.nnnMEASUREMENTS AND MAIN RESULTSnAt diagnosis, ACVRL1 mutation carriers were significantly younger (21.8 +/- 16.7 yr) than BMPR2 mutation carriers and noncarriers (35.7 +/- 14.9 and 47.6 +/- 16.3 yr, respectively; P < 0.0001). In seven of the nine patients from the French PAH Network, PAH diagnosis preceded manifestations of HHT. ACVRL1 mutation carriers had better hemodynamic status at diagnosis, but none responded to acute vasodilator challenge and they had shorter survival when compared with other patients with PAH despite similar use of specific therapies. ACVRL1 mutations in exon 10 were more frequently observed in patients with PAH, as compared with what was observed in the HHT Mutation Database (33.3 vs. 5%; P < 0.0001).nnnCONCLUSIONSnACVRL1 mutation carriers were characterized by a younger age at PAH diagnosis. Despite less severe initial hemodynamics and similar management, these patients had worse prognosis compared with other patients with PAH, suggesting more rapid disease progression.

Outcome of acute fulminant myocarditis in children

Objectives: To highlight clinical features and outcome of acute fulminant myocarditis (AFM) in children. Methods: Diagnostic criteria were (1) the presence of severe and acute heart failure; (2) left ventricular dysfunction on echocardiography; (3) recent history of viral illness; and (4) no history of cardiomyopathy. Results: Eleven children were included between 1998 and 2003, at a median age of 1 (0 to 9) year. Their mean left ventricular ejection fraction (LVEF) was 22 (SD 9)% at presentation. A virus was identified in five patients: human parvovirus B19 (n u200a=u200a 2), Epstein–Barr (n u200a=u200a 1), varicella zoster (n u200a=u200a 1), and coxsackie (nu200a=u200a1). The median intensive care unit course was 13 (2–34) days. Intravenous inotropic support was required by nine patients and eight were mechanically ventilated. All patients received corticosteroid, associated with intravenous immunoglobulin in seven. Five patients experienced cardiocirculatory arrest that was successfully resuscitated in four. At a median follow up of 58.7 (33.8–83.1) months, the 10 survivors are asymptomatic with normalised LVEF. Conclusion: Despite a severe presentation, the outcome of AFM is favourable. Aggressive symptomatic management is warranted and heart transplantation should be considered only when maximal supportive therapy does not lead to improvement.

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

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 parents and clinicians 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 tolerated.

Pulmonary atresia with ventricular septal defect, extremely hypoplastic pulmonary arteries, major aorto–pulmonary collaterals

OBJECTIVEnAmong 63 patients with pulmonary atresia and ventricular septal defect (VSD), 10 patients with extreme hypoplasia of the pulmonary arteries (PA) (mean Nakata index 20.6 mm(2)/m(2)), but with confluent arteries and a diminutive main PA, and major aorto-pulmonary collaterals (MAPCAS), have been submitted to a rehabilitation of the PA with several stages: (i) connection between RV and PAs, (ii) interventional catheterizations, (iii) complete correction with or without unifocalisation. We report here the results of this approach.nnnMETHODSnThe RV-PA connection was direct (nine cases) or with an homograft conduit (one case), done under normothermic cardiopulmonary by-pass in patients aged 4.9 months (range 0.1-18 months). Subsequently, six underwent interventional catheterizations (dilations and stents in the PA, MAPCAS occlusion by coils). Complete correction was done in seven patients (mean age 30 months, range 8-49). One patient is awaiting correction.nnnRESULTSnOne patient died after the first stage. All patients having had the third stage had a satisfactory development of the PA, had a complete closure of the VSD and a satisfactory reconstruction of the PA bifurcation. There was one death of severe pulmonary infection 6 months after repair. All other patients have been followed by catheterization and/or echocardiograms. With a follow-up of 83+/-65 months, all patients are improved, 50% have no cardiac medications, none has residual shunt, RV/LV pressure ratio is 0.6 (range 0.3-1).nnnCONCLUSIONSnThe strategy of rehabilitation of PA allowing: (i) antegrade flow in the PA, (ii) interventional catheterizations, (iii) growth of the PA with possible angiogenesis, (iv) complete correction, is a logical approach to be undertaken in the young patient and is a valid alternative to strategies relying more on MAPCAS for pulmonary vascular supply. The therapeutic sequences depend upon the individual anatomy.

Successful Use of Covered Stent to Treat Superior Systemic Baffle Obstruction and Leak After Atrial Switch Procedure

Progressive dyspnea and cyanosis occurred in a 41-year-old patient status after Mustard atrial switch repair for transposition of great arteries. Cardiac catheterization and magnetic resonance imaging revealed the association of superior limb systemic venous baffle obstruction and leaks with right-to-left shunting. He underwent successful dilation of the venous channel and obstruction of baffle leaks by using a covered stent.

Complete Atrioventricular Canal Repair Under 1 Year: Rastelli One-Patch Procedure Yields Excellent Long-Term Results

BACKGROUNDnConsidering more recently proposed techniques, we have evaluated our midterm and long-term results of Rastelli one-patch repair in complete atrioventricular canal.nnnMETHODSnBetween 1984 and 2005, 107 patients with a complete atrioventricular canal underwent a Rastelli one-patch procedure. Two groups were identified: 1984 to 1995 and 1995 to 2005 (respectively, 56 and 51 patients). Mean age at surgery was 5.3 +/- 3.4 months; mean weight was 5.5 +/- 3 kg; trisomy 21 was present in 81 patients; complete atrioventricular canal type A was found in 67 patients, type C in 40 patients. There were 12 cases of potentially parachute mitral valve and 14 associated anomalies treated simultaneously (pulmonary obstruction 11, coarctation 3). The coronary sinus was always left on the right side. After functional and anatomic evaluation, the cleft was closed completely in 8 and partially in 29, and was left intact in 70 cases.nnnRESULTSnEarly survival was 86% +/- 3%. Five patients underwent early reoperation for residual ventricular septal defect (n = 2) and mitral valve repair (n = 3). Nine patients underwent late reoperations with successful repair: subaortic stenosis (n = 4) and mitral valve repair (n = 5). Late survival at 10 and 15 years was 84% +/- 3%. Freedom from reoperation for mitral regurgitation was 94% +/- 3% at 10 years, and 91% +/- 3% at 15 and 20 years. At last follow-up 30 patients had mild and 3 had moderate mitral regurgitation.nnnCONCLUSIONSnRastelli single-patch repair in complete atrioventricular canal is a safe and reproducible technique. Among survivors, freedom from late reoperation for mitral regurgitation is very satisfactory. A properly taught, learned, and transmitted Rastelli one-patch technique compares very well with any other proposed technique.

Use of Amplatzer Fenestrated Atrial Septal Defect Device in a Child with Familial Pulmonary Hypertension

In a 4.5-year-old child with refractory pulmonary arterial hypertension, we performed atrial septostomy with the application of an Amplatzer fenestrated device designed to maintain patency. Continuous intravenous epoprostenol infusion was started concomitantly. Forty-two months after the procedure, the patient had no recurrent syncope and remained in New York Heart Association functional class II. Fenestration of the atrial septum is feasible in children with pulmonary artery hypertension. No conclusion regarding the patient’s need for an atrial septal defect can be drawn since concomitant prostanoid therapy was administered. The long-term patency of the atrial communication needs further confirmation and the optimal timing for its application has to be determined.

Acute myopathy of intensive care in a child after heart transplantation

Purpose: Acute myopathy of intensive care has been described infrequently in children and never after organ transplantation. We report a case of acute myopathy of intensive care in a child after heart transplantation.Clinical features: An II-yr-old girl, with no previous medical history, developed acute cardiomyopathy leading to cardiac shock. Family history revealed four cases of unidentified myopathy and/or cardiomyopathy. Preoperatively, while muscle biopsy was near normal, myocardial biopsy revealed non specific mitochondrial disorders. A few days after heart transplantation, she developed acute hypotonia and flaccid quadriplegia, consistent with the diagnosis of acute myopathy of intensive care. Nerve conduction studies were normal, electromyography showed myopathic changes and a new muscle biopsy from quadriceps femoris showed severe loss of myosin filaments and ATPase activity in type 2 fibres. A large laboratory screening failed to demonstrate a metabolic disease or a known myopathy. Muscle strength recovered progressively in three weeks allowing home discharge. A few months later, she was free of symptoms and muscle biopsy showed full histopathological recovery.Conclusion: Acute myopathy of intensive care can occur in children after heart transplantation. It should be suspected in the presence of muscle weakness and difficulty in weaning from ventilatory support. Electromyography confirmed a myogenic process and muscle biopsy allowed diagnosis. Full clinical and histopathological recovery usually occur within three weeks.RésuméObjectif: La myopathie aiguë de réanimation a été rarement décrite en pédiatrie, et jamais après transplantation d’organe chez l’enfant. Nous rapportons un cas pédiatrique de myopathie aiguë de réanimation après transplantation cardiaque.Éléments cliniques: Une enfant de II ans, sans antécédent, est hospitalisée pour choc cardiogénique sur cardiomyopathie aiguë. Dans sa fratrie, on note l’existence de myopathies et de cardiomyopathies non déterminées. La biopsie musculaire préopératoire est normale et la biopsie myocardique montre des anomalies mitochondriales non spécifiques. Quelques jours après une transplantation cardiaque, elle présente une hypotonie globale avec tétraplégie flasque. Une myopathie aiguë de réanimation, évoquée devant des vitesses de conduction nerveuses normales et un tracé électromyographique montrant une atteinte musculaire, est confirmée par une biopsie musculaire montrant une perte des fibres de myosine par dépolymérisation, avec perte de l’activité ATPasique dans les fibres de type 2. La recherche élargie d’une myopathie chronique ou d’une maladie métabolique est négative. En quelques semaines, l’enfant a progressivement récupéré sa force musculaire. Une biopsie musculaire, réalisée à distance, montre une architecture musculaire et une activité enzymatique normales.Conclusion: Une myopathie aiguë de réanimation peut se développer chez le transplanté pédiatrique, puisque des facteurs favorisants sont utilisés pour l’immunosuppression. Elle doit être évoquée devant une faiblesse musculaire et des difficultés de sevrage de la ventilation artificielle. L’électromyogramme objective un processus myogénique et c’est la biopsie musculaire qui permet le diagnostic. La récupération de la force musculaire et histopathologique est obtenue en quelques semaines.

Early surgical removal of membranous ventricular septal device might allow recovery of atrio-ventricular block.

Complete atrio-ventricular heart block is a well-reported complication after percutaneous closure of perimembranous ventricular septal defects. The incidence seems to be higher than after surgical closure. Early heart block can be transient and pacemaker implantation is not always required. Late heart block is also described. We describe two patients who both presented with complete atrio-ventricular block 4 days after device insertion. Surgical device removal was followed by a rapid and complete recovery of the atrio-ventricular conduction. Surgical device removal should be considered in cases of subacute heart block, as removal might result in recovery of the atrio-ventricular conduction.

FUTURE-2: Results from an open-label, long-term safety and tolerability extension study using the pediatric FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion

BACKGROUNDnA novel formulation of bosentan was evaluated in children with pulmonary arterial hypertension (PAH) in FUTURE-1, which characterized its pharmacokinetic and clinical profile. The subsequent phase III, open-label, long-term extension study, FUTURE-2, aimed to provide long-term tolerability, safety and exploratory efficacy data.nnnMETHODSnChildren (≥2 and <12 years) with idiopathic or heritable PAH, who completed 12-week treatment in FUTURE-1 and for whom bosentan was considered beneficial were enrolled, and continued to receive bosentan 4 mg/kg twice-daily, which could be down-titrated to 2mg/kg if not tolerated. Safety and tolerability were evaluated via treatment-emergent adverse events (AEs), serious AEs, growth, and laboratory measurements. Exploratory efficacy endpoints included time to PAH worsening and long-term survival. All analyses were conducted on pooled data of both studies.nnnRESULTSn36 patients were enrolled in FUTURE-1 and 33 continued in FUTURE-2. The overall median duration of exposure to bosentan was 27.7 (range 1.9-59.6) months. Treatment-emergent AEs occurred in 32 (88.9%) patients; AEs considered treatment-related in 15 (41.7%) patients. Of 51 serious AEs, three were considered treatment-related: two incidences of reported PAH worsening and one of autoimmune hepatitis. Six deaths occurred; none were considered treatment-related. Kaplan-Meier event-free estimates of PAH worsening were 78.9% and 73.6% at 2 and 4 years, respectively.nnnCONCLUSIONSnThe pediatric bosentan formulation was generally well tolerated, its safety profile comparable to that of the adult formulation when used in children. The results are in line with the efficacy profile of bosentan in previous pediatric and adult PAH studies of shorter duration.