Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension).

BACKGROUND: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. METHODS AND RESULTS: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 12 mmHg and pulmonary vascular resistance index [PVRI] of >3 WU × m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m(2,) 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001). CONCLUSION: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class.

[Congenital heart disease: from childhood to adulthood]. / Cardiopathie congénitale: de l'enfance à l'âge adulte.

With the improvement of congenital heart surgery, most children with congenital heart disease will survive into adulthood with a good quality of life. Regular cardiac follow-up is recommended for all patients. The adolescent period coincides often with medium and long term consequences and complications and repeat surgery or catheter interventions might be needed. It is therefore of prime importance to begin the transition process early and to pursue it well into adulthood. We have elaborated a formal transition program adapted to youngsters with congenital heart disease.

[Adults with congenital heart diseases: a growing population, a multidisciplinary approach]. / Cardiopathies congénitates de l'âge adulte: nouvelle population de patients, prise en charge multidisciplinaire.

Untill recently, congenital heart disease was considered as a childhood's disease. With improvement in pediatric survival, adults with a congenital heart disease (ACHD) represent an emerging group of patients who need specialized medical care. In 2010, the ESC published newguidelines on global and specific management of adults with congenital heart disease. ACHD centers organize appropriate medical care for these patients, promote specialist training and national scientific research in collaboration with other national ACHD centers.

[New treatments of pediatric pulmonary hypertension]. / Nouveaux traitements de l'hypertension pulmonaire en pédiatrie.

Pulmonary arterial hypertension is a serious condition, with an estimated prevalence of 4 children over a million. Symptoms of this condition are not specific, leading to a potential delay in the diagnosis. Treatment of pediatric pulmonary hypertension is currently based on adult guidelines, using new targeted therapies, separated in 3 main categories: Endothelin receptor antagonists, prostacyclin and analogues, and phosphodiesterase type 5 inhibitors. These therapies improve symptoms and survival, but neither of them can cure the condition. Various new molecules are being currently tested in children or in development, offering hope to further improve the prognosis of pulmonary arterial hypertension.

Novel approach to mitral valve repair in childhood dilated cardiomyopathy.

Evidence is mounting that mitral valve repair can improve symptoms in adults with dilated cardiomyopathy. Data is currently lacking for children with dilated cardiomyopathy and options for annuloplasty are limited in children. We report on the successful management of a 21 month-old child in heart failure from dilated cardiomyopathy and severe mitral regurgitation. The echocardiogram showed severely dilated left heart cavities, severe mitral regurgitation from a dilated annulus (23 mm, Z-score 1.74) with discrete anterior leaflet tethering, and moderate systolic dysfunction. The mitral valve was repaired using a 16 mm Bioring Kalangos biodegradable annuloplasty ring. The patient was extubated on the third postoperative hour and discharged on the fifth postoperative day with trivial mitral regurgitation and a 5 mmHg mean transvalvular gradient. At 12 months, the patient is in NYHA class I and presents trivial central mitral regurgitation without any transmitral gradient. This represents the first report in successfully managing a child with dilated cardiomyopathy with mitral regurgitation using a novel biodegradable annuloplasty ring, which has the potential to durably remodel the mitral annulus and grow with the patient.

Pulmonary arterial hypertension: a comparison between children and adults.

The characteristics of pulmonary arterial hypertension (PAH), including pathology, symptoms, diagnosis and treatment are reviewed in children and adults. The histopathology seen in adults is also observed in children, although children have more medial hypertrophy at presentation. Both populations have vascular and endothelial dysfunction. Several unique disease states are present in children, as lung growth abnormalities contribute to pulmonary hypertension. Although both children and adults present at diagnosis with elevations in pulmonary vascular resistance and pulmonary artery pressure, children have less heart failure. Dyspnoea on exertion is the most frequent symptom in children and adults with PAH, but heart failure with oedema occurs more frequently in adults. However, in idiopathic PAH, syncope is more common in children. Haemodynamic assessment remains the gold standard for diagnosis, but the definition of vasoreactivity in adults may not apply to young children. Targeted PAH therapies approved for adults are associated with clinically meaningful effects in paediatric observational studies; children now survive as long as adults with current treatment guidelines. In conclusion, there are more similarities than differences in the characteristics of PAH in children and adults, resulting in guidelines recommending similar diagnostic and therapeutic algorithms in children (based on expert opinion) and adults (evidence-based).

Issues related to the management and therapy of paediatric pulmonary hypertension.

An increasing number of medical services dedicated to the diagnosis, treatment and follow-up of pulmonary hypertension (PH) in children are being established. This has, in turn, increased the need to adapt current guidelines for the treatment of PH to be more relevant to paediatric patients with PH. This article will summarise the data obtained so far from paediatric registries, national cohorts and clinical trials and discuss the best approach for developing a treatment algorithm designed for children with different types of PH. The many unanswered questions, challenges and issues relating to the PH in the paediatric population will also be discussed.

Decreased bone turnover in children and adolescents with well controlled type 1 diabetes.

AIM: Osteoporosis is a common long-term complication of type 1 diabetes (T1DM). We aimed to determine whether bone mineral density (BMD) and turnover are already altered during childhood. PATIENTS AND METHODS: We recruited 27 T1DM children and 32 controls (age 10.5 +/- 2.5 yr.) and measured BMD (dual-energy x-ray absorptiometry); bone biomarkers levels (osteocalcin: OC; procollagen type 1 propeptides amino-terminal: PINP; crosslinking telopeptides of type 1 collagen C-terminal: CTX), glycated hemoglobin (HbA1c), dietary intake and physical activity. RESULTS: Patients with T1DM had lower levels of OC (70.3 +/- 3.3 vs 105.3 +/- 6.8), PINP (556.4 +/- 47.6 vs 716.3 +/- 53.8), CTX(0.97 +/- 0.07 vs 1.20 +/- 0.08), physical activity, and calcium intake. Biomarkers were negatively correlated with HbA1c. Though, BMD was similar among groups and not related to HbA1c, disease duration, physical activity or dietary intakes. CONCLUSIONS: Bone turnover is altered in T1DM children, whereas BMD remains normal during growth. Physical activity and optimal calcium intakes may improve bone metabolism and delay osteoporosis.

Biodegradable mitral annuloplasty for congenital ischemic mitral regurgitation.

An anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is associated with ischemic mitral regurgitation through a combination of papillary muscle ischemia or permanent fibrosis, left ventricular free wall ischemic dyskinesis and left ventricular dilatation. We report the successful management of a 27-month-old girl with ALCAPA and severe mitral regurgitation using a biodegradable mitral annuloplasty ring. It could represent a novel tool for mitral valve repair in ALCAPA-associated ischemic mitral regurgitation.

Paediatric pulmonary hypertension: monitoring progress and identifying unmet needs.

Recent advances in the field of pulmonary hypertension (PH) have provided clinicians with a range of treatment options, but effective disease management in children presents a unique challenge. The present article will discuss the steps being taken to address unmet needs in paediatric PH. Understanding the epidemiology of paediatric PH is essential to guide management decisions, but such epidemiological data are scarce. The first international paediatric PH registry, Tracking Outcomes in Paediatric Pulmonary Hypertension (TOPP), promises to become a vital resource. Studies of PH therapies are rare in children, and treatment of paediatric PH is generally guided by the adult treatment algorithm, with some adaptations. However, invasive management options, such as continuous prostacyclin infusion, even if effective, are challenging in children, and further research is required to develop appropriate treatment strategies, formulations and doses for paediatric PH. Measures of treatment success must also be defined, and the applicability of end-points from adult clinical studies remains an open question. In summary, further epidemiological and treatment data are needed for paediatric pulmonary hypertension. The international TOPP registry will provide a valuable insight, but this must be complemented by research and development of adapted paediatric therapies. Dedicated childhood pulmonary hypertension services would optimise the diagnosis and management of this life-threatening disease.

Pulmonary arterial hypertension in paediatric and adult patients with congenital heart disease.

Pulmonary arterial hypertension (PAH) commonly arises in patients with congenital heart disease (CHD). Greater numbers of patients with PAH associated with CHD (PAH-CHD) are now surviving into adulthood, many with increasingly complex cardiac defects. Patients with cardiac defects which result in left-to-right shunting are at risk of developing PAH, owing to the increased shear stress and circumferential stretch induced by increased pulmonary blood flow, which leads to endothelial dysfunction and progressive vascular remodelling and, thus, increased pulmonary vascular resistance. Although PAH-CHD shares similar lung histology with idiopathic PAH, differences do exist between these aetiologies. Management of PAH-CHD can involve surgical correction of the cardiac defect and/or treatment of the PAH, depending on the underlying cardiac defect and status of disease progression. Transplantation surgery can be curative but is not without limitations. The timing of intervention in patients with PAH-CHD is important, but the optimums are sometimes difficult to define, with limited robust data to inform management decisions. Uncontrolled studies suggest that prostacyclin analogues and phosphodiesterase type-5 inhibitors may have benefits in advanced pulmonary vascular disease. In the only randomised controlled trial dedicated to end-stage PAH-CHD, bosentan significantly reduced pulmonary vascular resistance and significantly increased 6-minute walk distance without compromising peripheral oxygen saturation, in patients with Eisenmenger syndrome. These data suggest that targeted therapies are beneficial in the PAH-CHD population, and warrant further research.

[Pulmonary arterial hypertension in children: new therapeutic approaches]. / Hypertension artérielle pulmonaire chez l'enfant: nouveautés dans la prise en charge.

Pulmonary arterial hypertension (PAH) contributes significantly to the morbidity and mortality of diverse cardiopulmonary disorders in paediatrics. The treatment of PAH has dramatically changed over the last decade. A better understanding of the pathophysiological mechanisms has lead to the introduction of several new therapies both in the field of idiopathic and familial PAH or PAH associated with underlying conditions (i.e. congenital heart disease, connective tissue disease, HIV) as well as in the field of acute PAH. The endothelial dysfunction, considered a one of the striking problems of this disease, is characterized by a decreased production of vasodilatory-antiproliferative substances (prostacyclins, nitric oxide) and increased production of vasoconstrictive-proliferative substances (endothelin, thromboxanes). It is currently possible to try to palliate to these deficits by administering prostacyclins or nitric oxide, as well as antagonizing the effect of endothelin through endothelin receptor antagonists. These progresses have first appeared in the adult population but have been rapidly applied to the paediatric population. This short review will discuss these new therapeutic approaches and refers to several large reviews recently published for a more comprehensive description.

Successful use of a new Amplatzer Vascular plug for percutaneous closure of a large aortopulmonary collateral artery in a pulmonary atresia with ventricular septal defect prior to complete repair.

We report the case of a 14 year-old girl with a pulmonary atresia with VSD and multiple aortopulmonary collaterals who underwent a successful complementary occlusion of a large collateral vessel using an Amplatzer vascular plug after a previously failed attempt of occlusion with a coil. The percutaneous procedure, performed from the femoral artery before the complete surgical repair, provided an immediate closure of the vessel. This new device is safe and effective for the occlusion of aortopulmonary collaterals, specifically if of large dimensions.

[Pulmonary hypertension associated with congenital heart disease]. / Hypertension artérielle pulmonaire des cardiopathies congénitales.

INTRODUCTION: Congenital heart diseases are among the most common congenital malformations at birth with an incidence of 8/1,000 live births. These defects are characterized by a heterogeneous group of abnormal defects and connections between the cardiac chambers and vessels with different haemodynamic consequences and hence, varying need for follow-up and interventions. The most common forms are congenital cardiac shunts (i.e.: ventricular septal defects, atrial septal defects, patent ductus arteriosus) that account for almost 60% of the malformations. STATE OF THE ART: Pulmonary hypertension remains a major complicating factor of many types of congenital heart disease characterized by a systemic to pulmonary shunt either by causing increased morbidity and mortality during or immediately after surgical repair, or even preventing complete repair for those with advanced pulmonary vascular disease. Similarities in histological lesions between congenital heart disease and idiopathic pulmonary arterial hypertension suggest similarities in pathobiological pathways and thus pulmonary arterial hypertension associated with congenital cardiac shunt has been classified in the group 1 of the classification of Venice. Even if these complex mechanisms are not completely elucidated, the role of hemodynamics (shear stress) in the development of pulmonary vascular disease has been clearly demonstrated. PERSPECTIVES AND CONCLUSION: Until recently, patients with advanced pulmonary vascular disease following congenital systemic to pulmonary shunt had no specific treatment and were managed empirically. Because of the similarities with idiopathic pulmonary arterial hypertension the use of novel therapies suggest new therapeutic possibilities for these patients. Randomized controlled trials are definitely needed to evaluate the safety and efficacy of these therapies in this very particular group of patients, both in the short and long term.

Current treatment options in children with pulmonary arterial hypertension and experiences with oral bosentan.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by vasoconstriction and progressive remodelling of the pulmonary arterial wall leading to right ventricular failure and death. Idiopathic PAH (IPAH) and PAH associated with congenital heart defects account for the majority of paediatric patients with PAH. During the last few decades, several pharmacological approaches have been introduced, including calcium channel-blockers (CCBs), prostacyclin analogues, endothelin receptor antagonists and, most recently, phosphodiesterase inhibitors. This paper reviews the treatment options available to children with a special focus on the initial experience with bosentan. Although CCBs have been shown to increase survival in IPAH, the beneficial effect appears to be limited to a small number of patients, defined as 'responders' to the vasoreactivity testing. With the availability of prostacyclin (intravenous epoprostenol) and then prostacyclin analogues, the treatment options have increased markedly and particularly in patients who have not responded to conventional therapy. Although epoprostenol has been shown to be efficacious in PAH, the drug is not ideal owing to serious complications arising from the invasive mode of application, particularly in children. Phosphodiesterase-5 inhibitors have also shown beneficial effects. Targeting the endothelin (ET) system with the oral, dual ET(A)/ET(B) receptor antagonist, bosentan has been demonstrated to improve the cardiopulmonary haemodynamics, exercise capacity, quality-of-life and survival in adult patients with PAH. Specific ET(A) antagonists may also present the same beneficial profile. Recent experience with bosentan in paediatric patients with PAH indicates that the results obtained in adult patients may be extrapolated to children, thus offering a safe and effective therapy that is easy to administer.

Bosentan for the treatment of pulmonary arterial hypertension associated with congenital heart defects.

BACKGROUND: Bosentan is an effective first-line therapy in New York Heart Association (NYHA) III patients with idiopathic pulmonary arterial hypertension (PAH). Pre-clinical data support the rationale for the potential benefit of bosentan in PAH associated with congenital heart disease (CHD). MATERIALS AND METHODS: We performed a retrospective analysis of patients with PAH-associated CHD who were treated with bosentan on top of conventional therapy. Bosentan was started at 62.5 mg bid for 4 weeks, then titrated to 125 mg bid. New York Heart Association (NYHA) functional class, 6-min walking distance (6MWD), Borg dyspnoea index, arterial oxygen saturation and cardiopulmonary haemodynamic data (cardiac output, pulmonary blood flow and systemic and pulmonary vascular resistances) were collected at baseline and at follow up. RESULTS: Twenty-seven patients (23 females, mean 35 +/- 15 years) with NYHA class III-IV PAH-associated CHD (not repaired in 23 cases) were treated with bosentan for a mean 18.3 +/- 9.9 months. Bosentan improved 6MWD from 298 +/- 92 m at baseline to 355 +/- 82 m at 3 months (P = 0.0002) and to 364 +/- 92 m (P = 0.0001) at the last follow up (mean 15.2 +/- 9.7 months). At the last follow up, 13 patients had improved (= 1 NYHA class) and 14 remained stable. A favourable effect was observed in pulmonary blood flow and pulmonary vascular resistance for the 11 available patients. No change in pulse oximetry or liver enzyme elevation was reported. CONCLUSIONS: Bosentan improves exercise capacity, functional class and haemodynamics in most patients with PAH-associated CHD, without serious side-effects, suggesting bosentan may be an important treatment option for these patients.

Coarctation of the aorta: pre and postoperative evaluation with MRI and MR angiography; correlation with echocardiography and surgery.

AIMS: To compare MRI and MRA with Doppler-echocardiography (DE) in native and postoperative aortic coarctation, define the best MR protocol for its evaluation, compare MR with surgical findings in native coarctation. MATERIALS AND METHODS: 136 MR studies were performed in 121 patients divided in two groups: Group I, 55 preoperative; group II, 81 postoperative. In group I, all had DE and surgery was performed in 35 cases. In group II, DE was available for comparison in 71 cases. MR study comprised: spin-echo, cine, velocity-encoded cine (VEC) sequences and 3D contrast-enhanced MRA. RESULTS: In group I, diagnosis of coarctation was made by DE in 33 cases and suspicion of coarctation and/or aortic arch hypoplasia in 18 cases. Aortic arch was not well demonstrated in 3 cases and DE missed one case. There was a close correlation between VEC MRI and Doppler gradient estimates across the coarctation, between MRI aortic arch diameters and surgery but a poor correlation in isthmic measurements. In group II, DE detected a normal isthmic region in 31 out of 35 cases. Postoperative anomalies (recoarctation, aortic arch hypoplasia, kinking, pseudoaneurysm) were not demonstrated with DE in 50% of cases. CONCLUSIONS: MRI is superior to DE for pre and post-treatment evaluation of aortic coarctation. An optimal MR protocol is proposed. Internal measurement of the narrowing does not correspond to the external aspect of the surgical narrowing.

Increase of fungal endocarditis in children.

BACKGROUND: Infective endocarditis (IE) is a rare and feared infection that mainly occurs in patients with underlying cardiac disease or altered function of the immune system. Recent epidemiological data on both sepsis and nosocomial infections indicate a rise in gram-negative bacterial and fungal infection, particularly in patients requiring critical care support. This study sought to characterize the change in the spectrum of IE encountered in a single pediatric tertiary care center during the last 18 years, to evaluate emergence of fungal IE and to identify contributing factors. PATIENTS AND METHODS: Review of all cases of IE diagnosed between January 1986 and August 2003 at a single university children's hospital. Patients were distributed between two equal time periods and compared according to the era of IE diagnosis. RESULTS: In 43 patients, 44 episodes of IE were identified with most cases occurring in children with congenital or acquired heart disease. The annual number of diagnosed cases fluctuated during the study (mean 2.4 cases/year). Blood or specimen cultures were positive in 34 cases (77%) with gram-positive organisms most frequently observed (n=20, 44.4%). Fungal IE cases (n=9, 20%) occurred preferentially during the second period (p<0.03), and were more common in children with noncardiac diseases (p=0.023). Factors associated with fungal IE were the use of broad-spectrum antibiotics (p<0.001) and the presence of an infected central venous catheter (p=0.01). Overall mortality did not differ between the two eras. CONCLUSION: The incidence of fungal IE seems to have significantly increased in more recent years. Use of broadspectrum antibiotics for prolonged time or/and central venous catheters were identified as predisposing factors to fungal infective endocarditis.