Mitochondrial Trifunctional Protein Deficiency: Severe Cardiomyopathy and Cardiac Transplantation.

We describe mitochondrial trifunctional protein deficiency (MTPD) in two male siblings who presented with severe cardiomyopathy in infancy. The first sibling presented in severe cardiac failure at 6 months of age and succumbed soon after. The second sibling came to attention after newborn screening identified a possible fatty acid oxidation defect. Dietary therapy and carnitine supplementation commenced in the neonatal period. Despite this the second child required cardiac transplantation at 3 years of age after a sudden and rapid decline in cardiac function. The outcome has been excellent, with no apparent extra-cardiac manifestations of a fatty acid oxidation disorder at the age of 7. Pathogenic HADHA mutations were subsequently identified via genome wide exome sequencing. This is the first reported case of MTPD to undergo cardiac transplantation. We suggest that cardiac transplantation could be considered in the treatment of cardiomyopathy in MTPD.

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.

A binational registry of adults with pulmonary arterial hypertension complicating congenital heart disease.

BACKGROUND: The management of children with congenital heart disease (CHD) has improved over recent decades and several patients surviving with CHD into adulthood are increasing. In developed countries, there are now as many adults as there are children living with CHD. Pulmonary arterial hypertension (PAH) occurs in ∼ 5% of patients with CHD. AIM: We aimed to understand the characteristics and outcomes of this emerging population. METHODS: We collected data retrospectively and prospectively from 12 contributing centres across Australia and New Zealand (2010-2013). Patients were included if they had been diagnosed with PAH and CHD and had been seen once in an adult centre after 1 January 2000. RESULTS: Of 360 patients with CHD-PAH, 60% were female and 90% were New York Heart Association functional class II or III at the time of adult diagnosis of PAH. Mean age at diagnosis of PAH in adulthood was 31.2 ± 14 years, and on average, patients were diagnosed with PAH 6 years after symptom onset. All-cause mortality was 12% at 5 years, 21% at 10 years and 31% at 15 years. One hundred and six patients (30%) experienced 247 hospitalisations during 2936 patient years of follow up. Eighty-nine per cent of patients were prescribed PAH specific therapy (mean exposure of 4.0 years). CONCLUSIONS: Adults with PAH and CHD often have this diagnosis made after significant delay, and have substantial medium-term morbidity and mortality. This suggests a need for children transitioning to adult care with CHD to be closely monitored for this complication.

Paediatric heart transplantation in Australia comes of age: 21 years of experience in a national centre.

BACKGROUND: Heart transplantation (HT) is established therapy for end-stage heart failure in children with cardiomyopathy or congenital heart disease. AIMS: This review summarises experience at a national referral centre since the first local transplant. METHODS: Medical records of children referred for HT between 1 April 1988 and 1 January 2010 were retrospectively reviewed. All patients listed for HT were included. Survival analysis was used to summarise wait-list time to death/transplant, and separately, time to death in HT patients. RESULTS: One hundred and thirty-nine children were accepted on to the HT waiting list during the study (median age 7.7 (interquartile range (IQR) 2.5, 13.6) years), of whom 93 underwent HT (median age 10.9 (IQR 4.4, 14.6) years). Wait-list mortality was 32% (45 of 139 patients), lowest among children aged >10 years at listing (P < 0.001). Median time to HT was 69 days (range 29-146). Survival post-transplantation was 90% (95% confidence interval 82-95) at 1 year, 82% (72-89%) at 5 years and 68% (50-80%) at 10 years. Increasing case complexity over the study period included pre- and post-transplant circulatory support, management of pulmonary hypertension and introduction of ABO-incompatible HT for infants. Post-transplant survival did not vary according to age, pre-transplant diagnosis or use of pre-transplant circulatory support (all P > 0.05). CONCLUSIONS: Results of paediatric HT in Australia are comparable with international results, despite limitations of geographic isolation, small population and low organ donation rate. Increasing case complexity has not impacted on post-transplant survival.

The Australia and New Zealand Fontan Registry: description and initial results from the first population-based Fontan registry.

BACKGROUND: The Fontan procedure is the final in a series of staged palliations for single-ventricle congenital heart disease, which encompasses rare and heterogeneous cardiac lesions. It represents an unusual and novel physiological state characterised by absence of a subpulmonary ventricle. AIMS: The population is growing steadily, prompting creation of this registry to study their epidemiology, demographic trends, treatment and outcomes. METHODS: This multicentre, binational, prospective and retrospective, web-based registry involving all congenital cardiac centres in the region has identified nearly all Fontan patients in Australia and New Zealand. Patients identified retrospectively were approached for recruitment. New recipients are automatically enrolled prospectively unless they choose to opt-out. Follow-up data are collected yearly. RESULTS: Baseline data were obtained in 1072 patients as at 1 January 2011. Ninety-nine patients died; 64 were lost to follow up. Forty-four per cent of patients lost were between 20 and 30 years of age. The size of the Fontan population is increasing steadily. Among 973 living patients, 541 (56%) gave consent for prospective collection of follow up. Between 1 January 2011 and 1 January 2013, an additional 47 subjects were enrolled prospectively. The current proportion of patients operated with hypoplastic left heart syndrome is currently 29% and is growing rapidly. CONCLUSION: The population surviving after the Fontan procedure has been growing in recent decades, especially since survival with hypoplastic left heart syndrome has improved. The Australia and New Zealand Fontan Registry provides population-based data, and only large databases like this will give opportunities for understanding the population and performing prospective trials.

Design and delivery of an e-learning curriculum for physicians involved in the management of pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a condition that affects more than 25 million individuals worldwide and causes premature disability and death. Despite advances in our understanding of this condition, education and training of health professionals has not kept pace with the rapid changes in diagnosis and treatment. The net effects of this gap between advancing knowledge and limited educational opportunity likely include clinically significant delays in both the diagnosis and commencement of effective evidence-based treatment - an unacceptable outcome for patients with a lethal condition. AIM: The Actelion Clinical Excellence Programme (ACEP) is an e-learning postgraduate curriculum, the purpose of which is to educate and mentor healthcare professionals, both theoretically and practically, in the diagnosis and treatment of patients with all forms of PH. This article reports on the development and delivery of the programme and outcomes from its first year of operation. RESULTS: Forty-three healthcare professionals from 22 institutions were enroled in the first iteration of the programme. In the 6 months from May to October 2011, participants successfully completed 285 lectures and/or activities. Overall, the programme was considered easily accessible, comprehensive in terms of both quality and quantity, provided an efficient means of self-paced learning, and was a highly regarded as reference source. Ninety-five per cent of participants said that they intended to change their clinical practice as a result of the information presented in the programme. CONCLUSION: ACEP represents a successful physician-industry partnership, which has resulted in a significant impact on clinical teaching and awareness of PH.

Congenital heart disease-associated pulmonary arterial hypertension: preliminary results from a novel registry.

BACKGROUND/AIMS: Pulmonary arterial hypertension (PAH) frequently accompanies childhood congenital heart disease (CHD) and may persist into adult life. The advent of specific PAH therapies for PAH prompted formation of a national Australian and New Zealand registry in 2010 to document the incidence, demographics, presentation and outcomes for these patients. METHODS: This multicentre, prospective, web-based registry enrols patients with CHD-associated PAH being followed in a tertiary centre. The inclusion criteria stipulated patient age ≥16 years, a measured mean pulmonary arterial pressure >25 mmHg at rest or echocardiographical evidence of PAH or a diagnosis of Eisenmenger syndrome, and followed since 1 January 2000. A single observer collected standardised data during a series of site visits. RESULTS: Of the first 50 patients enrolled, 30 (60%) were female. The mean age (standard deviation (SD)) at the time of PAH diagnosis or confirmation in an adult centre was 27.23 (10.07) years, and 32 (64%) patients are currently aged >30 years. Fourteen (28%) patients were in World Health Organization Functional Class II and 36 (72%) in Class III at the time of diagnosis. Forty-seven of 50 (94%) had congenital systemic-pulmonary shunts, and 36 (72%) never underwent intervention. Thirteen (26%) had Down syndrome. Confirmation of PAH by recent cardiac catheterisation was available in 30 (60%) subjects. During follow up, a total of 32 (64%) patients received a PAH-specific therapy. CONCLUSIONS: CHD associated with PAH in adult life has resulted in a new population with unique needs. This registry will allow documentation of clinical course and long-term outcomes for these patients.

The Bosentan Patient Registry: long-term survival in pulmonary arterial hypertension.

BACKGROUND/AIMS: The Bosentan Patient Registry (BPR) was a prospective, multicentre, Australian registry funded by Actelion Pharmaceuticals. The primary aim of the registry was to collect survival data in patients with pulmonary arterial hypertension (PAH) treated with bosentan. METHODS: The BPR was initiated in 15 specialized PAH centres. All patients on or starting bosentan were invited to enrol. Treating physicians notified the registry if patients discontinued bosentan, because of either a change in therapy, transplantation, intervention or death. Survival data were validated against the Australian Institute of Health and Welfare National Death Index. RESULTS: Between 2004 and 2007, a total of 528 patients (mean age 59 ± 17 years) were enrolled representing 69% of patients either previously taking or initiated on bosentan during that time. The BPR population was generally older with more advanced functional deficit than patients enrolled in randomized, placebo-controlled trials. Aetiology was idiopathic (iPAH) in 58% and connective tissue disease related (scleroderma (SSc)-PAH) in 42%. For iPAH patients, World Health Organisation functional classes II, III and IV at enrolment was 8.2%, 66.4% and 20.5%, and for the SSc-PAH cohort, 3.2%, 75.8% and 17.9% respectively. The observed annual mortality was 11.8% in patients with iPAH and 16.6% in patients SSc-PAH. CONCLUSION: This large Australian registry provides 'real life' information on the characteristics and management of PAH in clinical practice. Treatment with bosentan improved survival outcomes in both iPAH and SSc-PAH compared with historical controls. Age, disease severity and aetiology were critical factors in determining clinical outcomes.

From a declaration of values to the creation of value in global health: a report from Harvard University's Global Health Delivery Project.

To make best use of the new dollars available for the treatment of disease in resource-poor settings, global health practice requires a strategic approach that emphasises value for patients. Practitioners and global health academics should seek to identify and elaborate the set of factors that drives value for patients through the detailed study of actual care delivery organisations in multiple settings. Several frameworks can facilitate this study, including the care delivery value chain. We report on our efforts to catalyse the study of health care delivery in resource-limited settings in the hope that this inquiry will lead to insights that can improve the health of the neediest worldwide.

Cardiac manifestations in oxidative phosphorylation disorders of childhood.

OBJECTIVE: To determine the frequency, type, and severity of cardiac involvement in pediatric patients with oxidative phosphorylation (OXPHOS) disorders. STUDY DESIGN: Retrospective review of clinical and laboratory records of all patients with definitive OXPHOS disorders diagnosed and treated at the Royal Children's Hospital in Melbourne between 1984 and 2005. RESULTS: Of a total of 89 patients (male:female ratio 1.5:1) 29 (33%) had cardiac involvement: 9 as presenting symptoms, 9 developing on follow-up, and 11 with subclinical cardiac findings. Leigh or Leigh-like syndrome and complex I and combined complex I, III, and IV deficiencies were the most common clinical and laboratory diagnoses, respectively. Clinically symptomatic patients had hypertrophic cardiomyopathy (5 patients), dilated cardiomyopathy (4 patients), combined ventricular hypertrophy and systolic dysfunction (3 patients), and left ventricular noncompaction (3 patients) at first assessment. A change in the type of cardiomyopathy was noted on follow-up in 2 patients. Conduction and rhythm abnormalities were present in 7 symptomatic patients. CONCLUSIONS: Cardiac assessment in children with OXPHOS disorders may reveal subclinical abnormalities of cardiac function. Patients who present with primary cardiac features have a poor prognosis. OXPHOS disorders should be considered in the differential diagnosis of children presenting with otherwise unexplained cardiomyopathy.

Long term somatic growth after repair of tetralogy of Fallot: evidence for restoration of genetic growth potential.

OBJECTIVE: To compare actual with predicted long term growth after early repair of tetralogy of Fallot (TOF). DESIGN: Serial preoperative and postoperative anthropometric data were converted with z scores. The presence of restrictive physiology was assessed by echocardiography. PATIENTS: 45 otherwise healthy patients who underwent repair at median age 1.6 years (range 0.2-4.9) were studied. Predicted height was determined from mid-parental height corrected for sex. RESULTS: Mean (SD) weight and height z scores at the time of surgery were significantly depressed (-1.04 (0.82) and -0.93 (0.95), respectively; p < 0.0001 for both). At latest follow up at a median age of 14.2 years (range 11-20.5), mean weight and height z scores were 0.16 (1.1) and -0.05 (0.81) (p = 0.32 and p = 0.41, respectively). The improvement between surgical and late weight and height z scores was significant (p < 0.0001 for each comparison). Catch up growth was largely complete within two years. Age at correction, duration of follow up, and prior surgical procedures were unrelated to growth. Mean current height z scores were similar to those predicted by mid-parental height. Patients with restrictive right ventricular physiology (n = 24) had a significantly greater late z score for weight (0.49 v -0.34; p = 0.01), with a similar trend for height. Low birth weight patients experienced comparable catch up growth but remained shorter than patients with normal birth weight (mean height z score -0.64 v 0.06; p = 0.03). CONCLUSIONS: Early repair of TOF results in significant acceleration of weight and height, with normalisation of long term growth and fulfilment of genetic growth potential.

Mechanisms and management of gingival overgrowth in paediatric transplant recipients: a review.

UNLABELLED: Increasing numbers of children are receiving solid organ transplants namely kidney, liver, heart and lung. Patient survival rates following such transplants are essentially good with much of the success attributable to the development of Cyclosporine A (CyA), an immunosuppressive drug, that minimizes organ rejection. However the gingival overgrowth (GO) associated with the use of CyA is not only disfiguring but in paediatric recipients, may interfere with normal oral development and function. OBJECTIVE: The aim of this review is to summarize current knowledge concerning the aetiology, pathogenesis and management of gingival overgrowth. METHODS: Literature pertaining to gingival overgrowth is reviewed with particular reference to the paediatric population. Emphasis is placed on summarizing the evidence pertaining to the effectiveness of intervention. CONCLUSION: CyA undoubtedly causes gingival overgrowth, the effects and levels of which appears to be more severe in younger patients. There is conflicting evidence as to the effectiveness of oral hygiene regimes, antibiotics and surgery in reducing overgrowth. The introduction of an alternative immunosuppressive agent (Tacrolimus) offers potential as it does not appear to cause overgrowth, although research to date is limited by the small sample size of many of the studies. This is an area in which multicentre studies would be of great value.

Clinical, electrocardiographic, and histologic correlations in children with dilated cardiomyopathy.

OBJECTIVE: To determine whether presenting electrocardiography is related to histologic findings and clinical outcomes in children with dilated cardiomyopathy. BACKGROUND: Lymphocytic myocarditis is an important cause of childhood dilated cardiomyopathy, the outcome of which is unclear. The results of non-invasive investigations are often used to infer the presence or absence of lymphocytic myocarditis. METHODS: Thirty-four children, presenting acutely with dilated cardiomyopathy, underwent both early electrocardiography and endomyocardial biopsy. The parameters examined included heart rate, PR, QRS, and corrected QT intervals, R-wave voltages in Leads V(1) and V(6), S-wave voltages in Leads V(1) and V(6), and sum of SV(1) and RV(6). We expressed measurements as Z scores, based on published normal values for age and gender. RESULTS: A total of 15 patients had lymphocytic myocarditis on endomyocardial biopsy (Group I), and 19 had non-specific histologic findings (Group II). We did not distinguish the 2 groups by age, time to endomyocardial biopsy, or duration of follow-up. Group I patients had significantly smaller R-wave Z scores in Leads V(1) and V(6), and combined S in V(1) and R in V(6) Z scores (p < 0.02 for each). The positive and negative predictive values of an R-wave amplitude in V(6) < 5th percentile were 75% and 65%, respectively, for the diagnosis of lymphocytic myocarditis. An R-wave amplitude in V(6) > 95th percentile had a positive and negative predictive value of 80% and 63%, respectively, for the diagnosis of idiopathic dilated cardiomyopathy. Survival and freedom from late cardiac dysfunction were more common among Group I patients compared with Group II (p

Pulmonary vascular resistance and reactivity in children with end-stage cardiomyopathy.

Pulmonary vascular resistance (PVR) and reactivity were compared in 63 children with end-stage cardiomyopathy (CM) referred for cardiac transplantation. Diagnostic category of CM was the sole determinant of PVR. Compared with other patients, children with restrictive CM were younger at diagnosis and had a significantly higher pulmonary vascular resistance index (PVRI). Children with a baseline PVRI of up to 11.8 units per meter squared (U.m(2)) who showed reactivity underwent successful orthotopic cardiac transplantation.

Potassium concentrations and ventricular ectopy: a prospective, observational study in post-cardiac surgery patients.

OBJECTIVE: To determine whether a correlation exists between concentrations of intracellular and extracellular potassium and to determine the frequency of ventricular ectopy in patients after cardiac operations. DESIGN: Prospective, observational clinical evaluation. SETTING: Surgical-respiratory intensive care unit of a university-affiliated tertiary care center. PATIENTS: Continuous 24-hr electrocardiographic monitoring was performed, and serum (extracellular) and erythrocyte (intracellular) potassium concentrations ([K+]e and [K+]i) were determined, before cardiopulmonary bypass, immediately postoperatively, and at 2, 4, 12, and 20 hrs after elective coronary bypass grafting in 31 patients. INTERVENTIONS: None. Potassium replacement was left to the discretion of the attending physicians. MEASUREMENTS AND MAIN RESULTS: Although the mean [K+]e varied significantly during the postoperative 24-hr period (p<.0001), the [K+]i did not (p = .953). No significant correlations were found between premature ventricular beats and [K+]i, [K+]e, or [K+]i/[K+]e (all p>.05). However, among the few patients who had one or more episodes of ventricular tachycardia (VT) within 30 mins of a study K+ sample, the mean [K+]e was significantly lower during the episode(s) of VT compared with the mean [K+]e in the absence of VT (p<.01). CONCLUSIONS: Although it is clear that over the clinically acceptable range of [K+]e and [K+]i concentrations seen in this population, there is no correlation between potassium concentrations and the occurrence of premature ventricular beats, the infrequent association of more serious ventricular ectopy, VT, with lower [K+]e concentrations supports the practice of using serum potassium to guide potassium replacement in patients after cardiac operations.

Relationship of the dimension of cardiac structures to body size: an echocardiographic study in normal infants and children.

Normalization of the dimensions of cardiac structures to the size of the body, using so-called Z scores, is becoming increasingly common in the management of infants and children with congenital heart disease. Current published nomograms for the ascertainment of Z scores for cardiac structures in childhood are based largely on normal data obtained in formalin-fixed hearts. Since decisions concerning management are frequently based on the findings of cross-sectional echocardiograms, the dimensions of 15 cardiac structures were measured using cross-sectional echocardiography in 125 normal infants and children. Regression equations were derived relating cardiac dimensions to the size of the body. The expression of size with the highest correlation to cardiac dimensions was body surface area. Nomograms were then developed from which the Z score of a cardiac structure could be estimated from a knowledge of the body surface area and the echocardiographically derived measurement.