Matthew Fenton

New-Onset Heart Failure Due to Heart Muscle Disease in Childhood A Prospective Study in the United Kingdom and Ireland

Background— We undertook the first prospective, national, multicenter study to describe the incidence and outcome of heart muscle disease–induced heart failure in children. Methods and Results— Data were collected on patients admitted to a hospital through 2003 with a first episode of heart failure in the absence of congenital heart disease. All 17 pediatric cardiac centers in the United Kingdom and Ireland participated. Follow-up data were obtained to a minimum of 1 year. The incidence was 0.87/100 000 population <16 years (n=104; 53 girls; 95% confidence interval 0.71 to 1.05 per 100 000). Median age at presentation was 1 year, with 82% in New York Heart Association class III to IV. Causes of heart failure included dilated cardiomyopathy (50 idiopathic, 8 familial), probable myocarditis (23), occult arrhythmia (7), anthracycline toxicity (5), metabolic disease (4), left ventricular noncompaction (3), and other (4). Overall 1-year survival was 82%, and event (death or transplantation)-free survival was 66%. Regression analysis showed older age and reduced systolic function on admission echocardiogram increased the event risk. Only 8% of event-free survivors (n=69) remained in New York Heart Association class III to IV, but 35 required readmission during the study period, and all but 8 remained on medication. Conclusions— This first national prospective study of new-onset heart failure in children has shown an incidence of 0.87/100 000. Multivariable analysis of survival data indicates a better outcome for younger children and for those with better systolic function at presentation, but overall, one third of children die or require transplantation within 1 year of presentation.

Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes

Background: Restrictive cardiomyopathy (RCM) is rare in childhood, but has a grave prognosis. The cause of disease in most cases is unknown. Objective: To determine the prevalence of sarcomere protein gene mutations in children with idiopathic RCM. Methods: Twelve patients (9 female, mean age 5.1 years) with idiopathic RCM referred between 1991 and August 2006 underwent detailed clinical and genetic evaluation. Nine had received cardiac transplants at the time of the study. The entire coding sequences of the genes encoding eight cardiac sarcomere proteins and desmin were screened for mutations. Familial evaluation was performed on first-degree relatives. Results: Four patients (33%) had a family history of cardiomyopathy: RCM (n = 2); dilated cardiomyopathy (n = 1) and left ventricular non-compaction (n = 1). Sarcomere protein gene mutations were identified in four patients (33%): 2 in the cardiac troponin I gene (TNNI3) and 1 each in the troponin T (TNNT2) and α-cardiac actin (ACTC) genes. Two were de novo mutations and 3 were new mutations. All mutations occurred in functionally important and conserved regions of the genes. Conclusions: Sarcomere protein gene mutations are an important cause of idiopathic RCM in childhood. We describe the first mutation in ACTC in familial RCM. The identification of RCM in a child should prompt consideration of sarcomere protein disease as a possible cause and warrants clinical evaluation of the family.

Positive Pretransplantation Cytomegalovirus Serology Is a Risk Factor for Cardiac Allograft Vasculopathy in Children

Background— Cytomegalovirus (CMV) infection has been implicated as a cause of posttransplantation coronary artery disease in adults. The purpose of this retrospective observational study was to evaluate the effect of CMV on outcome after heart transplantation in children. Methods and Results— Risk factors tested were recipient age, sex, and pretransplantation CMV serology; use of anti-CMV prophylaxis; posttransplantation evidence of CMV infection; and donor CMV serology. Transplantations were stratified traditionally according to CMV risk as low risk (recipient negative/donor negative), intermediate risk (recipient positive), and high risk (recipient negative/donor positive). Primary outcome measures were (1) development of coronary artery vasculopathy, (2) mortality (or graft loss) that occurred outside the early postoperative period, and (3) death (or graft loss) due to vasculopathy. Analysis was by proportional hazards modeling. A total of 165 children underwent heart transplantation, with a mean age at transplantation of 7.8 (SD 5.6) years. Thirty-two children had laboratory evidence of CMV infection after transplantation, but only 6 developed CMV disease or syndrome. Traditional CMV risk stratification correlated well with CMV infection but did not predict mortality, coronary artery disease, or coronary death. In contrast, positive recipient CMV was the only independent predictor of all 3 outcome measures: coronary artery disease (hazard ratio=3.6), all-cause mortality (partial hazard ratio=4.1), and coronary death (hazard ratio=4.6). Conclusions— In children, pretransplantation recipient CMV status is a more powerful predictor for the development of clinically significant vasculopathy and subsequent death than traditional risk stratification. This phenomenon warrants further investigation.

Peak Oxygen Uptake Correlates With Survival Without Clinical Deterioration in Ambulatory Children With Dilated Cardiomyopathy

Background— Children stable at home with dilated cardiomyopathy remain at risk of death; there is evidence of survival benefit for transplantation out to 4 years postoperatively. The limited supply of donor organs makes risk stratification imperative, but although cardiopulmonary exercise test is well established as a powerful tool in adults with heart failure, no published studies have linked oxygen uptake to prognosis in children. Methods and Results— Between 2001 and 2009, using cardiopulmonary exercise test and echocardiography, we studied 82 children (mean age, 13.5±2.3 years) with dilated cardiomyopathy. All were ambulatory, outpatients, and >120 cm in height. All children completed a symptom-limited maximal exercise test. Resting left ventricular shortening fraction was 20±9%; peak heart rate was 87±13% of predicted; peak oxygen uptake (V[Combining Dot Above]O2) was 67±22% of predicted; and ventilatory efficiency was 32±8. Follow-up was available for 100% of the children, and was a mean of 32.3±7.5 months. Eighteen patients reached the defined clinical end point of death or listing for urgent heart transplantation. On univariate analysis, left ventricular shortening fraction, peak heart rate, peak V[Combining Dot Above]O2, peak systolic blood pressure, and ventilatory efficiency were all associated with adverse outcome. On multivariable Cox analysis, only peak V[Combining Dot Above]O2 (P=0.003) was associated with the study end point. Patients with a peak V[Combining Dot Above]O2 ⩽62% of predicted had a higher 24-month event rate (50.6% versus 4.4%; hazard ratio, 10.78). Conclusions— We have demonstrated that a cardiopulmonary exercise test is feasible in ambulatory children with dilated cardiomyopathy who are >120 cm height and for the first time have linked peak V[Combining Dot Above]O2 with outcome in children.

Endothelial Dysfunction and Cytomegalovirus Replication in Pediatric Heart Transplantation

Background— Cardiac allograft vasculopathy is the major limiting factor to the long-term success of pediatric heart transplantation. Cytomegalovirus (CMV) has been shown to be a significant risk factor for the development of cardiac allograft vasculopathy. Recent work has demonstrated CMV DNA in leukocytes in the absence of direct allograft infection, suggesting that vascular changes may not be limited to the allograft. Method and Results— Systemic arterial endothelial function was assessed with high-resolution ultrasound to determine brachial artery flow-mediated dilation in 50 pediatric heart transplant recipients (8 to 17 years of age; 27 male). Patients were separated into 2 groups according to CMV status: those without evidence of CMV replication after transplantation (n=38; 19 male) and patients with evidence of viremia after transplantation (n=12; 8 male). No patient had detectable viremia at the time of study. Flow-mediated dilation was significantly impaired in patients with evidence of CMV replication after transplantation (6.64±1.12%, mean±SE) compared with those without (9.48±0.56%; P=0.02). This difference remained after adjustment for age, time since transplantation, and medication. Pretransplantation recipient and donor CMV status and traditional CMV risk were not associated with flow-mediated dilation. Conclusions— CMV replication after cardiac transplantation is associated with chronic endothelial dysfunction in the systemic circulation in children. The implication for both systemic and coronary vascular health requires prospective evaluation.

Pediatric Heart Transplantation for Congenital and Restrictive Cardiomyopathy

BACKGROUND Recent reports suggest worse outcomes in pediatric orthotopic heart transplantation (OHT) for congenital heart disease (CHD) and restrictive cardiomyopathy (RCM). We examined early outcomes in these diverse groups of patients in comparison with patients with dilatated cardiomyopathy (DCM). METHODS From 2000 to 2011, 209 patients were included: 50 with CHD, 23 with RCM, and 136 with DCM. Early survival was studied, as was the occurrence of acute rejection, donor-specific antibodies (DSAs) and nondonor-specific antibodies (NSDAs), incidence of pulmonary hypertension (PHT), right ventricular failure (RVF), and the need for mechanical circulatory support (MCS). RESULTS The incidence of preoperative PHT was greatest in the RCM group (χ(2)p = 0.0006); the requirement for mechanical support before OHT was greatest in patients with DCM. Thirty-day survival was 92.0%, 97.1%, and 100% for patients with CHD, DCM, and RCM respectively. The incidence of RVF was highest for patients with RCM (43.5%; versus CHD, 26.0%; versus DCM, 14.7%). One-year survival estimates for patients with CHD, DCM, and RCM were 92.0%, 97.8%, and 82.6%, respectively (log-rank p = 0.165). Multivariable analysis revealed 4 significant risk factors for mortality: age, incidence of acute rejection, preoperative PHT, and the presence of NDSAs. The occurrence of DSAs was similar, although there was a significantly higher incidence of NDSAs in the CHD and RCM groups (36.0% and 30.4%, respectively, versus 14.0% in the DCM group; χ(2)p = 0.0024). CONCLUSIONS Equivalent outcomes are achievable in pediatric OHT despite marked heterogeneity in anatomic and physiologic complexity in recipients. Physiologic factors such as PHT are likely to be more important than anatomic complexities in determining survival. The potential relevance of NDSAs warrants further investigation.

Results of orthotopic heart transplantation for failed palliation of hypoplastic left heart

OBJECTIVES Previous studies have indicated that results for orthotopic heart transplantation (OHT) in patients with surgically palliated hypoplastic left heart (HLHS) are worse compared with patients with other forms of congenital heart disease (CHD) or acquired cardiomyopathy (CM) as well as those undergoing primary OHT for HLHS. In light of the decreasing donor pool for transplantation and increasing numbers of palliated HLHS patients with improving survival, we sought to review our results for OHT in surgically palliated HLHS patients and failing Glenn or Fontan circulations. METHODS We conducted a single centre, retrospective study of patients undergoing OHT from 2000 to 2011. Patients who were transplanted following any of the three stages of palliation were included. Indications for OHT were severe impairment of systemic right ventricular (RV) function with/without significant atrioventricular (AV) valve regurgitation or failure of Fontan physiology. The primary outcome of interest was survival; the secondary outcomes examined were the incidence of post-transplant RV failure and the need for extracorporeal membrane oxygenation (ECMO) support. RESULTS A total of 209 patients were transplanted during the study period. Of these, 16 were surgically palliated HLHS patients, 1 following Norwood I, 4 post-Fontan and 11 post-Glenn. Thirty-one patients had non-HLHS CHD and 154 patients had forms of acquired CM. Preoperative patient characteristics including age, weight and donor/recipient weight ratio were similar across groups, though the incidence of pulmonary hypertension (PHT) was higher in the CM group. Thirty-day survival was 100% in the palliated HLHS patients (vs 98.1% for the CM group), with 1- and 5-year Kaplan-Meier survivals of 100 and 87.5% (P = 0.393 vs CM; log-rank test). Intensive care unit stay was comparable with transplanted CM patients as was the incidence of RV failure and ECMO post-OHT. CONCLUSIONS Our results suggest that good early and mid-term outcomes following OHT in surgically palliated HLHS are achievable. These findings have implications for the optimal strategy and timing for managing palliated patients with HLHS as well as for counselling parents and affected children.

Detection and Grading of Coronary Allograft Vasculopathy in Children With Contrast-Enhanced Magnetic Resonance Imaging of the Coronary Vessel Wall

Background—Coronary allograft vasculopathy is the leading cause of late death after heart transplantation in children. It is poorly detected by conventional angiography. Intravascular ultrasound is invasive and costly. This study shows that magnetic resonance imaging (MRI) late gadolinium enhancement (LGE) of the coronary vessel wall can detect and grade coronary allograft vasculopathy. Methods and Results—Twenty-four children (10 male; age range, 9–17 years) underwent coronary angiography, intravascular ultrasound, and MRI. Maximal intimal thickness and mean intimal index were recorded. MRI included coronary magnetic resonance angiogram and LGE vessel wall imaging with 1.5 T (n=12) and 3.0 T (n=12). Ten healthy control subjects also underwent LGE MRI. Mean time posttransplantation was 5.5 years (range, 0.25–14 years). Seven patients had Stanford grade IV coronary allograft vasculopathy on intravascular ultrasound, 3 of whom had angiographic disease. Maximal intimal thickness and mean intimal index were 0.73±0.50 mm and 20.9±10.6%, respectively. On MRI, mean diameter of enhancement of vessel wall was 6.57±4.91 mm, and mean enhancement index (indexed to vessel lumen size) was 1.10±1.72. The control group showed little or no LGE. Correlation of LGE with maximal intimal thickness using the Pearson coefficient was 0.80 (P<0.001) and with mean intimal index was 0.92 (P<0.001). An MRI diameter >7.5 mm gave 86% sensitivity and 93% specificity. Conclusions—LGE scores correlate well with traditional intravascular ultrasound measures. These promising early results encourage larger-scale clinical studies to investigate whether LGE MRI will allow closer follow-up and better prevention of coronary allograft vasculopathy in children.

Acute rejection after paediatric heart transplantation: far less common and less severe

Despite improved immunosuppression, rejection accounts for significant morbidity and mortality in children after heart transplantation. We report the incidence and outcome of rejection of 105 children (male = 50; mean age of 8.3 ± 5.8 years) following heart transplantation between January 2002 and August 2007. A multi‐variant model was constructed for risk factors associated with significant rejection. In 271.9 patient‐years of follow‐up, there were 23 episodes of significant rejection (≥3A) in 21 patients (20%). Five presented in haemodynamic collapse requiring extracorporeal membrane oxygenation support 1.6–35.9 months after transplantation; four of five survived the rejection episode. Overall rejection episodes were more common in older children, boys and those treated with sirolimus. Whereas the risk for rejection in patients on an immunosuppression regime containing tacrolimus was significantly lower. The latter finding persisted on multivariate analysis (P < 0.002). Interestingly, none of the patients who presented with haemodynamic collapse was on mycophenolate mofetil. While our experience is of a far lower incidence of rejection than registry data, rejection remains a serious problem after paediatric heart transplantation. Sirolimus without a calcineurin inhibitor was associated with more rejection episodes, whereas tacrolimus and mycophenolate appeared to provide the best protective profile.

Tacrolimus in pediatric heart transplantation: ameliorated side effects in the steroid‐free, statin era

Abstract:  Due to concerns over the side effects of cyclosporine, tacrolimus is widely used in pediatric heart transplantation. However, tacrolimus therapy is also accompanied by potentially serious side effects. This paper examines the side effect profile of tacrolimus in a large group of pediatric heart recipients. Data on renal function, diabetes, hyperlipidemia and hypertension were collected by case‐note review of 100 patients who had received ≥ 12 months treatment with tacrolimus. Forty‐two patients received tacrolimus from the time of transplant (de novo), and 58 were initially treated with cyclosporine (switch). Mean estimated glomerular filtration rate improved in the first six months post transplant in the de novo group (66.7–84.6 mL/min/1.73 m2, p = 0.002). Conversely, it decreased in those initially treated with cyclosporine (82.1–68.8, p = 0.032), but improved after switch to tacrolimus (77.3–85.6, p = 0.006). Twenty‐one percent exhibited glucose intolerance, and 2% had diabetes. Borderline or elevated fasting cholesterol levels were present in 4.4%. Hypertension was seen in 67% at the point of switch from cyclosporine, which fell to 36% at latest follow‐up (p = 0.001). These results present an encouraging outlook for this cohort of patients. The relatively low levels of complications shown may be due to early weaning of steroids, and concomitant statin therapy.