Beth D. Kaufman

Idebenone in Friedreich ataxia cardiomyopathy—results from a 6-month phase III study (IONIA)

BACKGROUND Friedreich ataxia (FRDA) is commonly associated with hypertrophic cardiomyopathy, but little is known about its frequency, severity, or treatment. In this 6-month randomized, double-blind, controlled study, we sought to determine whether idebenone improves cardiac measures in FRDA. METHODS Seventy pediatric subjects were treated either with idebenone (450/900 mg/d or 1,350/2,250 mg/d) or with placebo. Electrocardiograms (ECGs) were assessed at each visit, and echocardiograms, at baseline and week 24. RESULTS We found ECG abnormalities in 90% of the subjects. On echocardiogram, 81.4% of the total cohort had left ventricular (LV) hypertrophy, as measured by increased LV mass index-Dubois, and the mean ejection fraction (EF) was 56.9%. In linear regression models, longer PR intervals at baseline were marginally associated with longer GAA repeat length (P = .011). Similarly, GAA repeat length did not clearly predict baseline EF (P = .086) and LV mass by M-mode (P = .045). Left ventricular mass index, posterior wall thickness, EF, and ECG parameters were not significantly improved by treatment with idebenone. Some changes in echocardiographic parameters during the treatment phase correlated with baseline status but not with treatment group. CONCLUSIONS Idebenone did not decrease LV hypertrophy or improve cardiac function in subjects with FRDA. The present study does not provide evidence of benefit in this cohort over a 6-month treatment period.

Incidence of and Risk Factors for Sudden Cardiac Death in Children with Dilated Cardiomyopathy: A Report from the Pediatric Cardiomyopathy Registry

OBJECTIVES The purpose of this study was to establish the incidence of and risk factors for sudden cardiac death (SCD) in pediatric dilated cardiomyopathy (DCM). BACKGROUND The incidence of SCD in children with DCM is unknown. The ability to predict patients at high risk of SCD will help to define who may benefit most from implantable cardioverter-defibrillators. METHODS The cohort was 1,803 children in the PCMR (Pediatric Cardiomyopathy Registry) with a diagnosis of DCM from 1990 to 2009. Cumulative incidence competing-risks event rates were estimated. We achieved risk stratification using Classification and Regression Tree methodology. RESULTS The 5-year incidence rates were 29% for heart transplantation, 12.1% non-SCD, 4.0% death from unknown cause, and 2.4% for SCD. Of 280 deaths, 35 were SCD, and the cause was unknown for 56. The 5-year incidence rate for SCD incorporating a subset of the unknown deaths is 3%. Patients receiving antiarrhythmic medication were at higher risk of SCD (hazard ratio: 3.0, 95% confidence interval: 1.1 to 8.3, p = 0.025). A risk stratification model based on most recent echocardiographic values had 86% sensitivity and 57% specificity. Thirty of 35 SCDs occurred in patients who met all these criteria: left ventricular (LV) end-systolic dimension z-score >2.6, age at diagnosis younger than 14.3 years, and the LV posterior wall thickness to end-diastolic dimension ratio <0.14. Sex, ethnicity, cause of DCM, and family history were not associated with SCD. CONCLUSIONS The 5-year incidence rate of SCD in children with DCM is 3%. A risk stratification rule (86% sensitivity) included age at diagnosis younger than 14.3 years, LV dilation, and LV posterior wall thinning. Patients who consistently meet these criteria should be considered for implantable cardioverter-defibrillator placement.

Outcomes of Children With Cardiomyopathy Listed for Transplant: A Multi-institutional Study

BACKGROUND Dilated (DCM), restrictive (RCM), and hypertrophic (HCM) cardiomyopathies (CM) in children have varying clinical courses and therapeutic options. Heart transplantation (HTx) offers a chance for long-term survival; but outcomes after listing have not been well defined. METHODS A multi-institutional registry of 3,147 patients listed for HTx (January 1993-December 2006) was used to compare outcomes of 1,320 children with CM (42%) and 1,827 with non-CM (58%) etiologies. Comparisons were made between sub-groups: 1,098 DCM (83%), 145 RCM (11%), and 77 HCM (6%). RESULTS CM patients had a waitlist mortality of 17% vs 32% for non-CM patients (p < 0.0001), with no difference between the CM sub-groups. Risk factors were younger age, black race (relative risk [RR], 1.65; p = 0.009), mechanical ventilation (RR, 3.17; p < 0.001), and extracorporeal membrane oxygenation (RR, 2.16; p < 0.001). Ten-year survival after listing was 66% for CM vs 53% for non-CM (p < 0.0001). HCM and RCM patients aged < 1 year at the time of listing had the highest waitlist mortality and the lowest overall survival. CM patients had a better 10-year survival after HTx (68% vs 61%, p < 0.0001). Risk factors for death early after HTx included mechanical ventilation at HTx (RR, 3.07; p < 0.001), longer ischemic time (RR, 1.27; p = 0.01), and earlier era (RR, 1.77; p = 0.002). Late risk factors included black race (RR, 3.01; p < 0.001), HCM or RCM (RR, 1.93; p = 0.007), and older age (RR, 1.9; p < 0.001). CONCLUSION Children with CM have a lower waitlist mortality and better survival post-HTx than children with a non-CM diagnosis. DCM patients have the best and HCM or RCM patients aged younger than 1 year have the worst overall outcomes.

Ventricular assist device-associated anti-human leukocyte antigen antibody sensitization in pediatric patients bridged to heart transplantation

BACKGROUND Ventricular assist devices (VAD) are associated with the formation of antibodies to anti-human leukocyte antigens (HLA) or sensitization. The incidence and effects of VAD-associated anti-HLA sensitization have not been well studied in the pediatric population. METHODS A retrospective review of all patients undergoing VAD implant at our institution from 1998 to 2008 was performed. Panel reactive antibody (PRA) results before VAD implant, after VAD implant, and after orthotopic heart transplantation (OHT) were recorded. Patients who became sensitized (PRA for class I and/or II immunoglobulin G antibodies >or= 10%) on VAD support were compared with non-sensitized patients with regard to demographics, diagnosis, device type, and blood product exposure on VAD support. Outcomes after OHT were also compared between groups. RESULTS VAD support was initiated in 20 patients (median age, 14.4 years), with 75% survival to OHT or recovery. PRA data before and after VAD implant were available for 17 patients. VAD-associated sensitization developed in 35% of recipients. There were no differences between those sensitized in association with VAD support and non-sensitized patients with regard to age, gender, diagnosis, device type, extracorporeal membrane oxygenation use, or blood product exposure on VAD support. Black race predicted sensitization on VAD (p = 0.02). There were no differences in survival or rejection between groups. CONCLUSIONS VAD therapy was associated with the development of anti-HLA sensitization in 35% of recipients. Black race predicted sensitization, but there were no differences in overall survival or outcomes after OHT.

Genomic Profiling of Left and Right Ventricular Hypertrophy in Congenital Heart Disease

BACKGROUND The right ventricle (RV) has a lower ability than the left ventricle (LV) to adapt to systemic load. The molecular basis of these differences is not known. We compared hypertrophy-signaling pathways between the RV and the LV in patients with congenital heart disease (CHD). METHODS Gene expression was measured using DNA microarrays in myocardium from children with CHD with LV or RV obstructive lesions undergoing surgery. The expression of 175 hypertrophy-signaling genes was compared between the LV (n=7) and the RV (n=11). Hierarchic clustering was performed. RESULTS Seventeen genes (10%) were differentially expressed between the LV and the RV. Expression of genes for angiotensin, adrenergic, G-proteins, cytoskeletal, and contractile components was lower (P < .05) and expression of maladaptive factors (fibroblast growth factors, transforming growth factor-beta, caspases, ubiquitin) was higher in the RV compared with the LV (P < .05). Five of 7 LV samples clustered together. Only 4 of 11 RV samples clustered with the LV. Genes critical to adaptive remodeling correlated with the degree of LV hypertrophy but not RV hypertrophy. CONCLUSION The transcription of pathways of adaptive remodeling was lower in the RV compared with the LV. This may explain the lower ability of the RV to adapt to hemodynamic load in CHD.

Failure of right ventricular adaptation in children with tetralogy of Fallot.

Background— The left ventricle (LV) adapts to chronic hypoxia by expressing protective angiogenic, metabolic, and antioxidant genes to improve O2 delivery and energy production, and to minimize reoxygenation injury. The ability of the right ventricle (RV) to adapt to hypoxia in children with tetralogy of Fallot (TOF) is unknown. Methods and Results— Gene expression using real-time polymerase chain reaction was measured in RV myocardium obtained during surgical repair of TOF from 23 patients: 13 cyanotic and 10 acyanotic. Results were compared between the 2 groups and correlated with age at surgery, severity of cyanosis, and early postoperative course. The cyanotic patients were younger at surgery compared with acyanotic (5±3 versus 9±4 months; P=0.01), had higher hematocrit (43±4 versus 38±3 grams/dL; P=0.004), and lower O2 saturations (84±4% versus 98±2%; (P<0.001). Cyanotic patients had a significantly lower expression of vascular endothelial growth factor (VEGF), glycolytic enzymes, and glutathione peroxidase (GPX) (P<0.05), and a higher expression of collagen (P<0.01) compared with acyanotic patients. Gene expression correlated inversely with severity of cyanosis ie, preoperative hematocrit (P<0.01) and positively with preoperative saturation (P<0.05). The relationship between gene expression and cyanosis was independent of age at surgery. Ca2+ handling genes did not correlate with the severity of hypoxia. Lower angiogenic, glycolytic, and antioxidant gene expression correlated with increasing postoperative lactate (P<0.05). Conclusions— The RV fails to up regulate adaptive pathways in response to increasing hypoxia in children with TOF. The implications of an early maladaptive response of the RV on long-term RV function require further investigation.

Invasive fungal infections in pediatric heart transplant recipients: Incidence, risk factors, and outcomes

Zaoutis TE, Webber S, Naftel DC, Chrisant MA, Kaufman B, Pearce FB, Spicer R, Dipchand AI on behalf of the Pediatric Heart Transplant Study Investigators. Invasive fungal infections in pediatric heart transplant recipients: Incidence, risk factors, and outcomes. 
Pediatr Transplantation 2011: 15: 465–469.

Cardiomyopathy Phenotypes and Outcomes for Children With Left Ventricular Myocardial Noncompaction: Results From the Pediatric Cardiomyopathy Registry

BACKGROUND Left ventricular noncompaction (LVNC) is a distinct form of cardiomyopathy characterized by hypertrabeculation of the left ventricle. The LVNC phenotype may occur in isolation or with other cardiomyopathy phenotypes. Prognosis is incompletely characterized in children. METHODS AND RESULTS According to diagnoses from the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry from 1990 to 2008, 155 of 3,219 children (4.8%) had LVNC. Each LVNC patient was also classified as having an associated echocardiographically diagnosed cardiomyopathy phenotype: dilated (DCM), hypertrophic (HCM), restrictive (RCM), isolated, or indeterminate. The time to death or transplantation differed among the phenotypic groups (P = .035). Time to listing for cardiac transplantation significantly differed by phenotype (P < .001), as did time to transplantation (P = .015). The hazard ratio for death/transplantation (with isolated LVNC as the reference group) was 4.26 (95% confidence interval [CI] 0.78-23.3) for HCM, 6.35 (95% CI 1.52-26.6) for DCM, and 5.66 (95% CI 1.04-30.9) for the indeterminate phenotype. Most events occurred in the 1st year after diagnosis. CONCLUSIONS LVNC is present in at least 5% of children with cardiomyopathy. The specific LVNC-associated cardiomyopathy phenotype predicts the risk of death or transplantation and should inform clinical management.

Too Fat or Too Thin? Body Habitus Assessment in Children Listed for Heart Transplant and Impact on Outcome

BACKGROUND Body habitus assessment (BHA), be it wasted or obese, is a useful marker of nutritional status and overall medical condition. Wasting and obesity pre-heart transplant adversely affects outcomes in adults. The utility of BHA as a prognostic factor in children post-transplant is unknown. METHODS Weight and height at listing and standard growth charts were used to determine the ideal body weight (%IBW) and percentiles for body mass index for age (BMI%) and weight-for-length (W:L%). Wasting was defined as <90%IBW and/or <or=5th percentile for BMI% or W:L%. Obesity was defined as >120%IBW and/or >or=95th percentile BMI% or W:L%. Outcomes of cohorts based on these criteria were compared. RESULTS From June 1990 to December 2006, 180 children, aged 5.81 +/- 6 years, were listed for transplant. Wasting occurred in 66 (37%) and obesity in 22 (12%) children, without differences between diagnoses of cardiomyopathy or congenital heart disease. %IBW was a prognostic factor for survival post-transplant on multivariate analysis: obese patients had a hazard ratio (HR) of 3.82 (95% confidence interval [CI] 1.81 to 8.06) compared with normal BHA (p < 0.001). Wasting had a survival advantage compared with normal BHA (HR 0.51, 95% CI 0.27 to 0.94, p = 0.032). There were no significant differences between cohorts in incidence of infections, first-year rejections or graft vasculopathy. CONCLUSIONS Abnormal BHA at listing was a prognostic factor for survival post-transplant. Obese children had increased mortality, but wasting did not adversely affect post-transplant survival in our population. Body habitus assessment may risk-stratify children at listing, potentially providing a complex target for intervention.

Ventricular assist devices in a contemporary pediatric cohort: Morbidity, functional recovery, and survival

BACKGROUND Limited availability of donor organs has led to the use of ventricular assist devices (VADs) to treat heart failure in pediatric patients, primarily as bridge to transplantation. How effective VAD therapy is in promoting functional recovery in children is currently not known. METHODS We report morbidity and mortality as defined by the Interagency Registry for Mechanically Assisted Circulatory Support Modified for Pediatrics (PediMACS) and the use of the Treatment Intensity Score to assess functional status for 50 VAD patients supported at a single pediatric program from 2004 to 2013. RESULTS In this cohort, 30-day survival on VAD was 98%, and 180-day survival was 83%. Stroke occurred in 11 patients (22%), with 8 (16%) resulting in persistent neurologic deficit or death. The adverse event rate was 2-fold to 3-fold higher in the first 7 days of support compared with the subsequent support period. Functional status, as measured by the Treatment Intensity Score, improved with duration of support. Successful bridge to transplantation was associated with fewer adverse events during support and greater improvement in the Treatment Intensity Score during the period of support. CONCLUSIONS Overall survival in this cohort is excellent. The risk of serious adverse events decreases over the first month of support. However, a clinically significant risk of morbidity and mortality persists for the duration of pediatric VAD support. Measures of functional status improve with duration of support and are associated with survival to transplantation.