Doctor of Philosophy (PHD)
Date of Defense
First Committee Member
David J. Lee - Committee Chair
Second Committee Member
Lora E. Fleming - Committee Member
Third Committee Member
Steven E. Lipshultz - Mentor
Fourth Committee Member
James D. Wilkinson - Mentor
Fifth Committee Member
E. John Orav - Outside Committee Member
Background: Dilated Cardiomyopathy (DCM) is the most common functional type of cardiomyopathy in children with significant morbidity and the leading indication for cardiac transplant over 5 years of age. Identification of baseline risk factors for failing medical management by etiologic grouping remain to be elucidated in a large populationbased study. The competing risk for heart death between all-cause mortality and heart transplantation is often overestimated in the literature and may obscure additional novel risk factors associated with poor clinical outcomes. Methods: The National Heart Lung and Blood Institute Pediatric Cardiomyopathy Registry collected longitudinal data from 1731 children with DCM in North America from 1990 to 2007. Composite endpoint (CEP) was the earlier occurrence of death or heart transplant. Univariate and multivariate predictors were identified from demographic and echocardiographic data (expressed as z-scores) collected within 30 days of diagnosis. A competing risk analysis was performed calculating cumulative incidence and identifying novel prognostic factors. All analyses were performed by etiologic group. Results: Multivariate Cox regression identified the highest mortality risk among children with idiopathic disease (N=1192, CEP: 41%) when diagnosed over age 6 years, and with congestive heart failure (CHF) and decreased left ventricular fractional shortening (FS). Risk factors for those with myocarditis (N=272, CEP: 26%) were older age, CHF, and increased left ventricular (LV) end-diastolic dimension (EDD); while for neuromuscular disease (N=139, CEP: 40%), it was a decreased FS and increased EDD. Only univariate predictors were identified for children with familial isolated cardiomyopathy (N=79, CEP: 44%) including: CHF, increased EDD, end-systolic dimension, or LV mass, and decreased FS or ejection fraction), while for children with inborn errors of metabolism (N=43, CEP: 33%) risk factors included: a positive family history of cardiomyopathy or genetic syndromes. The group of children with malformation syndromes (N=6, CEP: 50%) was not large enough to model. Comparison of cause-specific event rates between Kaplan-Meier and cumulative incidence demonstrated an overestimation with the former method. Competing risk multivariate regression showed similar models to those for CEP, with the following exceptions: for neuromuscular disease, an increased EDD had a larger hazard ratio for transplant than for death; for idiopathic disease, an increased EDD was associated with transplant, but not with death, and growth retardation (height-for-age zscore) was associated with death but not transplant. Conclusions: Within etiologic grouping, demographics and echocardiographic values at diagnosis have varying predictive value. Generally, the presence of symptomatic disease in the form of CHF, echocardiographic evidence of more severe DCM, and increased age were indicative of worse outcomes. These results help to validate those from conflicting studies; however, they suggest that etiology modifies the importance of particular factors. Analysis of competing risk provides an alternate interpretation of studies with composite endpoints and assists in the transfer of clinically relevant information. For children with idiopathic and neuromuscular disease, the degree of dilation had a differential effect that has gone unrecognized. The novel finding of reduced stature and its effect on mortality suggests a potential for treatment and mitigation of poor outcomes in idiopathic DCM. Both increased dilation and reduced stature could be used to improve the triage process and refer children to cardiac transplantation who otherwise might die prematurely and unnecessarily. Subsequent studies on the utility of these factors and their effect on improving survival are warranted.
Competing Risk Analysis; Transplant; Cumulative Incidence; Idiopathic; Myocarditis; Neuromuscular Disease
Alvarez, Jorge Alex, "Pediatric Dilated Cardiomyopathy: Baseline Predictors of Outcomes in the Pediatric Cardiomyopathy Registry" (2009). Open Access Dissertations. 475.