Risk stratification at diagnosis for children with hypertrophic cardiomyopathy: an analysis of data from the Pediatric Cardiomyopathy Registry

Abstract

Background: Treatment of children with hypertrophic cardiomyopathy might be improved if the risk of death or heart transplantation could be predicted by risk factors present at the time of diagnosis.

Methods: We analysed data from the Pediatric Cardiomyopathy Registry, which collected longitudinal data for 1085 children with hypertrophic cardiomyopathy from 1990 to 2009. Our goal was to understand how patient factors measured at diagnosis predicted the subsequent risk of the primary outcome of death or heart transplantation. The Kaplan-Meier method was used to calculate time-to-event rates from time of diagnosis to the earlier of heart transplantation or death for children in each subgroup. Cox proportional-hazards regression was used to identify univariable and multivariable predictors of death or heart transplantation within each causal subgroup.

Findings: The poorest outcomes were recorded for the 69 children with pure hypertrophic cardiomyopathy with inborn errors of metabolism, for whom the estimated rate of death or heart transplantation was 57% (95% CI 44-69) at 2 years. Children with mixed functional phenotypes also did poorly, with rates of death or heart transplantation of 45% (95% CI 32-58) at 2 years for the 69 children with mixed hypertrophic and dilated cardiomyopathy and 38% (95% CI 25-51) at 2 years for the 58 children with mixed hypertrophic and restrictive cardiomyopathy. For children diagnosed with hypertrophic cardiomyopathy at younger than 1 year, the rate of death or transplantation was 21% (95% CI 16-27) at 2 years. For children diagnosed with hypertrophic cardiomyopathy and a malformation syndrome, the rate of death or transplantation was 23% (95% CI 12-34) at 2 years. Excellent outcomes were reported for the 407 children who were diagnosed with idiopathic hypertrophic cardiomyopathy at age 1 year or older, with a rate of death or heart transplantation of 3% (95% CI 1-5) at 2 years. The risk factors for poor outcomes varied according to hypertrophic cardiomyopathy subgroup, but they generally included young age, low weight, presence of congestive heart failure, lower left ventricular fractional shortening, or higher left ventricular end-diastolic posterior wall thickness or end-diastolic ventricular septal thickness at the time of cardiomyopathy diagnosis. For all hypertrophic cardiomyopathy subgroups, the risk of death or heart transplantation was significantly increased when two or more risk factors were present and also as the number of risk factors increased.

Interpretation: In children with hypertrophic cardiomyopathy, the risk of death or heart transplantation was greatest for those who presented as infants or with inborn errors of metabolism or with mixed hypertrophic and dilated or restrictive cardiomyopathy. Risk stratification by subgroup of cardiomyopathy, by characteristics such as low weight, congestive heart failure, or abnormal echocardiographic findings, and by the presence of multiple risk factors allows for more informed clinical decision making and prognosis at the time of diagnosis.

Funding: US National Institutes of Health and Children's Cardiomyopathy Foundation.

Figure 1

The survival rates, using the Kaplan-Meier method, from diagnosis of hypertrophic cardiomyopathy to death or heart transplantation of subgroups of children with hypertrophic cardiomyopathy based on age at diagnosis, aetiology, or phenotype. Panel A shows the rates for 252 patients with pure hypertrophic cardiomyopathy diagnosed at under 1 year of age (black solid line), 407 patients with pure hypertrophic cardiomyopathy diagnosed at 1 year of age or older (red dashed line), and 60 patients with pure hypertrophic cardiomyopathy with malformation syndromes (green dotted line). Panel B shows the rates for 69 patients with pure hypertrophic cardiomyopathy with inborn errors of metabolism (black solid line), 58 patients with mixed hypertrophic and restrictive or other cardiomyopathies (red dashed line), and 69 patients with mixed hypertrophic and dilated cardiomyopathy (green dotted line).

Figure 2

The probability of death or heart transplantation (Tx) two years after the diagnosis (Dx) of hypertrophic cardiomyopathy (HCM) according to the number of risk factors across the six subgroups of children with hypertrophic cardiomyopathy based on age at diagnosis, aetiology, or phenotype. The sample sizes and number of deaths or Tx for each HCM subgroup are: 1) Idiopathic HCM < 1 year at Dx (N=128, Death or Tx N=23); 2) Idiopathic HCM ≥ 1 year at Dx (N=316, Death or Tx N=23); 3) HCM with malformation syndrome (N=42, Death or Tx N=9); 4) HCM with inborn error of metabolism (N=34, Death or Tx N=22); 5) Mixed HCM with restrictive cardiomyopathy (N=39, Death or Tx N=19); 6) Mixed HCM with dilated cardiomyopathy (N=36, Death or Tx N=18). The threshold values for scoring a point in the risk scores by HCM subgroup are: 1) Idiopathic HCM <1 year at DX (weight Z score < 1·4; age at Dx <0·01 years; end-diastolic posterior wall thickness (EDPT) Z score > 4·42); 2) Idiopathic HCM ≥1 year at Dx: (age at Dx > 14·4 years; fractional shortening (FS) Z score < 1·85); 3) HCM with malformation syndrome (age at Dx <0·2 years; FS Z score < 3·45); 4) HCM with inborn errors of metabolism (weight Z score < −1·8; age at Dx < 0·2 years; EDPT Z score < 6·7); 5) Mixed HCM with restrictive cardiomyopathy (age at Dx < 0·6 years; EDPT Z score >3·9); 6) Mixed HCM with dilated cardiomyopathy (weight Z score < 1·8 years; end-diastolic septal thickness Z score > 3·1). Binomial risk factors (gender, CHF status) do not have threshold values.