A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy

Abstract

Background: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies.

Methods: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285).

Results: Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z-score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively).

Conclusion: Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.

Trial registration: ClinicalTrials.gov NCT04036799.

Keywords: cardiomyopathies; cardiomyopathy, hypertrophic; death, sudden, heart; defibrillators, implantable; hypertrophy; pediatrics.

Figure 1.

Cumulative proportion of SCD events estimated using competing risk models in PRIMaCY and SHaRe cohorts. A, PRIMaCY cohort (n=572): The cumulative proportion of SCD events in patients with pediatric HCM at 1-year follow-up was 2.8% (95% CI, 1.4%–4.2%), at 5 years was 9.1% (95% CI, 6.3%–11.9%), and at 10 years was 15.0% (95% CI, 10.0%–19.7%). The cumulative proportion of death from other causes at 1-year follow-up was 0.9% (95% CI, 0.1%–1.8%), at 5 years was 1.8% (95% CI, 0.6%–3.0%), and at 10 years was 1.8% (95% CI, 0.6%–3.0%). B, SHaRe cohort (n=285): The cumulative proportion of SCD events at 1-year follow-up was 2.3% (95% CI, 0.5%–4.1%), at 5 years was 6.8% (95% CI, 3.2%–10.3%), and at 10 years was 13.7% (95% CI, 6.5%–20.4%). The cumulative proportion of death from other causes at 1-year follow-up was 0.7% (95% CI, 0.0%–1.7%), at 5 years was 2.1% (95% CI, 0.2%–3.9%), and at 10 years was 4.5% (95% CI, 0.6%–8.2%). Echo indicates echocardiogram; HCM, hypertrophic cardiomyopathy; PRIMaCY, Precision Medicine for Cardiomyopathy Study; SCD, sudden cardiac death; and SHaRe, Sarcomeric Human Cardiomyopathy Registry.

Figure 2.

Regression-adjusted effects of continuous covariates and clinical SCD risk prediction model performance (n=572). A through E, The top of each figure shows the observed values of the continuous risk predictor among patients with pediatric HCM in the training cohort who experienced the composite SCD outcome; the bottom shows the observed values of the predictor among those who did not experience the composite SCD outcome. SCD risk increased with age at diagnosis(A); increase in IVSD z score(B); LVPWD z score(C); and LA diameter z score(D). E, The risk associated with peak resting LVOT gradient remained flat when the gradient was ≤100 mm Hg and decreased as the gradient increased to >100 mm Hg. F, The cumulative proportion of SCD events stratified by tertiles of risk predicted by the clinical-only model, that is, predicted risk <4.7%, 4.7% to 8.3%, and >8.3%. G, The calibration curve for the clinical model applied to the training cohort shows the predicted versus the observed 5-year risk of the composite SCD outcome. The prediction accuracy, that is, c-statistic of the model, was 0.75. The dashed line, the 45° line through 0, represents a perfectly calibrated model between the observed and the predicted 5-year survival probabilities. Echo indicates echocardiogram; HCM, hypertrophic cardiomyopathy; IVSD, interventricular septal diameter; LA, left atrium; LVOT, left ventricular outflow tract; LVPWD, left ventricular posterior wall diameter; and SCD, sudden cardiac death.

Figure 3.

Regression-adjusted effects of continuous covariates and clinical/genetic SCD risk prediction model performance (n=572). A through E, The top of each figure shows the observed values of the continuous risk predictor among patients with pediatric HCM in the training cohort who experienced the composite SCD outcome; the bottom shows the observed values of the predictor among those who did not experience the composite SCD outcome. SCD risk increased with age at first evaluation(A); increase in IVSD z score(B); LVPWD z score(C); and LA diameter z score(D). E, The risk associated with peak resting LVOT gradient remained flat when the gradient was ≤100 mm Hg and decreased as the gradient increased above 100 mm Hg. F, Cumulative proportion of SCD events stratified by tertiles of risk predicted by the clinical/genetic model, that is, predicted risk <4.7%, 4.7% to 8.3%, and >8.3%. G, The calibration curve for the clinical/genetic model applied to the training cohort shows the predicted versus the observed 5-year risk of the composite SCD outcome. The prediction accuracy, that is, c-statistic of the model, was 0.762. The dashed line, the 45° line through 0, represents a perfectly calibrated model between the observed and the predicted 5-year survival probabilities. Echo indicates echocardiogram; HCM, hypertrophic cardiomyopathy; IVSD, interventricular septal diameter; LA, left atrium; LVOT, left ventricular outflow tract; LVPWD, left ventricular posterior wall diameter; and SCD, sudden cardiac death.