Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry

Abstract

Background: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children.

Methods: Data from patients with HCM in the international, multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. LVSD was defined as left ventricular ejection fraction <50% on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models.

Results: We studied 1010 patients diagnosed with HCM during childhood (<18 years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0-15.3), and 393 (36%) patients were female. At initial SHaRe site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3-41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3-66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age <12 years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13-2.62), male sex (HR, 3.1 [CI, 1.88-5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08-4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42-3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38-1.69] per 5% decrease). Forty percent of patients with LVSD and HCM diagnosed during childhood met the composite outcome, with higher rates in female participants (HR, 2.60 [CI, 1.41-4.78]) and patients with a left ventricular ejection fraction <35% (HR, 3.76 [2.16-6.52]).

Conclusions: Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care.

Keywords: cardiomyopathies; cardiomyopathy, hypertrophic; genetics; heart failure; ventricular dysfunction.

Figure 1.

Cumulative incidence of left ventricular systolic dysfunction in patients with childhood-diagnosed hypertrophic cardiomyopathy. Cumulative incidence of left ventricular systolic dysfunction (LVSD) in patients with childhood-diagnosed hypertrophic cardiomyopathy (HCM) from time (in years) since initial SHaRe (Sarcomeric Human Cardiomyopathy Registry) evaluation (A), time (in years) since diagnosis with HCM (B), and birth (age in years; C). Of the 954 patients with childhood-diagnosed HCM and no left ventricular systolic dysfunction at initial SHaRe visit, 59 patients did not have follow-up.

Figure 2.

Predictors of developing incident left ventricular systolic dysfunction in patients with childhood-diagnosed hypertrophic cardiomyopathy, from the time of first SHaRe Registry evaluation. Patients with prevalent left ventricular systolic dysfunction (LVSD) or with missing values on left ventricular ejection fraction (LVEF) at initial evaluation were excluded. Results are reported from a multiple Cox proportional hazards model. HCM indicates hypertrophic cardiomyopathy; P/LP, pathogenic or likely pathogenic; SHaRe, Sarcomeric Human Cardiomyopathy Registry; and VUS, variant of unknown significance.

Figure 3.

Cumulative and age-specific incidence of major adverse outcomes in patients with childhood-diagnosed hypertrophic cardiomyopathy stratified by the presence of left ventricular systolic dysfunction. A, Cumulative incidence of death, cardiac transplantation (Txp), or left ventricular assist device (LVAD) implantation in patients with childhood diagnosis of hypertrophic cardiomyopathy and left ventricular systolic dysfunction (LVSD). B, Age-specific incidence of death, Txp, or LVAD implantation in patients with childhood-diagnosed hypertrophic cardiomyopathy stratified by the presence of LVSD. The error bars denote the 95% CIs, and the groups have been slightly offset in the horizontal plane to avoid overlap.

Figure 4.

Predictors of the primary outcome of death, cardiac transplantation, or left ventricular assist device implantation in patients with childhood-diagnosed hypertrophic cardiomyopathy who develop left ventricular systolic dysfunction. Results are reported from a multiple Cox proportional hazards model, in which age was used as the time scale with left-truncation at time of left ventricular systolic dysfunction. LVAD indicates left ventricular assist device; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction; Txp, cardiac transplantation; and VUS, variant of unknown significance.

Figure 5.

Cumulative incidence of the composite outcome of death, cardiac transplant, or left ventricular device implantation from time of clinical recognition of left ventricular systolic dysfunction. The figure includes patients with prevalent and incident left ventricular systolic dysfunction (LVSD). HCM indicates hypertrophic cardiomyopathy; LVAD, left ventricular assist device; SHaRe, Sarcomeric Human Cardiomyopathy Registry; and Txp, cardiac transplantation.