Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy

Abstract

Aims: Childhood-onset hypertrophic cardiomyopathy (HCM) is far less common than adult-onset disease, thus natural history is not well characterized. We aim to describe the characteristics and outcomes of childhood-onset HCM.

Methods and results: We performed an observational cohort study of 7677 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Hypertrophic cardiomyopathy patients were stratified by age at diagnosis [<1 year (infancy), 1-18 years (childhood), >18 years (adulthood)] and assessed for composite endpoints reflecting heart failure (HF), life-threatening ventricular arrhythmias, atrial fibrillation (AF), and an overall composite that also included stroke and death. Stratifying by age of diagnosis, 184 (2.4%) patients were diagnosed in infancy; 1128 (14.7%) in childhood; and 6365 (82.9%) in adulthood. Childhood-onset HCM patients had an ∼2%/year event rate for the overall composite endpoint, with ventricular arrhythmias representing the most common event in the 1st decade following baseline visit, but HF and AF becoming more common by the end of the 2nd decade. Sarcomeric variants were more common in childhood-onset HCM (63%) and carried a worse prognosis than non-sarcomeric disease, including a greater than two-fold increased risk of HF [HRadj 2.39 (1.36-4.20), P = 0.003] and 67% increased risk of the overall composite outcome [HRadj 1.67 (1.16-2.41), P = 0.006]. When compared with adult-onset HCM, childhood-onset was 36% more likely to develop life-threatening ventricular arrhythmias [HRadj 1.36 (1.03-1.80)] and twice as likely to require transplant or ventricular assist device [HRadj 1.99 (1.23-3.23)].

Conclusion: Patients with childhood-onset HCM are more likely to have sarcomeric disease, carry a higher risk of life-threatening ventricular arrythmias, and have greater need for advanced HF therapies. These findings provide insight into the natural history of disease and can help inform clinical risk stratification.

Keywords: Atrial fibrillation; Genetics; Heart failure; Ventricular arrhythmias; Hypertrophic cardiomyopathy.

Natural history of sarcomeric HCM may differ depending on age of diagnosis with HCM.

Figure 1

Age at diagnosis with hypertrophic cardiomyopathy. (A) Distribution of age at diagnosis in patients with hypertrophic cardiomyopathy (n = 7677). There are three peaks when hypertrophic cardiomyopathy is diagnosed throughout the lifespan: infancy (the 1st year of life), adolescence (teenage years), and middle adulthood (∼50 years of age). (B) Distribution of age at diagnosis in patients with genetic testing (n = 4746), stratified by sarcomeric variant status. Sarcomeric hypertrophic cardiomyopathy (teal) presents 9.3 years earlier than non-sarcomeric hypertrophic cardiomyopathy (pink). Sarcomeric hypertrophic cardiomyopathy is more common prior to age 50, and non-sarcomeric hypertrophic cardiomyopathy is more common thereafter.

Figure 2

Genotype distribution by age of hypertrophic cardiomyopathy diagnosis. Childhood-onset is predominantly sarcomeric hypertrophic cardiomyopathy, whereas infant- and adult-onset hypertrophic cardiomyopathies are more commonly non-sarcomeric. Of those with sarcomeric hypertrophic cardiomyopathy, MYH7 variants are more common earlier in life whereas the proportion of patients with MYBPC3 variants increases with age.

Figure 3

Cumulative incidence of cardiac events in childhood-onset hypertrophic cardiomyopathy. Approximately half of the events in the first 10 years after baseline visit to a Sarcomeric Human Cardiomyopathy Registry site are life-threatening ventricular arrhythmias; atrial fibrillation and heart failure are less common over this timeframe. By 25 years after baseline, nearly 50% of patients reached the overall cardiac composite outcome. Heart failure and atrial fibrillation are more common later in the disease course. AF, atrial fibrillation; HF, heart failure composite outcome; OC, overall composite outcome; VA, ventricular arrhythmia composite outcome.

Figure 4

Comparison of outcomes in childhood-onset (n = 617) vs. adult-onset hypertrophic cardiomyopathy (n = 3779). Childhood-onset hypertrophic cardiomyopathy is associated with 36% increased risk of life-threatening ventricular arrhythmias [HR_adj 1.36 (1.03–1.80)] and two-fold risk of requiring transplant or ventricular assist device [HR_adj 1.99 (1.23–3.23)] compared with adult-onset hypertrophic cardiomyopathy. Adjusted for sex, sarcomeric variant status, proband status, and age at disgnosis.