Long-term outcomes of childhood onset Noonan compared to sarcomere hypertrophic cardiomyopathy

Abstract

Background: To compare outcome and cardiac pathology between patients with Noonan syndrome (N-HCM) and sarcomere protein-associated (S-HCM) childhood onset hypertrophic cardiomyopathy (HCM).

Methods: Clinical data were recorded from medical charts. Primary endpoint was survival. Secondary endpoints were survival without hospitalization, without intervention or without arrhythmic events. Functional clinical status and results from genetic testing, imaging, electrocardiographic (ECG) studies, cardiopulmonary exercise testing (CPET) and histopathology were compared between groups.

Results: Childhood HCM was diagnosed in 29 N-HCM and 34 S-HCM patients. Follow-up time was greater than 10 years in more than half of all patients. Mortality was below 7% and not different between groups. Children with N-HCM presented at a younger age and there was less time of survival without hospitalization for heart failure or intervention in N-HCM compared to S-HCM patients. Clinical functional status improved over time in N-HCM patients. On long-term follow-up, left ventricular posterior wall thickness indexed to body surface area decreased in N-HCM and increased in S-HCM patients. There was a trend to lower risk for severe arrhythmic events in N-HCM patients and only S-HCM individuals received an implantable cardioverter-defibrillator. There were no differences between groups in ventricular function, ECG and CPET parameters. Myocardial fibrosis as assessed by histopathology of myocardial specimens and cardiovascular magnetic resonance with late gadolinium enhancement or T1 mapping was present in both groups.

Conclusions: When compared to S-HCM patients, children with N-HCM have increased morbidity during early disease course, but favorable long-term outcome with low mortality, stagnation of myocardial hypertrophy, and low risk for malignant arrhythmias.

Keywords: Hypertrophic cardiomyopathy (HCM); Noonan syndrome; childhood; disease course; outcome.

Figure 1

Study design. *, MYL2 (N=1), TNNT2 (N=2), TNNI3 (N=1). TTE, transthoracic echocardiographic; ECG, electrocardiographic; CPET, cardiopulmonary exercise testing; HCM, hypertrophic cardiomyopathy; CMR, cardiovascular magnetic resonance.

Figure 2

Primary and secondary outcomes of patients with Noonan syndrome compared to sarcomere-associated childhood hypertrophic cardiomyopathy. Shown are survival curves until death (A), first hospitalization for heart failure (B), first hospitalization for intervention (percutaneous cardiac intervention or surgery) (C), or first severe arrhythmic event (sudden cardiac death, survived sudden cardiac death, appropriate implantable cardioverter-defibrillator discharge, sustained supraventricular or ventricular tachycardia) (D). Log-rank P value compares probability curves of N-HCM and S-HCM patients.

Figure 3

Clinical functional status and myocardial hypertrophy. Shown are the clinical functional status (A), left ventricular interventricular thickness z-score (B), and left ventricular posterior wall thickness z-score (C,D) on transthoracic echocardiography at the time of diagnosis and on last follow-up. Patients with Noonan syndrome and hypertrophic cardiomyopathy (N-HCM, meshed boxes) present with worse clinical functional status which improves over time (A). Relative myocardial thickness decreases over time in N-HCM patients (N-HCM, meshed boxes), and increases in patients with familial non-syndromic sarcomere hypertrophic cardiomyopathy (S-HMC, white boxes) (B,C). Panel D depicts those trends if separated into patients without septal myectomy surgery and those having undergone surgical septal myectomy (D). N-HCM, patients with Noonan syndrome and hypertrophic cardiomyopathy; S-HCM, patients with sarcomere protein-associated hypertrophic cardiomyopathy; ns, not significant.