Compound Mutation in Cardiac Sarcomere Proteins Is Associated with Increased Risk for Major Arrhythmic Events in Pediatric Onset Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is associated with adverse left ventricular (LV) remodeling causing dysfunction and malignant arrhythmias. Severely affected patients present with disease onset during childhood and sudden cardiac death risk (SCD) stratification is of the highest importance in this cohort. This study aimed to investigate genotype-phenotype association regarding clinical outcome and disease progression in pediatric onset HCM. Medical charts from forty-nine patients with pediatric HCM who had undergone genetic testing were reviewed for retrospective analysis. Demographic, clinical, transthoracic echocardiographic, electrocardiographic, long-term electrocardiogram, cardiopulmonary exercise test, cardiac magnetic resonance, and medication data were recorded. Childhood onset HCM was diagnosed in 29 males and 20 females. Median age at last follow-up was 18.7 years (range 2.6-51.7 years) with a median follow-up time since diagnosis of 8.5 years (range 0.2-38.0 years). Comparison of patients carrying mutations in distinct genes and comparison of genotype-negative with genotype-positive individuals, revealed no differences in functional classification, LV morphology, hypertrophy, systolic and diastolic function, fibrosis and cardiac medication. Patients with compound mutations had a significantly higher risk for major arrhythmic events than a single-mutation carrier. No association between affected genes and disease severity or progression was identified in this cohort.

Keywords: genotype–phenotype association; major arrhythmic events; pediatric onset hypertrophic cardiomyopathy; sudden cardiac death risk stratification.

Figure 1

Study design and population with disease-causing mutations in affected genes encoding for sarcomere proteins in the myocardium. Shown are the flow chart of study design and population as well as the distribution of disease-causing mutations in genes encoding for sarcomere proteins in the myocardium as schematic illustrations of the affected proteins of the contractile apparatus of the cardiomyocyte in relation to their location of the thick and thin filament: β myosin heavy chain (MYH7), myosin binding protein C (MYBPC3), cardiac troponin T2 (TNNT2), cardiac troponin I3 (TNNI3), α tropomyosin (TPM1), myosin light chain 2 (MYL2). ^A, isolated hypertrophic cardiomyopathy according to current European Society of Cardiology and American Heart Association definitions; ^B, β myosin heavy chain; ^C, myosin binding protein C; ^D, cardiac troponin T2; ^E, cardiac troponin I3; ^F, α tropomyosin; ^G, myosin light chain 2; ^H, electrocardiogram; ^I, cardiopulmonary exercise test; ^J, major arrhythmic events: reanimation and/or appropriate discharge of cardioverter-defibrillator and/or sudden cardiac death; ^K, implantable cardioverter defibrillator; ^L, New York Heart Association; ^M, cardiac magnetic resonance imaging; ^N, end-diastolic volume index; ^O, end-systolic volume index; ^P, left ventricular outflow tract obstruction; ^Q, transthoracic echocardiography; ^R, end-diastolic septal wall thickness; ^S, end-diastolic left ventricular posterior wall thickness; ^T, late gadolinium enhancement; ^U, ejection fraction; ^V, stroke volume index; ^W, mitral valve; ^X, left atrial.

Figure 2

Specific protein modifications of the study population.

Figure 3

Morbidity and clinical outcome Part I: (a) Kaplan–Meier calculation of survival without major arrhythmic events (MAEs) (reanimation or appropriate implantable cardioverter defibrillator discharge or sudden cardiac death) in hypertrophic cardiomyopathy (HCM) patients, depending on different mutations; (b) Kaplan–Meier calculation of overall survival; SCD: sudden cardiac death, G−: genotype-negative patients, G+ MYH7: genotype-positive patients with β-myosin heavy chain single-mutation, G+ MYBPC3: genotype-positive patients with myosin binding protein C single-mutation, G+ others: genotype-positive patients with cardiac troponin T2, cardiac troponin I3, α tropomyosin and myosin light chain 2 single-mutations, G+ multiple mutation: genotype-positive patients with compound mutations.

Figure 4

Morbidity and clinical outcome Part II: (a) Kaplan–Meier calculation of survival without hospitalization in hypertrophic cardiomyopathy (HCM) patients, depending on different mutations; (b) Kaplan–Meier calculation of survival without medication use. SCD: sudden cardiac death, G−: genotype-negative patients, G+ MYH7: genotype-positive patients with β-myosin heavy chain single-mutation, G+ MYBPC3: genotype-positive patients with myosin binding protein C single-mutation, G+ others: genotype-positive patients with cardiac troponin T2, cardiac troponin I3, α tropomyosin and myosin light chain 2 single-mutations, G+ multiple mutation: genotype-positive patients with compound mutations.

Figure 5

Disease progression Part I. Clinical outcome parameter of pediatric onset HCM patients are presented by the (a) New York Heart Association or modified Ross class and by (b) the need of cardiac medications. Imaging parameters are presented by (c) maximum myocardial wall thickness and by (d) the left atrial diameter measured by transthoracic echocardiography. p-values were calculated with the non-parametric Kruskal–Wallis test. The delta of the respective parameter between first presentation (FP) and last follow up (LFU) did not differ between consecutive groups. G−: genotype-negative patients, G+ MYH7: genotype-positive patients with β-myosin heavy chain single-mutation, G+ MYBPC3: genotype-positive patients with myosin binding protein C single-mutation, G+ others: genotype-positive patients with cardiac troponin T2, cardiac troponin I3, α tropomyosin and myosin light chain 2 single-mutations, G+ multiple mutation: genotype-positive patients with compound mutations, °: outliers.

Figure 5

Disease progression Part I. Clinical outcome parameter of pediatric onset HCM patients are presented by the (a) New York Heart Association or modified Ross class and by (b) the need of cardiac medications. Imaging parameters are presented by (c) maximum myocardial wall thickness and by (d) the left atrial diameter measured by transthoracic echocardiography. p-values were calculated with the non-parametric Kruskal–Wallis test. The delta of the respective parameter between first presentation (FP) and last follow up (LFU) did not differ between consecutive groups. G−: genotype-negative patients, G+ MYH7: genotype-positive patients with β-myosin heavy chain single-mutation, G+ MYBPC3: genotype-positive patients with myosin binding protein C single-mutation, G+ others: genotype-positive patients with cardiac troponin T2, cardiac troponin I3, α tropomyosin and myosin light chain 2 single-mutations, G+ multiple mutation: genotype-positive patients with compound mutations, °: outliers.