RIKADA Study Reveals Risk Factors in Pediatric Primary Cardiomyopathy

Abstract

Background Cardiomyopathies are heterogeneous diseases with clinical presentations varying from asymptomatic to life-threatening events, including severe heart failure and sudden cardiac death. The role of underlying genetic and disease-modulating factors in children and adolescents is relatively unknown. In this prospective study, in-depth phenotypic and genetic characterization of pediatric patients with primary cardiomyopathy and their first-degree family members (FMs) was performed. Outcome was assessed to identify clinical risk factors. Methods and Results Sixty index patients with primary cardiomyopathy (median age: 7.8 years) and 124 FMs were enrolled in the RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study. Family screening included cardiac workup and genetic testing. Using cardiologic screening, we identified 17 FMs with cardiomyopathies and 30 FMs with suspected cardiomyopathies. Adverse events appeared in 32% of index patients and were more common in those with lower body surface area (P=0.019), increased NT-proBNP (N-terminal pro-brain natriuretic peptide; P<0.001), and left ventricular dysfunction (P<0.001) and dilatation (P=0.005). The worst prognosis was observed in dilated and restrictive cardiomyopathies. Genetic variants of interest were detected in patients (79%) and FMs (67%). In all 15 families with at least 1 FM with cardiomyopathy, we found a variant of interest in the index patient. Increased number of variants of interest per patient was associated with adverse events (P=0.021). Late gadolinium enhancement was related to positive genotypes in patients (P=0.041). Conclusions Lower body surface area, increased NT-proBNP, left ventricular dysfunction or dilatation, late gadolinium enhancement, and increased number of variants of interest were associated with adverse outcome and should be considered for risk assessment in pediatric primary cardiomyopathies. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03572569.

Keywords: cardiomyopathy; heart failure; pediatrics; risk assessment.

Figures

Figure 1

Study design. The protocol of the RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study involved in‐depth family screening of 60 pediatric index patients and all available first‐degree family members (FMs). CMR was performed in index patients and FMs, including siblings aged ≤18 years, for preclinical detection of cardiomyopathy. CMR indicates cardiovascular magnetic resonance; CPET, cardiopulmonary exercise testing; TTE, transthoracic echocardiography.

Figure 2

Clinical diagnosis and genetic information in the family context. For the RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study, 60 index patients and 124 family members (FMs) were enrolled. These 60 families were classified according to their clinical diagnosis of the first‐degree FM either as family with cardiomyopathy (group 1), family with a suspected cardiac phenotype (group 2), or as family without detection of any cardiovascular signs (group 3). In families with a suspected cardiac phenotype, we most frequently observed left ventricular hypertrabeculation. Overall, 57 of 60 index patients underwent genetic testing. The genetic information was implemented by counting the highest graded VOIs in each family. Families with a de novo VOI were listed as families without cardiovascular signs. In 12 families, we did not detect any VOI. CMP indicates cardiomyopathy; VOI, variant of interest; VUS, variant of unknown significance.

Figure 3

Cardiovascular magnetic resonance (CMR) in pediatric primary cardiomyopathy. A, CMR images highlight typical cardiomyopathy phenotypes for DCM, HCM, LVNC, and ARVC. Cine (upper row) and corresponding LGE (lower row) images are presented. Red arrows indicate regions with positive LGE. B, Hypertrabeculation is shown for individual 1‐II:1 in short‐axis, 2‐, 3‐ and 4‐chamber views (yellow arrows). ARVC indicates arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LGE, late gadolinium enhancement; LVNC, left ventricular noncompaction cardiomyopathy.

Figure 4

Clinical characterization of index patients and family members. Clinical information for all study individuals is presented in absolute values for each subgroup. Heart failure was defined as acute right or left heart failure with peripheral edema and/or pulmonary congestion. Arrhythmias included supraventricular and nonsustained ventricular tachycardia and were recorded with Holter ECG. MACE summarizes mechanical circulatory support, heart transplantation, and death. Values for arrhythmogenic right ventricular cardiomyopathy (n=2) are not presented. Of note, 4 of 8 HCM patients tested LGE positive. The full clinical information for each group is available in Tables S2 through S5. The sample size value indicates the number of analyzed individuals for a given parameter. CMR indicates cardiovascular magnetic resonance; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; IQR, interquartile range; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; LVNC, left ventricular noncompaction cardiomyopathy; MACE, major adverse cardiovascular events; NT‐proBNP, N‐terminal pro–brain natriuretic peptide; RCM, restrictive cardiomyopathy.

Figure 5

Adverse events in index patients with cardiomyopathy. Kaplan–Meier curves illustrate the event‐free survival to the combined end point of death, heart transplantation, and mechanical circulatory support: (A) in all index patients, (B) between the different cardiomyopathy subgroups DCM, HCM, LVNC, RCM, and ARVC, (C) with regard to the absolute number of VOIs, and (D) in genetic vs sporadic cardiomyopathy. No VOI but positive family history of cardiomyopathy was seen in only 1 index patient who was thus excluded from the Kaplan–Meier analysis. ARVC indicates arrhythmogenic right ventricular cardiomyopathy; CMP, cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction cardiomyopathy; RCM, restrictive cardiomyopathy; VOI, variant of interest.

Figure 6

Pedigrees of RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study families. A through F, The affected individuals of the selected families demonstrate with LVNC, DCM, or HCM (black‐filled symbols). Family members may present without cardiomyopathy but with a suspected cardiac phenotype (gray symbols). Detected VOIs are given for each family member. In families 1 and 2, VOI2 is a de novo variant. DCM indicates dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HTx, heart transplant; LVNC, left ventricular noncompaction cardiomyopathy; VOI, variant of interest. ACTC1, actin, alpha, cardiac muscle 1; ACTN2, actinin alpha 2; CBL, CBL proto‐oncogene; EYA4, EYA transcriptional coactivator and phosphatase 4; LDB3, LIM domain binding 3; MYBPC3, myosin binding protein C, cardiac; MYH7, myosin heavy chain 7; MYLK2, myosin light chain kinase 2; PKP2, plakophilin 2; TAZ, tafazzin; TPM1, tropomyosin 1.