Midwall fibrosis and cardiac mechanics: rigid body rotation is a novel marker of disease severity in pediatric primary dilated cardiomyopathy

BACKGROUND: Midwall fibrosis (MWF) detected by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) predicts adverse outcome in adults with dilated cardiomyopathy (DCM). Its relevance in children and adolescents is relatively unknown. Left ventricular (LV) strain, rotation and twist are important parameters of cardiac function; yet, their role in pediatric heart failure is understudied. This study aimed to evaluate MWF and cardiac mechanics in pediatric DCM. METHODS: Patients ≤21 years with primary DCM were prospectively enrolled and underwent standardized CMR including LGE. All participants were categorized according to the presence or absence of MWF (MWF+ vs. MWF–). Cardiac mechanics were assessed using CMR feature tracking. Impaired LV twist with apex and base rotating in the same direction was termed rigid body rotation (RBR). RESULTS: In total, 17 patients (median age 11.2 years) were included. MWF was present in seven patients (41%). Median N-terminal pro brain natriuretic peptide (NT-proBNP) was higher (5,959 vs. 242 pg/ml, p = 0.887) and LV ejection fraction (LVEF) lower (28 vs. 39%, p = 0.536) in MWF+ vs. MWF– patients, yet differences were not statistically significant. MWF+ patients had reduced global longitudinal (GLS), circumferential (GCS) and radial strain (GRS), again without statistical significance (p = 0.713, 0.492 and 1.000, respectively). A relationship between MWF and adverse outcome was not seen (p = 0.637). RBR was more common in MWF+ (67 vs. 50%), and was associated with the occurrence of adverse events (p = 0.041). Patients with RBR more frequently were in higher New York Heart Association classes (p = 0.035), had elevated NT-proBNP levels (p = 0.002) and higher need for catecholamines (p = 0.001). RBR was related to reduced GLS (p = 0.008), GCS (p = 0.031), GRS (p = 0.012), LV twist (p = 0.008), peak apical rotation (p < 0.001), and LVEF (p = 0.001), elevated LV end-diastolic volume (p = 0.023) and LV end-systolic volume (p = 0.003), and lower right ventricular stroke volume (p = 0.023). CONCLUSIONS: MWF was common, but failed to predict heart failure. RBR was associated with clinical and biventricular functional signs of heart failure as well as the occurrence of adverse events. Our findings suggest that RBR may predict outcomes and may serve as a novel marker of disease severity in pediatric DCM. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier: NCT03572569

Measuring myocardial extracellular volume of the right ventricle in patients with congenital heart disease

The right ventricle's (RV) characteristics - thin walls and trabeculation - make it challenging to evaluate extracellular volume (ECV). We aimed to assess the feasibility of RV ECV measurements in congenital heart disease (CHD), and to introduce a novel ECV analysis tool. Patients (n = 39) and healthy controls (n = 17) underwent cardiovascular magnetic resonance T1 mapping in midventricular short axis (SAX) and transverse orientation (TRANS). Regions of interest (ROIs) were evaluated with regard to image quality and maximum RV wall thickness per ROI in pixels. ECV from plane ROIs was compared with values obtained with a custom-made tool that derives the mean T1 values from a "line of interest" (LOI) centered in the RV wall. In CHD, average image quality was good (no artifacts in the RV, good contrast between blood/myocardium), and RV wall thickness was 1-2 pixels. RV ECV was not quantifiable in 4/39 patients due to insufficient contrast or wall thickness < 1 pixel. RV myocardium tended to be more clearly delineated in SAX than TRANS. ECV from ROIs and corresponding LOIs correlated strongly in both directions (SAX/TRANS: r = 0.97/0.87, p < 0.001, respectively). In conclusion, RV ECV can be assessed if image quality allows sufficient distinction between myocardium and blood, and RV wall thickness per ROI is ≥ 1 pixel. T1 maps in SAX are recommended for RV ECV analysis. LOI application simplifies RV ECV measurements

Pathogenic variants associated with dilated cardiomyopathy predict outcome in pediatric myocarditis

BACKGROUND: Myocarditis is one of the most common causes leading to heart failure in children and a possible genetic background has been postulated. We sought to characterize the clinical and genetic characteristics in patients with myocarditis ≤18 years of age to predict outcome. METHODS: A cohort of 42 patients (MYCPEDIG) with biopsy-proven myocarditis underwent genetic testing with targeted panel sequencing of cardiomyopathy-associated genes. MYCPEDIG patients were divided into subgroups according to the phenotype of dilated cardiomyopathy (DCM) at presentation, resulting in 22 patients without DCM (MYC-NonDCM) and 20 patients with DCM (MYC-DCM). RESULTS: MYC-DCM patients (median age 1.4 years) were younger than MYC-NonDCM patients (median age 16.1 years; p<0.001) and were corresponding to heart failure-like and coronary syndrome-like phenotypes, respectively. At least one likely pathogenic/pathogenic (LP/P) variant was identified in 9/42 patients (22%), 8 of them were heterozygous, and 7/9 were in MYC-DCM. LP/P variants were found in genes validated for primary DCM (BAG3, DSP, LMNA, MYH7, TNNI3, TNNT2, and TTN). Rare variant enrichment analysis revealed significant accumulation of high impact disease variants in MYC-DCM versus healthy individuals (p=0.0003). Event-free survival was lower (p=0.008) in MYC-DCM patients compared to MYC-NonDCM and primary DCM. CONCLUSIONS: We report heterozygous LP/P variants in biopsy-proven pediatric myocarditis. Myocarditis patients with DCM phenotype were characterized by early-onset heart failure, significant enrichment of LP/P variants, and poor outcome. These phenotype- and age-group specific findings will be useful for personalized management of these patients. Genetic evaluation in children newly diagnosed with myocarditis and DCM phenotype is warranted

Diffuse myocardial fibrosis by T1 mapping is associated with heart failure in pediatric primary dilated cardiomyopathy

BACKGROUND: In adult cardiomyopathy (CM), diffuse myocardial fibrosis is associated with adverse clinical outcome. However, its relevance in pediatric patients remains relatively unknown. The study aimed to evaluate myocardial extracellular volume (ECV) reflecting diffuse myocardial fibrosis with cardiovascular magnetic resonance (CMR) T1 mapping, and to analyze correlations with clinical and functional data in children and adolescents with different CM phenotypes. METHODS: Patients with primary dilated (DCM), hypertrophic (HCM) or left ventricular non-compaction CM (LVNC) were prospectively enrolled and compared with healthy controls. Study participants underwent standardized CMR with modified Look-Locker Inversion recovery (MOLLI) T1 mapping. RESULTS: In total, 33 patients (median age 12.0 years; DCM: n = 10, HCM: n = 13; LVNC: n = 10) and 7 controls (14.5 years) were included. DCM: ECV was higher than in controls (38.1 ± 7.5 vs. 27.2 ± 3.6%; p = 0.014). Patients with elevated ECV were younger than those with normal values (p = 0.044). ECV correlated with N-terminal pro brain natriuretic peptide (r = 0.66, p = 0.038), left ventricular ejection fraction (r = -0.63, p = 0.053), and stroke volume of left (r = -0.75, p = 0.013) and right ventricle (r = -0.67, p = 0.033). During a median follow-up of 25.3 months, 3 patients underwent heart transplantation (HTx), and 2 were listed for HTx. All 5 patients had elevated ECV. HCM/LVNC: ECV was within normal range in HCM (25.5 ± 4.5%) and LVNC (29.6 ± 4.2), and was not related with clinical and/or functional parameters. CONCLUSIONS: Our results indicate an increased burden of diffuse myocardial fibrosis in relation with younger age in pediatric DCM. ECV was associated with clinical and biventricular functional markers of heart failure in DCM