Myocardial extracellular volume is a non-invasive tissue marker of heart failure in patients with transposition of the great arteries and systemic right ventricle.

Background: Focal myocardial fibrosis in the systemic right ventricle (RV) is related to ventricular dysfunction and adverse outcome in patients with d-transposition of the great arteries (dTGA) post atrial redirection and those with congenitally corrected TGA (ccTGA). The role of diffuse fibrotic lesions in these conditions remains poorly understood. Our study aimed to investigate diffuse myocardial fibrosis by measuring extracellular volume (ECV) with cardiovascular magnetic resonance (CMR) and to explore correlations between ECV and clinical as well as functional markers of heart failure in patients with TGA and systemic RV. Methods: We prospectively included dTGA and ccTGA patients aged ≥14 years and compared them to healthy controls. Standardized CMR included modified Look-Locker Inversion recovery T1 mapping to quantify diffuse myocardial fibrosis in the systemic RV and the subpulmonary left ventricle (LV). The centerline of RV and LV myocardium was marked with a line of interest tool to determine native and post-contrast T1 for quantification of ECV. Results: In total, 13 patients (dTGA: n = 8, ccTGA: n = 5) with a median age of 30.3 years were enrolled. LV ECV was higher in patients than in controls [34% (30%-41%) vs. 26% (23%-27%), p < 0.001], with values increased above the upper limit of normal in 10/13 patients (77%). RV ECV tended to be higher in patients than in controls, albeit without statistical significance [29% (27%-32%) vs. 28% (26%-29%), p = 0.316]. Patients with elevated LV ECV had lower LV ejection fraction than those with normal ECV (52 ± 5% vs. 65 ± 4%, p = 0.007). Correlations with clinical parameters were not observed. LV ECV was significantly higher than RV ECV (p = 0.016) in the patient group. Conclusions: In this study, LV ECV was significantly increased in TGA patients compared to controls, and was associated with LV dysfunction. Our data suggest that ECV may serve as a non-invasive tissue marker of heart failure in TGA with systemic RV. Further research is necessary to evaluate the prognostic implications and the potential role of ECV in monitoring disease progression and guiding therapy, aiming to maintain LV function or train the LV for subaortic location in TGA patients from infancy to adulthood.

Cardiovascular magnetic resonance findings in non-hospitalized paediatric patients after recovery from COVID-19.

AIMS: Our study aimed to investigate the cardiac involvement with sensitive tissue characterization in non-hospitalized children with coronavirus disease 2019 (COVID-19) infection using cardiovascular magnetic resonance (CMR) imaging. METHODS AND RESULTS: We prospectively enrolled children who recovered from mildly symptomatic COVID-19 infection between November 2020 and January 2021. Patients underwent CMR at 1.5 T (Achieva, Philips Healthcare, Best, the Netherlands) including cine images, native T1 and T2 mapping. Healthy children and paediatric patients with biopsy-proven myocarditis served as control groups. We performed CMR in 18 children with a median (25th-75th percentile) age of 12 (10-15) years, 38 (24-47) days after positive PCR test, and compared them with 7 healthy controls [15 (10-19) years] and 9 patients with myocarditis [10 (4-16) years]. The COVID-19 patients reported no cardiac symptoms. None of the COVID-19 patients showed CMR findings consistent with a myocarditis. Three patients (17%) from the COVID-19 cohort presented with minimal pericardial effusion. CMR parameters of COVID-19 patients, including volumetric and strain values as well as T1 and T2 times, were not significantly different from healthy controls, but from myocarditis patients. These had significantly reduced left ventricular (LV) ejection fraction (P = 0.035), LV global longitudinal strain, and left atrial strain values as well as elevated native T1 values compared with COVID-19 patients (P < 0.001, respectively). CONCLUSIONS: There was no evidence of myocardial inflammation, fibrosis, or functional cardiac impairment in the studied cohort of children recently. CMR findings were comparable with those of healthy controls. Pericardial effusion suggests a mild pericarditis in a small subgroup. This is pointing to a minor clinical relevance of myocardial involvement in children after mildly symptomatic COVID-19 infections.

Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy.

Background: Left ventricular noncompaction cardiomyopathy (LVNC CMP) is a genetic cardiomyopathy. Genotype-phenotype correlation and clinical outcome of genetic variants in pediatric and adult LVNC CMP patients are still unclear. Methods: The retrospective multicenter study was conducted in unrelated index patients with LVNC CMP, diagnosed between the years 1987 and 2017, and all available family members. All index patients underwent next-generation sequencing for genetic variants in 174 target genes using the Illumina TruSight Cardio Sequencing Panel. Major adverse cardiac events (MACE) included mechanical circulatory support, heart transplantation, survivor of cardiac death, and/or all-cause death as combined endpoint. Results: Study population included 149 LVNC CMP patients with a median age of 27.8 (9.2-44.8) years at diagnosis; 58% of them were symptomatic, 18% suffered from non-sustained and sustained arrhythmias, and 17% had an implantable cardioverter defibrillator (ICD) implanted. 55/137 patients (40%) were ≤ 18 years at diagnosis. A total of 134 variants were identified in 87/113 (77%) index patients. 93 variants were classified as variant of unknown significance (VUS), 24 as likely pathogenic and 15 as pathogenic. The genetic yield of (likely) pathogenic variants was 35/113 (31%) index patients. Variants occurred most frequently in MYH7 (n=19), TTN (n = 10) and MYBPC3 (n = 8). Altogether, sarcomere gene variants constituted 42.5% (n = 57) of all variants. The presence or absence of (likely) pathogenic variants or variants in specific genes did not allow risk stratification for MACE. Reduced left ventricular (LV) systolic function and increased left ventricular end-diastolic diameter (LVEDD) were risk factors for event-free survival in the Kaplan-Meier analysis. Through multivariate analysis we identified reduced LV systolic function as the main risk factor for MACE. Patients with reduced LV systolic function were at a 4.6-fold higher risk for MACE. Conclusions: Genetic variants did not predict the risk of developing a MACE, neither in the pediatric nor in the adult cohort. Multivariate analysis emphasized reduced LV systolic function as the main independent factor that is elevating the risk for MACE. Genetic screening is useful for cascade screening to identify family members at risk for developing LVNC CMP.

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 (Genetics in Pediatric Myocarditis) with biopsy-proven myocarditis underwent genetic testing with targeted panel sequencing of cardiomyopathy-associated genes. Genetics in Pediatric Myocarditis patients were divided into subgroups according to the phenotype of dilated cardiomyopathy (DCM) at presentation, resulting in 22 patients without DCM (myocarditis without phenotype of DCM) and 20 patients with DCM (myocarditis with phenotype of DCM). RESULTS: Myocarditis with phenotype of DCM patients (median age 1.4 years) were younger than myocarditis without phenotype of DCM 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 variant was identified in 9 out of 42 patients (22%), 8 of them were heterozygous, and 7 out of 9 were in myocarditis with phenotype of DCM. Likely pathogenic/pathogenic 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 myocarditis with phenotype of DCM versus healthy individuals (P=0.0003). Event-free survival was lower (P=0.008) in myocarditis with phenotype of DCM patients compared with myocarditis without phenotype of DCM and primary DCM. CONCLUSIONS: We report heterozygous likely pathogenic/pathogenic variants in biopsy-proven pediatric myocarditis. Myocarditis patients with DCM phenotype were characterized by early-onset heart failure, significant enrichment of likely pathogenic/pathogenic variants, and poor outcome. These phenotype-specific 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.

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.

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.

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3.

The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next-generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation-not only in adult-but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.

RIKADA Study Reveals Risk Factors in Pediatric Primary Cardiomyopathy.

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.

Cardiac T1 mapping in congenital heart disease: bolus vs. infusion protocols for measurements of myocardial extracellular volume fraction.

Myocardial extracellular volume fraction (ECV) reflecting diffuse myocardial fibrosis can be measured with T1 mapping cardiovascular magnetic resonance (CMR) before and after the application of a gadolinium-based extracellular contrast agent. The equilibrium between blood and myocardium contrast concentration required for ECV measurements can be obtained with a primed contrast infusion (equilibrium contrast-CMR). We hypothesized that equilibrium can also be achieved with a single contrast bolus to accurately measure diffuse myocardial fibrosis in patients with congenital heart disease (CHD). Healthy controls (n = 17; median age 24.0 years) and patients with CHD (n = 19; 25.0 years) were prospectively enrolled. Using modified Look-Locker inversion recovery T1 mapping before, 15 min after bolus injection, and during constant infusion of gadolinium-DOTA, T1 values were obtained for blood pool and myocardium of the left ventricle (LV), the interventricular septum (IVS), and the right ventricle (RV) in a single midventricular plane in short axis or in transverse orientation. ECV of LV, IVS and RV by bolus-only and bolus-infusion correlated significantly in CHD patients (r = 0.94, 0.95, and 0.74; p < 0.01, respectively) and healthy controls (r = 0.96, 0.89, and 0.64; p < 0.05, respectively). Bland-Altman plots revealed no significant bias between the techniques for any of the analyzed regions. ECV of LV and RV myocardium measured by bolus-only T1 mapping agrees well with bolus-infusion measurements in patients with CHD. The use of a bolus-only approach facilitates the integration of ECV measurements into existing CMR imaging protocols, allowing for assessment of diffuse myocardial fibrosis in CHD in clinical routine.