Design and implementation of multicenter pediatric and congenital studies with cardiovascular magnetic resonance: Big data in smaller bodies.

Cardiovascular magnetic resonance (CMR) has become the reference standard for quantitative and qualitative assessment of ventricular function, blood flow, and myocardial tissue characterization. There is a preponderance of large CMR studies and registries in adults; However, similarly powered studies are lacking for the pediatric and congenital heart disease (PCHD) population. To date, most CMR studies in children are limited to small single or multicenter studies, thereby limiting the conclusions that can be drawn. Within the PCHD CMR community, a collaborative effort has been successfully employed to recognize knowledge gaps with the aim to embolden the development and initiation of high-quality, large-scale multicenter research. In this publication, we highlight the underlying challenges and provide a practical guide toward the development of larger, multicenter initiatives focusing on PCHD populations, which can serve as a model for future multicenter efforts.

Society for Cardiovascular Magnetic Resonance 2022 Cases of SCMR case series.

"Cases of SCMR" is a case series on the SCMR website (https://www.scmr.org) for the purpose of education. The cases reflect the clinical presentation, and the use of cardiovascular magnetic resonance (CMR) in the diagnosis and management of cardiovascular disease. The 2022 digital collection of cases are presented in this manuscript.

Transseptal coronary artery-a pictorial review.

A transseptal coronary artery course, also known as a transconal course, is an anomalous course of the left main coronary artery (LMCA) or the left anterior descending artery (LAD) through the conal septal myocardium. The conal septal myocardium is the posterior wall of the right ventricular outflow tract (RVOT), acting as a dividing myocardial wall between the subaortic and subpulmonary outflow tracts. The initial segment of a transseptal coronary artery has an extraconal course between the aorta and the RVOT cranial to the true intramyocardial segment. The transseptal coronary artery then emerges out of the conal septal myocardium at the epicardial surface on the lateral aspect of the RVOT. Many consider the transseptal coronary artery to be a benign entity. However, there are few case reports of severe cardiac symptoms such as myocardial ischemia, arrhythmia, and even sudden cardiac deaths due to potential coronary artery compression in the systolic phase.​ In this article, we seek to describe the imaging findings of transseptal coronary artery course on coronary computed tomography angiography (CTA), discuss their clinical analysis, and briefly discuss the management of these lesions.

Echocardiography phenotyping in murine genetic reference population of BXD strains reveals significant QTLs associated with cardiac function and morphology.

The genetic reference population of recombinant inbred BXD mice has been derived from crosses between C57BL/6J and DBA/2J strains. The DBA/2J parent exhibits cardiomyopathy phenotypes, whereas C57BL/6J has normal heart. BXD mice are sequenced for studying genetic interactions in cardiomyopathies. The study aimed to assess cardiomyopathy traits in BXDs and investigate the quantitative genetic architecture of those traits. Echocardiography, blood pressure, and cardiomyocyte size parameters obtained from 44 strains of BXD family (n > 5/sex) at 4-5 mo of age were associated with heart transcriptomes and expression quantitative trait loci (eQTL) mapping was performed. More than twofold variance in ejection fraction (EF%), fractional shortening (FS%), left ventricular volumes (LVVols), internal dimensions (LVIDs), mass (LVM), and posterior wall (LVPW) thickness was found among BXDs. In male BXDs, eQTL mapping identified Ndrg4 on chromosome 8 QTL to be positively correlated with LVVol and LVID and negatively associated with cardiomyocyte diameter. In female BXDs, significant QTLs were found on chromosomes 7 and 3 to be associated with LVPW and EF% and FS%, respectively, and Josd2, Dap3, and Tpm3 were predicted as strong candidate genes. Our study found variable cardiovascular traits among BXD strains and identified multiple associated QTLs, suggesting an influence of genetic background on expression of echocardiographic and cardiomyocyte diameter traits. Increased LVVol and reduced EF% and FS% represented dilated cardiomyopathy, whereas increased LV mass and wall thickness indicated hypertrophic cardiomyopathy traits. The BXD family is ideal for identifying candidate genes, causal and modifier, that influence cardiovascular phenotypes.NEW & NOTEWORTHY This study aimed to establish a cardiac phenotype-genotype correlation in murine genetic reference population of BXD RI strains by phenotyping the echocardiography, blood pressure, and cardiomyocyte diameter traits and associating each collected phenotype with genetic background. Our study identified several QTLs and candidate genes that have significant association with cardiac hypertrophy, ventricular dilation, and function including systolic hyperfunction and dysfunction.

Progressive Reduction in Right Ventricular Contractile Function Attributable to Altered Actin Expression in an Aging Mouse Model of Arrhythmogenic Cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder of desmosomal dysfunction, and PKP2 (plakophilin-2) has been reported to be the most common disease-causing gene when mutation-positive. In the early concealed phase, the ACM heart is at high risk of sudden cardiac death before cardiac remodeling occurs because of mistargeted ion channels and altered Ca2+ handling. However, the results of pathogenic PKP2 variants on myocyte contraction in ACM pathogenesis remain unknown. METHODS: We studied the outcomes of a human truncating variant of PKP2 on myocyte contraction using a novel knock-in mouse model with insertion of thymidine in exon 5 of Pkp2, which mimics a familial case of ACM (PKP2-L404fsX5). We used serial echocardiography, electrocardiography, blood pressure measurements, histology, cardiomyocyte contraction, intracellular calcium measurements, and gene and protein expression studies. RESULTS: Serial echocardiography of Pkp2 heterozygous (Pkp2-Het) mice revealed progressive failure of the right ventricle (RV) in animals older than 3 months. By contrast, left ventricular function remained normal. ECGs of 6-month-old anesthetized Pkp2-Het mice showed normal baseline heart rates and QRS complexes. Cardiac responses to ß-adrenergic agonist isoproterenol (2 mg/kg) plus caffeine (120 mg/kg) were also normal. However, adrenergic stimulation enhanced the susceptibility of Pkp2-Het hearts to tachyarrhythmia and sudden cardiac death. Histological staining showed no significant fibrosis or adipocyte infiltration in the RVs and left ventricles of 6- and 12-month-old Pkp2-Het hearts. Contractility assessment of isolated myocytes demonstrated progressively reduced Pkp2-Het RV cardiomyocyte function consistent with RV failure measured by echocardiography. However, aging Pkp2-Het and control RV myocytes loaded with intracellular Ca2+ indicator Fura-2 showed comparable Ca2+ transients. Western blotting of Pkp2-RV homogenates revealed a 40% decrease in actin, whereas actin immunoprecipitation followed by a 2,4-dinitrophenylhydrazine staining showed doubled oxidation level. This correlated with a 39% increase in troponin-I phosphorylation. In contrast, Pkp2-Het left ventricular myocytes had normal contraction, actin expression and oxidation, and troponin-I phosphorylation. Last, Western blotting of cardiac biopsies revealed that actin expression was 40% decreased in RVs of patients with end-stage ACM. CONCLUSIONS: During the early concealed phase of ACM, reduced actin expression drives loss of RV myocyte contraction, contributing to progressive RV dysfunction.

The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model.

The transmembrane protein 43 (TMEM43/LUMA) p.S358L mutation causes arrhythmogenic cardiomyopathy named as ARVC5, a fully penetrant disease with high risk of ventricular arrhythmias, sudden death, and heart failure. Male gender and vigorous exercise independently predicted deleterious outcome. Our systems genetics analysis revealed the importance of Tmem43 for cardiac and metabolic pathways associated with elevated lipid absorption from small intestine. This study sought to delineate gender-specific cardiac, intestinal, and metabolic phenotypes in vivo and investigate underlying pathophysiological mechanisms of S358L mutation. Serial echocardiography, surface electrocardiography (ECG), treadmill running, and body EchoMRI have been used in knock-in heterozygous (Tmem43WT/S358L), homozygous (Tmem43S358L), and wildtype (Tmem43WT) littermate mice. Electron microscopy, histology, immunohistochemistry, transcriptome, and protein analysis have been performed in cardiac and intestinal tissues. Systolic dysfunction was apparent in 3-mo-old Tmem43S358L and 6-mo-old Tmem43WT/S358L mutants. Both mutant lines displayed intolerance to acute stress at 6 mo of age, arrhythmias, fibro-fatty infiltration, and subcellular abnormalities in the myocardium. Microarray analysis found significantly differentially expressed genes between left ventricular (LV) and right ventricular (RV) myocardium. Mutants displayed diminished PPARG activities and significantly reduced TMEM43 and ß-catenin expression in the heart, whereas junctional plakoglobin (JUP) translocated into nuclei of mutant cardiomyocytes. Conversely, elongated villi, fatty infiltration, and overexpression of gut epithelial proliferation markers, ß-catenin and Ki-67, were evident in small intestine of mutants. We defined Tmem43 S358L-induced pathological effects on cardiac and intestinal homeostasis via distinctly disturbed WNT-ß-catenin and PPARG signaling thereby contributing to ARVC5 pathophysiology. Results suggest that cardiometabolic assessment in mutation carriers may be important for predictive and personalized care.NEW & NOTEWORTHY This manuscript describes the findings of our investigation of cardiac, small intestine, and metabolic features of Tmem43-S358L mouse model. By investigating interorgan pathologies, we uncovered multiple mechanisms of the S358L-induced disease, and these unique mechanisms likely appear to contribute to the disease pathogenesis. We hope our findings are important and novel and open new avenues in the hunting for additional diagnostic and therapeutic targets in subjects carrying TMEM43 mutation.

Imaging of pediatric cardiac tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Cardiac tumors in children are rare and the majority are benign. The most common cardiac tumor in children is rhabdomyoma, usually associated with tuberous sclerosis complex. Other benign cardiac masses include fibromas, myxomas, hemangiomas, and teratomas. Primary malignant cardiac tumors are exceedingly rare, with the most common pathology being soft tissue sarcomas. This paper provides consensus-based imaging recommendations for the evaluation of patients with cardiac tumors at diagnosis and follow-up, including during and after therapy.

Long-Term Cardiovascular Outcomes of Multisystem Inflammatory Syndrome in Children Associated with COVID-19 Using an Institution Based Algorithm.

Cardiovascular involvement is a major cause of inpatient and intensive care unit morbidity related to Multisystem inflammatory syndrome in children (MIS-C). The objective of this study was to identify long-term cardiovascular manifestations of MIS-C. We included 80 consecutive patients admitted to the intensive care unit with MIS-C who were evaluated for a year in our follow-up clinic using an institution protocol. The outcome measures were cardiac biomarkers (troponin and BNP), electrocardiogram changes, echocardiographic findings cardiovascular magnetic resonance (CMR) and graded-exercise stress test (GXT) findings. The cohort included patients aged between 6 months and 17 years (median 9 years; 48.8% females). At the peak of the disease 81.3% had abnormal BNP and 58.8% had troponin leak which reduced to 33.8% and 18.8% respectively at discharge with complete normalization by 6 weeks post-discharge. At admission 33.8% had systolic dysfunction, which improved to 11.3% at discharge with complete resolution by 2 weeks. Coronary artery abnormalities were seen in 17.5% during the illness with complete resolution by 2 weeks post discharge except one (1.9%) with persistent giant aneurysm at 1 year-follow up. CMR was performed at 6 months in 23 patient and demonstrated 4 patients with persistent late gadolinium enhancement (17.4%). Normal exercise capacity with no ectopy was seen in the 31 qualifying patients that underwent a GXT. There is significant heterogeneity in the cardiovascular manifestations of MIS-C. Although majority of the cardiovascular manifestations resolve within 6 weeks, diastolic dysfunction, CAA and myocardial scar may persist in a small subset of patients warranting a structured long-term follow-up strategy.

Systems genetics analysis defines importance of TMEM43/LUMA for cardiac- and metabolic-related pathways.

Broad cellular functions and diseases including muscular dystrophy, arrhythmogenic right ventricular cardiomyopathy (ARVC5) and cancer are associated with transmembrane protein43 (TMEM43/LUMA). The study aimed to investigate biological roles of TMEM43 through genetic regulation, gene pathways and gene networks, candidate interacting genes, and up- or downstream regulators. Cardiac transcriptomes from 40 strains of recombinant inbred BXD mice and two parental strains representing murine genetic reference population (GRP) were applied for genetic correlation, functional enrichment, and coexpression network analysis using systems genetics approach. The results were validated in a newly created knock-in Tmem43-S358L mutation mouse model (Tmem43S358L) that displayed signs of cardiac dysfunction, resembling ARVC5 phenotype seen in humans. We found high Tmem43 levels among BXDs with broad variability in expression. Expression of Tmem43 highly negatively correlated with heart mass and heart rate among BXDs, whereas levels of Tmem43 highly positively correlated with plasma high-density lipoproteins (HDL). Through finding differentially expressed genes (DEGs) between Tmem43S358L mutant and wild-type (Tmem43WT) lines, 18 pathways (out of 42 found in BXDs GRP) that are involved in ARVC, hypertrophic cardiomyopathy, dilated cardiomyopathy, nonalcoholic fatty liver disease, Alzheimer's disease, Parkinson's disease, and Huntington's disease were verified. We further constructed Tmem43-mediated gene network, in which Ctnna1, Adcy6, Gnas, Ndufs6, and Uqcrc2 were significantly altered in Tmem43S358L mice versus Tmem43WT controls. Our study defined the importance of Tmem43 for cardiac- and metabolism-related pathways, suggesting that cardiovascular disease-relevant risk factors may also increase risk of metabolic and neurodegenerative diseases via TMEM43-mediated pathways.

Society for Cardiovascular Magnetic Resonance 2021 cases of SCMR and COVID-19 case collection series.

The Society for Cardiovascular Magnetic Resonance (SCMR) is an international society focused on the research, education, and clinical application of cardiovascular magnetic resonance (CMR). "Cases of SCMR" is a case series hosted on the SCMR website ( https://www.scmr.org ) that demonstrates the utility and importance of CMR in the clinical diagnosis and management of cardiovascular disease. The COVID-19 Case Collection highlights the impact of coronavirus disease 2019 (COVID-19) on the heart as demonstrated on CMR. Each case in series consists of the clinical presentation and the role of CMR in diagnosis and guiding clinical management. The cases are all instructive and helpful in the approach to patient management. We present a digital archive of the 2021 Cases of SCMR and the 2020 and 2021 COVID-19 Case Collection series of nine cases as a means of further enhancing the education of those interested in CMR and as a means of more readily identifying these cases using a PubMed or similar literature search engine.

Cardiovascular Magnetic Resonance in Children with Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: Institutional Protocol-Based Medium-Term Follow-up Study.

Multisystem inflammatory syndrome in children (MIS-C) secondary to COVID-19 infection in previously healthy children often results in subtle but persistent echocardiographic abnormalities despite complete clinical recovery. This study was done to investigate medium-term cardiovascular outcomes of patients with MIS-C using cardiovascular magnetic resonance imaging (CMR). This is a single-center retrospective study of patients aged less than 21 years, diagnosed with MIS-C who received an outpatient CMR, around 6 months after discharge. CMR was done in patients with significant troponin leak or depressed LVEF. CMR performed on a GE Signa HDxt 1.5 Tesla magnet with a myocarditis protocol. Diagnosis of myocarditis was determined by the original Lake Louise Criteria. There were 21 patients with a median age of 11 years, (IQR 8-13 years), who underwent CMR at median follow-up duration of 6 months (IQR 5-7 months). At the peak of illness during admission, there were 95.2% patients with abnormal Troponin I and BNP. By echocardiogram, 76.2% had left ventricular systolic dysfunction and 9.5% had coronary ectasia, which all resolved by 6 months. By CMR, there were five patients (23.8%) with abnormal left atrial volume, one patient (4.8%) with an abnormal indexed left ventricular end-diastolic volume, and three patients (15%) with abnormal LVEF. There was no evidence of myocardial edema in T2-weighted image sequence. There were three patients with persistent late gadolinium enhancement (14.3%). Follow-up CMR is a useful tool in diagnosing subtle myocardial abnormalities and guide necessity for future follow-up.

Society for Cardiovascular Magnetic Resonance 2020 Case of the Week series.

The Society for Cardiovascular Magnetic Resonance (SCMR) is an international society focused on the research, education, and clinical application of cardiovascular magnetic resonance (CMR). Case of the week is a case series hosted on the SCMR website ( https://www.scmr.org ) that demonstrates the utility and importance of CMR in the clinical diagnosis and management of cardiovascular disease. Each case consists of the clinical presentation and a discussion of the condition and the role of CMR in diagnosis and guiding clinical management. The cases are all instructive and helpful in the approach to patient management. We present a digital archive of the 2020 Case of the Week series of 11 cases as a means of further enhancing the education of those interested in CMR and as a means of more readily identifying these cases using a PubMed or similar search engine.

Society for Cardiovascular Magnetic Resonance 2019 Case of the Week series.

The Society for Cardiovascular Magnetic Resonance (SCMR) is an international society focused on the research, education, and clinical application of cardiovascular magnetic resonance (CMR). The SCMR web site ( https://www.scmr.org ) hosts a case series designed to present case reports demonstrating the unique attributes of CMR in the diagnosis or management of cardiovascular disease. Each clinical presentation is followed by a brief discussion of the disease and unique role of CMR in disease diagnosis or management guidance. By nature, some of these are somewhat esoteric, but all are instructive. In this publication, we provide a digital archive of the 2019 Case of the Week series as a means of further enhancing the education of those interested in CMR and as a means of more readily identifying these cases using a PubMed or similar search engine.

Consensus Guidelines for the Prevention and Management of Periprocedural Complications of Transcatheter Patent Ductus Arteriosus Closure with the Amplatzer Piccolo Occluder in Extremely Low Birth Weight Infants.

Transcatheter closure of patent ductus arteriosus (PDA) in premature infants is a feasible, safe, and an effective alternative to surgical ligation and may be performed with an implant success rate of 97%. Major procedural complications related to transcatheter PDA closure in extremely low birth weight (ELBW) infants are relatively infrequent (< 3%) ,but may be associated with a fatality if not optimally managed. Operators performing transcatheter PDA closures should be knowledgeable about these potential complications and management options. Prompt recognition and treatment are often necessary to avoid serious consequences. With strict guidelines on operator training, proctoring requirements, and technical refinements, transcatheter PDA closure in ELBW infants can be performed safely with low complication rates. This article summarizes the consensus guidelines put forward by a panel of physicians for the prevention and management of periprocedural complications of transcatheter PDA closure with the Amplatzer Piccolo Occluder in ELBW infants.

Cumulative radiation exposure and cancer risk estimation in children with heart disease.

BACKGROUND: Children with heart disease are frequently exposed to imaging examinations that use ionizing radiation. Although radiation exposure is potentially carcinogenic, there are limited data on cumulative exposure and the associated cancer risk. We evaluated the cumulative effective dose of radiation from all radiation examinations to estimate the lifetime attributable risk of cancer in children with heart disease. METHODS AND RESULTS: Children ≤6 years of age who had previously undergone 1 of 7 primary surgical procedures for heart disease at a single institution between 2005 and 2010 were eligible for the study. Exposure to radiation-producing examinations was tabulated, and cumulative effective dose was calculated in millisieverts. These data were used to estimate lifetime attributable risk of cancer above baseline using the approach of the Committee on Biological Effects of Ionizing Radiation VII. The cohort included 337 children exposed to 13 932 radiation examinations. Conventional radiographs represented 92% of examinations, whereas cardiac catheterization and computed tomography accounted for 81% of cumulative exposure. Overall median cumulative effective dose was 2.7 mSv (range, 0.1-76.9 mSv), and the associated lifetime attributable risk of cancer was 0.07% (range, 0.001%-6.5%). Median lifetime attributable risk of cancer ranged widely depending on surgical complexity (0.006%-1.6% for the 7 surgical cohorts) and was twice as high in females per unit exposure (0.04% versus 0.02% per 1-mSv effective dose for females versus males, respectively; P<0.001). CONCLUSIONS: Overall radiation exposures in children with heart disease are relatively low; however, select cohorts receive significant exposure. Cancer risk estimation highlights the need to limit radiation dose, particularly for high-exposure modalities.

Corynebacterium endocarditis of a percutaneously placed transcatheter pulmonary valve.

We report a case of endocarditis of a transcatheter pulmonary valve-in-valve in a 14-year-old boy with tetralogy of Fallot. He presented with recurrent low-grade fevers, lethargy, and anorexia. Multiple blood cultures grew a gram-positive rod, Corynebacterium pseudodiphtheriticum. He was taken to the operating room for removal of the vegetative endocarditis and pulmonary valve replacement.

Lessons from the Pandemic: Role of Percutaneous ECMO and Balloon Atrial Septostomy in Multi-System Inflammatory Syndrome in Children.

Multi-system inflammatory syndrome in children (MIS-C) in the setting of COVID-19 can be associated with severe cardiopulmonary dysfunction. This clinical deterioration may sometimes necessitate veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. We describe an algorithmic approach including the role of balloon atrial septostomy in this cohort. This is the first reported series of percutaneous VA-ECMO in pediatric patients with MIS-C for better outcomes. The lessons from this approach can be replicated in other pediatric clinical conditions and adds to the armament of multiple pediatric specialties.

Modifiable Cardiometabolic Risk Factors in Survivors of Childhood Cancer: JACC: CardioOncology State-of-the-Art Review.

The growing community of childhood cancer survivors faces a heavy burden of late onset morbidities and mortality, with cardiovascular diseases being the leading noncancer cause. In addition to demographics and cancer treatment exposures, which cannot be altered, cardiometabolic risk factors (obesity, hypertension, diabetes, and dyslipidemia) and frailty potentiate the risk of morbidity and mortality associated with chronic health conditions. Important opportunities exist to target these risk factors and improve late health outcomes for survivors. Unfortunately, limited evidence exists on the optimal methods to prevent, screen, and treat cardiometabolic risk factors among survivors, resulting in significant underdiagnosis and undertreatment. In this review, we discuss the prevalence of, risk factors for, current survivor-specific recommendations, and gaps in knowledge to mitigate potentially modifiable cardiometabolic risk factors and frailty among survivors of childhood cancer.