Prevalence and Progression of Late Gadolinium Enhancement in Children and Adolescents With Hypertrophic Cardiomyopathy.

BACKGROUND: Late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is believed to represent dense replacement fibrosis. It is seen in ≈60% of adult patients with hypertrophic cardiomyopathy (HCM). However, the prevalence of LGE in children and adolescents with HCM is not well established. In addition, longitudinal studies describing the development and evolution of LGE in pediatric HCM are lacking. This study assesses the prevalence, progression, and clinical correlations of LGE in children and adolescents with, or genetically predisposed to, HCM. METHODS: CMR scans from 195 patients ≤21 years of age were analyzed in an observational, retrospective study, including 155 patients with overt HCM and 40 sarcomere mutation carriers without left ventricular (LV) hypertrophy. The extent of LGE was quantified by measuring regions with signal intensity >6 SD above nulled remote myocardium. RESULTS: Patients were 14.3±4.5 years of age at baseline and 68% were male. LGE was present in 70 (46%) patients with overt HCM (median extent, 3.3%; interquartile range, 0.8-7.1%), but absent in mutation carriers without LV hypertrophy. Thirty-one patients had >1 CMR (median interval between studies, 2.4 years; interquartile range, 1.5-3.2 years). LGE was detected in 13 patients (42%) at baseline and in 16 patients (52%) at follow-up CMR. The median extent of LGE increased by 2.4 g/y (range, 0-13.2 g/y) from 2.9% (interquartile range, 0.8-3.2%) of LV mass to 4.3% (interquartile range, 2.9-6.8%) ( P=0.02). In addition to LGE, LV mass and left atrial volume, indexed to body surface area, and z score for LV mass, as well, increased significantly from first to most recent CMR. CONCLUSIONS: LGE was present in 46% of children and adolescents with overt HCM, in contrast to ≈60% typically reported in adult HCM. In the subset of patients with serial imaging, statistically significant increases in LGE, LV mass, and left atrial size were detected over 2.5 years, indicating disease progression over time. Further prospective studies are required to confirm these findings and to better understand the clinical implications of LGE in pediatric HCM.

Cardiomyopathies Due to Left Ventricular Noncompaction, Mitochondrial and Storage Diseases, and Inborn Errors of Metabolism.

The normal function of the human myocardium requires the proper generation and utilization of energy and relies on a series of complex metabolic processes to achieve this normal function. When metabolic processes fail to work properly or effectively, heart muscle dysfunction can occur with or without accompanying functional abnormalities of other organ systems, particularly skeletal muscle. These metabolic derangements can result in structural, functional, and infiltrative deficiencies of the heart muscle. Mitochondrial and enzyme defects predominate as disease-related etiologies. In this review, left ventricular noncompaction cardiomyopathy, which is often caused by mutations in sarcomere and cytoskeletal proteins and is also associated with metabolic abnormalities, is discussed. In addition, cardiomyopathies resulting from mitochondrial dysfunction, metabolic abnormalities, storage diseases, and inborn errors of metabolism are described.

A Novel Mechanism for Improved Exercise Performance in Pediatric Fontan Patients After Cardiac Rehabilitation.

Patients with a Fontan circulation have impaired exercise capacity. Cardiac rehabilitation (CR) has shown promise in enhancing peak exercise parameters in this population, but an improvement in submaximal exercise has not been consistently demonstrated. We assessed the hypothesis that participation in CR will be associated with more efficient oxygen extraction and ventilation during submaximal exercise. In this prospective study, pediatric Fontans completed two 60 min CR sessions per week for 12 weeks. Cardiopulmonary exercise testing and stress echocardiography were performed at baseline and last CR session, and then compared with a paired sample t test. Ten pediatric Fontans completed the study. Five had tricuspid atresia and five had hypoplastic left heart syndrome. No serious adverse events occurred during CR sessions. Peak indexed oxygen consumption increased by a mean of 3.7 mL/kg/min (95% CI 1.5-5.9; p = 0.004), and peak oxygen pulse increased by a mean of 0.9 mL/beat (95% CI 0.4-1.4; p = 0.004). The peak respiratory exchange ratio did not change significantly. The significant difference in oxygen pulse became evident during submaximal exercise without a corresponding difference in echocardiographic stroke volume. Indexed oxygen consumption at ventilatory anaerobic threshold increased by a mean of 3.0 mL/kg/min (95% CI - 0.07 to 6.0; p = 0.055). The slope for the volume of expired ventilation to volume of carbon dioxide production improved by a mean of 4.5 (95% CI - 8.4 to - 0.6; p = 0.03). We observed significant improvements in both submaximal and peak exercise performance in pediatric Fontans undergoing CR with no serious adverse events. These changes appeared to be mediated, at least in part, by more efficient oxygen extraction and ventilation.

Hypertrophic Cardiomyopathy Genotype Prediction Models in a Pediatric Population.

The Toronto Hypertrophic Cardiomyopathy (HCM) Genotype Score and Mayo HCM Genotype Predictor are risk assessment models developed to estimate a patient's likelihood of testing positive for a pathogenic variant causative of HCM. These models were developed from adult populations with HCM based on factors that have been associated with a positive genotype and have not been validated in external populations. The purpose of this study was to evaluate the overall predictive abilities of these models in a clinical pediatric HCM setting. A retrospective medical record review of 77 pediatric patients with gene panel testing for HCM between September 2005 and June 2015 was performed. Clinical and echocardiographic variables used in the developed models were collected and used to calculate scores for each patient. To evaluate model performance, the ability to discriminate between a carrier and non-carrier was assessed by area under the ROC curve (AUC) and overall calibration was evaluated by the Hosmer-Lemeshow goodness-of-fit statistic. Discrimination assessed by AUC was 0.72 (P < 0.001) for the Toronto model and 0.67 (P = 0.004) for the Mayo model. The Toronto model and the Mayo model showed P values of 0.36 and 0.82, respectively, for model calibration. Our findings suggest that these models are useful in predicting a positive genetic test result in a pediatric HCM setting. They may be used to aid healthcare providers in communicating risk and enhance patient decision-making regarding pursuit of genetic testing.

Left ventricular non-compaction cardiomyopathy.

Left ventricular non-compaction, the most recently classified form of cardiomyopathy, is characterised by abnormal trabeculations in the left ventricle, most frequently at the apex. It can be associated with left ventricular dilation or hypertrophy, systolic or diastolic dysfunction, or both, or various forms of congenital heart disease. Affected individuals are at risk of left or right ventricular failure, or both. Heart failure symptoms can be induced by exercise or be persistent at rest, but many patients are asymptomatic. Patients on chronic treatment for compensated heart failure sometimes present acutely with decompensated heart failure. Other life-threatening risks of left ventricular non-compaction are ventricular arrhythmias or complete atrioventricular block, presenting clinically as syncope, and sudden death. Genetic inheritance arises in at least 30-50% of patients, and several genes that cause left ventricular non-compaction have been identified. These genes seem generally to encode sarcomeric (contractile apparatus) or cytoskeletal proteins, although, in the case of left ventricular non-compaction with congenital heart disease, disturbance of the NOTCH signalling pathway seems part of a final common pathway for this form of the disease. Disrupted mitochondrial function and metabolic abnormalities have a causal role too. Treatments focus on improvement of cardiac efficiency and reduction of mechanical stress in patients with systolic dysfunction. Further, treatment of arrhythmia and implantation of an automatic implantable cardioverter-defibrillator for prevention of sudden death are mainstays of therapy when deemed necessary and appropriate. Patients with left ventricular non-compaction and congenital heart disease often need surgical or catheter-based interventions. Despite progress in diagnosis and treatment in the past 10 years, understanding of the disorder and outcomes need to be improved.

Early detection of acute kidney injury after pediatric cardiac surgery.

Acute kidney injury (AKI) is increasingly recognized as a common problem in children undergoing cardiac surgery, with well documented increases in morbidity and mortality in both the short and the long term. Traditional approaches to the identification of AKI such as changes in serum creatinine have revealed a large incidence in this population with significant negative impact on clinical outcomes. However, the traditional diagnostic approaches to AKI diagnosis have inherent limitations that may lead to under-diagnosis of this pathologic process. There is a dearth of randomized controlled trials for the prevention and treatment of AKI associated with cardiac surgery, at least in part due to the paucity of early predictive biomarkers. Novel non-invasive biomarkers have ushered in a new era that allows for earlier detection of AKI. With these new diagnostic tools, a more consistent approach can be employed across centers that may facilitate a more accurate representation of the actual prevalence of AKI and more importantly, clinical investigation that may minimize the occurrence of AKI following pediatric cardiac surgery. A thoughtful management approach is necessary to mitigate the effects of AKI after cardiac surgery, which is best accomplished in close collaboration with pediatric nephrologists. Long-term surveillance for improvement in kidney function and potential development of chronic kidney disease should also be a part of the comprehensive management strategy.

PROGRESSION OF CHRONIC KIDNEY DISEASE AFTER ACUTE KIDNEY INJURY.

The incidence of chronic kidney disease (CKD) in children and adults is increasing. Cardiologists have become indispensable members of the care provider team for children with CKD. This is partly due to the high incidence of CKD in children and adults with congenital heart disease, with current estimates of 30-50%. In addition, the high incidence of acute kidney injury (AKI) due to cardiac dysfunction or following pediatric cardiac surgery that may progress to CKD is also well documented. It is now apparent that AKI and CKD are uniquely intertwined as interconnected syndromes. Furthermore, the well-known long-term cardiovascular morbidity and mortality associated with CKD require the joint attention of both nephrologists and cardiologists. Children with both congenital heart disease and CKD are increasingly surviving to adulthood, with synergistically negative medical, financial, and quality of life impact. An improved understanding of the epidemiology, mechanisms, early diagnosis, and preventive measures is of importance to cardiologists, nephrologists, scientists, economists, and policy makers alike. Herein, we report the current definitions, epidemiology, and complications of CKD in children, with an emphasis on children with congenital heart disease. We then focus on the clinical and experimental evidence for the progression of CKD after episodes of AKI commonly encountered in children with heart disease, and explore the role of novel biomarkers for the prediction of CKD progression.

Erratum to: Abnormal Myocardial Strain Indices in Children Receiving Anthracycline Chemotherapy.

Erratum to: Pediatr Cardiol DOI 10.1007/s00246-015-1203-8. The original version of this article unfortunately contained a mistake in the author's group. The given name of Payam Ghazi was misspelled and the first and middle names of John Lynn Jefferies were interchanged. The two co-author names are corrected with this erratum.

Abnormal Myocardial Strain Indices in Children Receiving Anthracycline Chemotherapy.

Anthracycline chemotherapy (AC) is associated with impaired left ventricular (LV) systolic function. LV ejection fraction (EF %) obtained by two-dimensional echocardiography is the current gold standard for detection and monitoring of LV systolic function. However, dependence on LVEF has been shown to be unreliable due to its inherent limitations. Speckle tracking echocardiography (STE) measures myocardial strain and is a sensitive method to detect LV systolic dysfunction with demonstrated utility in such detection in adult and pediatric cohort studies. Compare myocardial strain indices derived by STE with LVEF to detect ACT-induced LV systolic dysfunction. Prospective, cross-sectional measurements of LV myocardial strain indices derived from STE with LVEF. Pediatric cohort of 25 patients (pts): 17 females, eight males with a mean age 9.8 ± 5.8 years, who received anthracyclines (AC); median cumulative dose ≥150 ± 124.4 mg/m(2), range 60-450 mg/m(2) showing normal LV end-diastolic diameter (mm) and normal LVEF (≥55 %) underwent STE to obtain LV myocardial strain indices: strain and strain rate. The inter- and intraobserver variability for the strain indices was 5 %. Fifteen of 25 pts (60 %) showed abnormal global longitudinal peak systolic strain (GLPSS) and 19/25 pts (76 %) showed abnormal peak circumferential strain (PCS) compared to age-matched controls (p = 0.005). In contrast, no significant differences was observed in either indices with the dose of AC. Likewise, no significant changes in the systolic or diastolic strain rate were noted with the dose of AC (r (2) = 0.0076 for peak E, r (2) = 0.072 for peak A, p = NS). GLPSS and PCS were diminished and, however, correlated poorly with the cumulative dose of AC. These observations indicate an early onset of LV systolic dysfunction by the strain indices in pts who continue to show a normal LVEF implying presence of occult LV systolic dysfunction. These novel strain indices may assist in early detection of LV systolic dysfunction with implications for monitoring and prevention of AC-induced LV systolic dysfunction.

Outcomes of restrictive cardiomyopathy in childhood and the influence of phenotype: a report from the Pediatric Cardiomyopathy Registry.

BACKGROUND: Restrictive cardiomyopathy (RCM) has been associated with poor prognosis in childhood. The goal of the present analysis was to use the Pediatric Cardiomyopathy Registry to analyze outcomes of childhood RCM, with a focus on the impact of phenotype comparing pure RCM with cases that have additional features of hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: We analyzed the Pediatric Cardiomyopathy Registry database (1990-2008; N=3375) for cases of RCM. Cases were defined as pure when RCM was the only assigned diagnosis. Additional documentation of HCM at any time was used as the criterion for RCM/HCM phenotype. RCM accounted for 4.5% of cases of cardiomyopathy. In 101 (66%), pure RCM was diagnosed; in 51 (34%), there was a mixed phenotype. Age at diagnosis was not different between groups, but 10% of the pure RCM group was diagnosed in infancy versus 24% of the RCM/HCM group. Freedom from death was comparable between groups with 1-, 2-, and 5-year survival of RCM 82%, 80%, and 68% versus RCM/HCM 77%, 74%, and 68%. Transplant-free survival was 48%, 34%, and 22% and 65%, 53%, and 43%, respectively (P=0.011). Independent risk factors at diagnosis for lower transplant-free survival were heart failure (hazard ratio 2.20, P=0.005), lower fractional shortening z score (hazard ratio 1.12 per 1 SD decrease in z score, P=0.014), and higher posterior wall thickness in the RCM/HCM group only (hazard ratio 1.32, P<0.001). Overall, outcomes were worse than for all other forms of cardiomyopathy. CONCLUSIONS: Transplant-free survival is poor for RCM in childhood. Survival is independent of phenotype; however, the RCM/HCM phenotype has significantly better transplant-free survival. CLINICAL TRIALS REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00005391.

Cardiorenal [corrected] syndrome: an emerging problem in pediatric critical care.

The cardiorenal syndrome (CRS) refers to a complex pathophysiologic state in which heart and kidney dysfunction coexist. Although a robust amount of adult literature exists, limited reports have been made regarding CRS in pediatric patients. However, CRS is increasingly being recognized as an impactful clinical problem that can have important implications regarding the need for treatment and prognosis. Although wide acceptance of a unified definition of CRS is lacking, a general consensus exists that CRS can be either primarily caused by cardiac disease with secondary effects on the kidney, or vice versa, as well as systemic conditions in which cardiac and renal disease are both considered to be secondary. Convincing data in the pediatric perioperative population have been reported, but there is a paucity of information in acute and chronic heart failure (HF), as well as acute kidney injury (AKI) and chronic kidney disease (CKD). Herein, we briefly report on the adult literature and summarize the current pediatric experience.

Cardiac Amyloidosis: A Rare TTR Mutation Found in an Asian Female.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR) is a life-threatening, debilitating disease caused by abnormal formation and deposit of transthyretin (TTR) protein in multiple tissues, including myocardial extracellular matrix. It can be challenging to diagnose due to the myriad of presenting signs and symptoms. Additionally, numerous TTR mutations exist in certain ethnicities. Interestingly, our patient was discovered to have a very rare Gly67Ala TTR mutation typically not found in individuals of Asian descent. Recent advances in cardiovascular imaging techniques have allowed for earlier recognition and, therefore, management of this disease. Although incurable, there are now new, emerging treatments that are available for symptom control of cardiac amyloidosis, making early diagnosis vital for these patients, specifically their quality of life. CASE SUMMARY: We outline a case of a 50-year-old Asian female who was initially hospitalized for nausea and vomiting and persistent orthostatic hypotension. She underwent a multitude of laboratory and imaging tests, resulting in a diagnosis of cardiac amyloidosis, which was confirmed to be due to a rare TTR mutation via genetic testing. CONCLUSIONS: Our objective is to describe various TTR mutations, existing diagnostic imaging modalities, and available treatments, as well as highlight the importance of early screening and awareness of cardiac amyloidosis, allowing for quicker diagnosis and treatment of this disease.

The Roles of Coronary Computed Tomography Angiography in Characterizing Coronary Plaque: Screening, Treatment, and Prevention.

One of the major risk factors for coronary atherosclerosis is the gradual formation and maturation of coronary atherosclerotic plaque (CAP) [...].

Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy resulting from a mutation in one of several cardiac sarcomeric proteins [...].

Novel Device Therapies for Heart Failure.

Heart failure (HF) therapeutics have advanced significantly over the past few years [...].

2022 HRS expert consensus statement on evaluation and management of arrhythmic risk in neuromuscular disorders.

This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. End-of-life management of arrhythmias in patients with NMDs is also covered. The document sections were drafted by the writing committee members according to their area of expertise. The recommendations represent the consensus opinion of the expert writing group, graded by class of recommendation and level of evidence utilizing defined criteria. The recommendations were made available for public comment; the document underwent review by the Heart Rhythm Society Scientific and Clinical Documents Committee and external review and endorsement by the partner and collaborating societies. Changes were incorporated based on these reviews. By using a breadth of accumulated available evidence, the document is designed to provide practical and actionable clinical information and recommendations for the diagnosis and management of arrhythmias and thus improve the care of patients with NMDs.

Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations.

NODAL and its signaling pathway are known to play a key role in specification and patterning of vertebrate embryos. Mutations in several genes encoding components of the NODAL signaling pathway have previously been implicated in the pathogenesis of human left-right (LR) patterning defects. Therefore, NODAL, a member of TGF-beta superfamily of developmental regulators, is a strong candidate to be functionally involved in congenital LR axis patterning defects or heterotaxy. Here we have investigated whether variants in NODAL are present in patients with heterotaxy and/or isolated cardiovascular malformations (CVM) thought to be caused by abnormal heart tube looping. Analysis of a large cohort of cases (n = 269) affected with either classic heterotaxy or looping CVM revealed four different missense variants, one in-frame insertion/deletion and two conserved splice site variants in 14 unrelated subjects (14/269, 5.2%). Although similar with regard to other associated defects, individuals with the NODAL mutations had a significantly higher occurrence of pulmonary valve atresia (P = 0.001) compared with cases without a detectable NODAL mutation. Functional analyses demonstrate that the missense variant forms of NODAL exhibit significant impairment of signaling as measured by decreased Cripto (TDGF-1) co-receptor-mediated activation of artificial reporters. Expression of these NODAL proteins also led to reduced induction of Smad2 phosphorylation and impaired Smad2 nuclear import. Taken together, these results support a role for mutations and rare deleterious variants in NODAL as a cause for sporadic human LR patterning defects.

Dilated cardiomyopathy.

Dilated cardiomyopathy is characterised by left ventricular dilation that is associated with systolic dysfunction. Diastolic dysfunction and impaired right ventricular function can develop. Affected individuals are at risk of left or right ventricular failure, or both. Heart failure symptoms can be exercise-induced or persistent at rest. Many patients are asymptomatic. Chronically treated patients sometimes present acutely with decompensated heart failure. Other life-threatening risks are ventricular arrhythmias and atrioventricular block, syncope, and sudden death. Genetic inheritance arises in 30-48% of patients, and inflammatory disorders such as myocarditis or toxic effects from medications, alcohol, or illicit drugs also result in dilated cardiomyopathy. Genes that cause dilated cardiomyopathy generally encode cytoskeletal and sarcomeric (contractile apparatus) proteins, although disturbance of calcium homeostasis also seems to be important. In children, disrupted mitochondrial function and metabolic abnormalities have a causal role. Treatments focus on improvement of cardiac efficiency and reduction of mechanical stress. Arrhythmia therapy and prevention of sudden death continue to be mainstays of treatment. Despite progress over the past 10 years, outcomes need to be improved.