The genetic architecture of pediatric cardiomyopathy.

To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10-16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.

The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, abnormal results on exercise stress testing are predictive of heart failure outcomes. Our goal was to determine whether an abnormal exercise response is associated with adverse outcomes in pediatric patients with HCM. METHODS: In an international cohort study including 20 centers, phenotype-positive patients with primary HCM who were <18 years of age at diagnosis were included. Abnormal exercise response was defined as a blunted blood pressure response and new or worsened ST- or T-wave segment changes or complex ventricular ectopy. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted sudden cardiac arrest. Using Kaplan-Meier survival, competing outcomes, and Cox regression analyses, we analyzed the association of abnormal exercise test results with transplant and SCD event-free survival. RESULTS: Of 724 eligible patients, 630 underwent at least 1 exercise test. There were no major differences in clinical characteristics between those with or without an exercise test. The median age at exercise testing was 13.8 years (interquartile range, 4.7 years); 78% were male and 39% were receiving beta-blockers. A total of 175 (28%) had abnormal test results. Patients with abnormal test results had more severe septal hypertrophy, higher left atrial diameter z scores, higher resting left ventricular outflow tract gradient, and higher frequency of myectomy compared with participants with normal test results (P<0.05). Compared with normal test results, abnormal test results were independently associated with lower 5-year transplant-free survival (97% versus 88%, respectively; P=0.005). Patients with exercise-induced ischemia were most likely to experience all-cause death or transplant (hazard ratio, 4.86 [95% CI, 1.69-13.99]), followed by those with an abnormal blood pressure response (hazard ratio, 3.19 [95% CI, 1.32-7.71]). Exercise-induced ischemia was also independently associated with lower SCD event-free survival (hazard ratio, 3.32 [95% CI, 1.27-8.70]). Exercise-induced ectopy was not associated with survival. CONCLUSIONS: Exercise abnormalities are common in childhood HCM. An abnormal exercise test result was independently associated with lower transplant-free survival, especially in those with an ischemic or abnormal blood pressure response with exercise. Exercise-induced ischemia was also independently associated with SCD events. These findings argue for routine exercise testing in childhood HCM as part of ongoing risk assessment.

Genetic Testing Resources and Practice Patterns Among Pediatric Cardiomyopathy Programs.

The use of genetic testing has enhanced the diagnostic accuracy of heritable genetic cardiomyopathies. However, it remains unclear how genetic information is interpreted and incorporated into clinical practice for children with cardiomyopathy. The primary aim of this study was to understand how clinical practice differs regarding sequence variant classifications amongst pediatric cardiologists who treat children with cardiomyopathy. A secondary aim was to understand the availability of genetic testing and counseling resources across participating pediatric cardiomyopathy programs. An electronic survey was distributed to pediatric heart failure, cardiomyopathy, or heart transplantation physicians between August and September 2022. A total of 106 individual providers from 68 unique centers responded to the survey. Resources for genetic testing and genetic counseling vary among large pediatric cardiomyopathy programs. A minority of centers reported having a geneticist (N = 16, 23.5%) or a genetic counselor (N = 21, 31%) on faculty within the division of pediatric cardiology. A total of 9 centers reported having both (13%). Few centers (N = 13, 19%) have a formal process in place to re-engage patients who were previously discharged from cardiology follow-up if variant reclassification would alter clinical management. Clinical practice patterns were uniform in response to pathogenic or likely pathogenic variants but were more variable for variants of uncertain significance. Efforts to better incorporate genetic expertise and resources into the clinical practice of pediatric cardiomyopathy may help to standardize the interpretation of genetic information and better inform clinical decision-making surrounding heritable cardiomyopathies.

Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy.

BACKGROUND: Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. METHODS: A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. RESULTS: In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE >2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness (P < .001), but not LGE. CONCLUSIONS: Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM.

QTc and QRS Abnormalities are Associated with Outcome in Pediatric Heart Failure.

Adult studies have shown that depolarization and repolarization abnormalities are associated with worsening heart failure; however, this relationship is not well understood in pediatric congenital heart disease. We evaluated the association between QTc and QRS duration to systolic function and outcome in children with heart failure and reduced ejection fraction (HFrEF). We performed a retrospective, single-center, 14-year cohort study of HFrEF children. Clinical records, echocardiograms, and electrocardiograms were reviewed for every clinical encounter. Diagnosis, interventions, outcomes, QRS and QTc duration, and systolic function were collected. Repeated-measure ANOVA evaluated the association between depolarization and repolarization to cardiac function. Cox regression analysis examined the effects of age, time since diagnosis, and measured and change in QTc and QRS duration on time to transplant/death. We enrolled 136 cardiomyopathy (CM) and 47 structural heart disease (SHD) patients. Prolonged QRS (p = 0.0001) and QTc (p = 0.02) were associated with systolic dysfunction. This association was significant in SHD group (QRS p < 0.0001, QTc p = 0.048), but not CM group (QRS p = 0.5, QTc p = 0.3). Progressive lengthening of QTc was significantly associated with transplant or death in the overall cohort (HR 1.02, CI 1.011-1.028), SHD, (HR 1.020, CI 1.001-1.039), and CM (HR 1.017, CI 1.007-1.027). QTc and QRS prolongation are each associated with ventricular dysfunction in pediatric SHD with heart failure. QTc prolongation is an indication for poor outcomes in SHD and CM groups, leading to a higher risk of death or transplantation. Progressive lengthening of QTc over time in children with HFrEF may indicate increased risk in this population.

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies. METHODS: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285). RESULTS: Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z-score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively). CONCLUSION: Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.

Self-reported and Accelerometer-Measured Physical Activity in Children With Cardiomyopathy.

PURPOSE: Children with cardiomyopathy are at risk of heart failure with reduced physical activity (PA) as a cardinal manifestation. Clinical assessment of PA in children is challenging due to the limited validity of subjective reports. The aim of the study was to compare accelerometery measurement with parental report and to identify factors associated with movement behavior (PA, sedentary time, steps per day). METHOD: Fifteen patients with cardiomyopathy (mean, 9.7 years; 64% male) were asked to wear an Actigraph GT3X accelerometer in Edmonton, Canada. Demographics, clinical characteristics, parental-reported PA, and health-related quality of life data were also collected. RESULTS: Participants engaged in a median of 38 minutes of moderate-vigorous PA per day with higher levels in boys versus girls (73.9 [25.03, 78.91] vs 4.13 [2.53, 37.67] minutes, P = .03). Children participating in recreational sports showed a higher level of moderate-vigorous PA (73.92 min/d) compared with those who did not participate (73.9 vs 22.7 min/d, P = .05), and positive family outlook on the child's health was associated with less sedentary time (P = .04). CONCLUSION: Accelerometer measurement in children with cardiomyopathy is an achievable and more objective measure of PA compared with parental report alone and highlighted low levels of PA among these children.

Correction: Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

In the original version of this Article, the Statement on Conflict of Interest originally submitted by the authors was not published. Furthermore, in the Acknowledgements section we neglected to state that this article is an abbreviated version of "Genetic Evaluation of Cardiomyopathy-a Heart Failure Society of America Practice Guideline," published in Journal of Cardiac Failure. The PDF and HTML versions of the Article have now been corrected.

Update on pediatric heart failure.

PURPOSE OF REVIEW: This review highlights recent advances in the diagnosis and management of children with heart failure. We emphasize the clinical approach to patient care in the areas of acute decompensated heart failure, chronic heart failure, and failure of the patient with single ventricle physiology. RECENT FINDINGS: Important guidelines regarding the recognition and management of heart failure in children have been proposed and adopted, providing guidance for early recognition and ongoing management. Early diuresis, and avoidance of excessive inotropic agent use, in favor of milrinone as an inotropic-vasodilator agent, are emphasized. Close monitoring of airway pressures to improve ventricular filling, and extubation to positive pressure or high-flow nasal cannula therapy are also important. Chronic heart failure therapy requires combination treatment with diuretics, and the three major classes of drugs. Management of the failing Fontan requires attention to the hepatic, pulmonary and lymphatic circulations. SUMMARY: Improved outcomes in children with heart failure are possible. Inherent in this success is the engagement of an interdisciplinary team-based approach to care, with early recognition and escalation of care for specific patients who are not improving as predicted.

Cardiac Biomarkers in Pediatric Cardiomyopathy: Study Design and Recruitment Results from the Pediatric Cardiomyopathy Registry.

BACKGROUND: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy. STUDY DESIGN: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure. RESULTS: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years. CONCLUSION: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children. CLINICAL TRIAL REGISTRATION NCT01873976: https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=1.

The clinical impact of donor-specific antibodies on antibody-mediated rejection and long-term prognosis after heart transplantation.

PURPOSE OF REVIEW: Outcomes after cardiac transplantation have improved over past decades, but long-term graft survival remains limited in part because of uncertainty regarding clinical implications of donor-specific antibodies (DSAs). The purpose of this review is to consolidate recent advances in knowledge on the topic of DSA and their potential to impact long-term prognosis after heart transplantation. RECENT FINDINGS: The presence of persistent DSA increases the risk of poor outcome after heart transplantation, including development of antibody-mediated rejection (AMR), graft failure, cardiac allograft vasculopathy, and mortality. Importantly, different DSA vary in clinical significance. DSA capable of activating the complement cascade portend a higher risk of developing AMR. human leukocyte antigen class I and class II antigens are expressed differently within the heart, and so, clinical manifestations of class I and class II DSA vary accordingly. Further, compared with class I, class II DSA carry an increased risk of graft loss and mortality. When comparing preexisting DSA with formation of de-novo DSA, de-novo DSA are associated with worse outcome. SUMMARY: DSAs are generally associated worse long-term prognosis after heart transplantation but vary in their clinical significance. Recognition of specific risk profiles is essential for guiding posttransplant antibody management.

Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

PURPOSE: The purpose of this document is to provide updated guidance for the genetic evaluation of cardiomyopathy and for an approach to manage secondary findings from cardiomyopathy genes. The genetic bases of the primary cardiomyopathies (dilated, hypertrophic, arrhythmogenic right ventricular, and restrictive) have been established, and each is medically actionable; in most cases established treatments or interventions are available to improve survival, reduce morbidity, and enhance quality of life. METHODS: A writing group of cardiologists and genetics professionals updated guidance, first published in 2009 for the Heart Failure Society of America (HFSA), in a collaboration with the American College of Medical Genetics and Genomics (ACMG). Each recommendation was assigned to teams of individuals by expertise, literature was reviewed, and recommendations were decided by consensus of the writing group. Recommendations for family history, phenotype screening of at-risk family members, referral to expert centers as needed, genetic counseling, and cardiovascular therapies, informed in part by phenotype, are presented in the HFSA document. RESULTS: A genetic evaluation of cardiomyopathy is indicated with a cardiomyopathy diagnosis, which includes genetic testing. Guidance is also provided for clinical approaches to secondary findings from cardiomyopathy genes. This is relevant as cardiomyopathy is the phenotype associated with 27% of the genes on the ACMG list for return of secondary findings. Recommendations herein are considered expert opinion per current ACMG policy as no systematic approach to literature review was conducted. CONCLUSION: Genetic testing is indicated for cardiomyopathy to assist in patient care and management of at-risk family members.

Genetic Evaluation of Cardiomyopathy-A Heart Failure Society of America Practice Guideline.

This guideline describes the approach and expertise needed for the genetic evaluation of cardiomyopathy. First published in 2009 by the Heart Failure Society of America (HFSA), the guideline has now been updated in collaboration with the American College of Medical Genetics and Genomics (ACMG). The writing group, composed of cardiologists and genetics professionals with expertise in adult and pediatric cardiomyopathy, reflects the emergence and increased clinical activity devoted to cardiovascular genetic medicine. The genetic evaluation of cardiomyopathy is a rapidly emerging key clinical priority, because high-throughput sequencing is now feasible for clinical testing and conventional interventions can improve survival, reduce morbidity, and enhance quality of life. Moreover, specific interventions may be guided by genetic analysis. A systematic approach is recommended: always a comprehensive family history; an expert phenotypic evaluation of the proband and at-risk family members to confirm a diagnosis and guide genetic test selection and interpretation; referral to expert centers as needed; genetic testing, with pre- and post-test genetic counseling; and specific guidance as indicated for drug and device therapies. The evaluation of infants and children demands special expertise. The approach to managing secondary and incidental sequence findings as recommended by the ACMG is provided.

Activating PPARα prevents post-ischemic contractile dysfunction in hypertrophied neonatal hearts.

RATIONALE: Post-ischemic contractile dysfunction is a contributor to morbidity and mortality after the surgical correction of congenital heart defects in neonatal patients. Pre-existing hypertrophy in the newborn heart can exacerbate these ischemic injuries, which may partly be due to a decreased energy supply to the heart resulting from low fatty acid ß-oxidation rates. OBJECTIVE: We determined whether stimulating fatty acid ß-oxidation with GW7647, a peroxisome proliferator-activated receptor-α (PPARα) activator, would improve cardiac energy production and post-ischemic functional recovery in neonatal rabbit hearts subjected to volume overload-induced cardiac hypertrophy. METHODS AND RESULTS: Volume-overload cardiac hypertrophy was produced in 7-day-old rabbits via an aorto-caval shunt, after which, the rabbits were treated with or without GW7647 (3 mg/kg per day) for 14 days. Biventricular working hearts were subjected to 35 minutes of aerobic perfusion, 25 minutes of global no-flow ischemia, and 30 minutes of aerobic reperfusion. GW7647 treatment did not prevent the development of cardiac hypertrophy, but did prevent the decline in left ventricular ejection fraction in vivo. GW7647 treatment increased cardiac fatty acid ß-oxidation rates before and after ischemia, which resulted in a significant increase in overall ATP production and an improved in vitro post-ischemic functional recovery. A decrease in post-ischemic proton production and endoplasmic reticulum stress, as well as an activation of sarcoplasmic reticulum calcium ATPase isoform 2 and citrate synthase, was evident in GW7647-treated hearts. CONCLUSIONS: Stimulating fatty acid ß-oxidation in neonatal hearts may present a novel cardioprotective intervention to limit post-ischemic contractile dysfunction.

Histological validation of cardiovascular magnetic resonance T1 mapping markers of myocardial fibrosis in paediatric heart transplant recipients.

BACKGROUND: Adverse fibrotic remodeling is detrimental to myocardial health and a reliable method for monitoring the development of fibrotic remodeling may be desirable during the follow-up of patients after heart transplantation (HTx). Quantification of diffuse myocardial fibrosis with cardiovascular magnetic resonance (CMR) has been increasingly applied and validated histologically in adult patients with heart disease. However, comparisons of CMR findings with histological fibrosis burden in children are lacking. This study aimed to compare native T1 times and extracellular volume fraction (ECV) derived from CMR with the degree of collagen on endomyocardial biopsy (EmBx), and to investigate the association between myocardial fibrosis and clinical as well as functional markers in children after HTx. METHODS: EmBx and CMR were performed on the same day. All specimens were stained with picrosirius red. The collagen volume fraction (CVF) was calculated as ratio of stained collagen area to total myocardial area on EmBx. Native T1 values and ECV were measured by CMR on a mid-ventricular short axis slice, using a modified look-locker inversion recovery approach. RESULTS: Twenty patients (9.9 ± 6.2 years of age; 9 girls) after HTx were prospectively enrolled, at a median of 1.3 years (0.02-12.6 years) post HTx, and compared to 24 controls (13.9 ± 2.6 years of age; 12 girls). The mean histological CVF was 10.0 ± 3.4%. Septal native T1 times and ECV were higher in HTx patients compared to controls (1008 ± 32 ms vs 979 ± 24 ms, p < 0.005 and 0.30 ± 0.03 vs 0.22 ± 0.03, p < 0.0001, respectively). CVF showed a moderate correlation with native T1 (r = 0.53, p < 0.05) as well as ECV (r = 0.46, p < 0.05). Native T1 time, but not ECV and CVF, correlated with ischemia time (r = 0.46, p < 0.05). CONCLUSIONS: CMR-derived fibrosis markers correlate with histological degree of fibrosis on EmBx in children after HTx. Further, native T1 times are associated with longer ischemia times.

Abnormal Myocardial Contractility After Pediatric Heart Transplantation by Cardiac MRI.

Acute cellular rejection (ACR) compromises graft function after heart transplantation (HTX). The purpose of this study was to describe systolic myocardial deformation in pediatric HTX and to determine whether it is impaired during ACR. Eighteen combined cardiac magnetic resonance imaging (CMR)/endomyocardial biopsy (EMBx) examinations were performed in 14 HTX patients (11 male, age 13.9 ± 4.7 years; 1.2 ± 1.3 years after HTX). Biventricular function and left ventricular (LV) circumferential strain, rotation, and torsion by myocardial tagging CMR were compared to 11 controls as well as between patients with and without clinically significant ACR. HTX patients showed mildly reduced biventricular systolic function when compared to controls [LV ejection fraction (EF): 55 ± 8% vs. 61 ± 3, p = 0.02; right ventricular (RV) EF: 48 ± 7% vs. 53 ± 6, p = 0.04]. Indexed LV mass was mildly increased in HTX patients (67 ± 14 g/m2 vs. 55 ± 13, p = 0.03). LV myocardial deformation indices were all significantly reduced, expressed by global circumferential strain (-13.5 ± 2.3% vs. -19.1 ± 1.1%, p < 0.01), basal strain (-13.7 ± 3.0% vs. -17.5 ± 2.4%, p < 0.01), mid-ventricular strain (-13.4 ± 2.7% vs. -19.3 ± 2.2%, p < 0.01), apical strain (-13.5 ± 2.8% vs. -19.9 ± 2.0%, p < 0.01), basal rotation (-2.0 ± 2.1° vs. -5.0 ± 2.0°, p < 0.01), and torsion (6.1 ± 1.7° vs. 7.8 ± 1.1°, p < 0.01). EMBx demonstrated ACR grade 0 R in 3 HTX cases, ACR grade 1 R in 11 HTX cases and ACR grade 2 R in 4 HTX cases. When comparing clinically non-significant ACR (grades 0-1 R vs. ACR 2 R), basal rotation, and apical rotation were worse in ACR 2 R patients (-1.4 ± 1.8° vs. -4.2 ± 1.4°, p = 0.01 and 10.2 ± 2.9° vs. 2.8 ± 1.9°, p < 0.01, respectively). Pediatric HTX recipients demonstrate reduced biventricular systolic function and decreased myocardial contractility. Myocardial deformation indices by CMR may serve as non-invasive markers of graft function and, perhaps, rejection in pediatric HTX patients.

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart.

Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid ß-oxidation rates increased in 21-day vs. 1- and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and ß-hydroxyacyl-CoA dehydrogenase (ß-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid ß-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and ß-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxia-inducible factor-1α, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation.

Cardiomyopathy Phenotypes and Outcomes for Children With Left Ventricular Myocardial Noncompaction: Results From the Pediatric Cardiomyopathy Registry.

BACKGROUND: Left ventricular noncompaction (LVNC) is a distinct form of cardiomyopathy characterized by hypertrabeculation of the left ventricle. The LVNC phenotype may occur in isolation or with other cardiomyopathy phenotypes. Prognosis is incompletely characterized in children. METHODS AND RESULTS: According to diagnoses from the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry from 1990 to 2008, 155 of 3,219 children (4.8%) had LVNC. Each LVNC patient was also classified as having an associated echocardiographically diagnosed cardiomyopathy phenotype: dilated (DCM), hypertrophic (HCM), restrictive (RCM), isolated, or indeterminate. The time to death or transplantation differed among the phenotypic groups (P = .035). Time to listing for cardiac transplantation significantly differed by phenotype (P < .001), as did time to transplantation (P = .015). The hazard ratio for death/transplantation (with isolated LVNC as the reference group) was 4.26 (95% confidence interval [CI] 0.78-23.3) for HCM, 6.35 (95% CI 1.52-26.6) for DCM, and 5.66 (95% CI 1.04-30.9) for the indeterminate phenotype. Most events occurred in the 1st year after diagnosis. CONCLUSIONS: LVNC is present in at least 5% of children with cardiomyopathy. The specific LVNC-associated cardiomyopathy phenotype predicts the risk of death or transplantation and should inform clinical management.