Abnormal Global Longitudinal Strain During Anthracycline Treatment Predicts Future Cardiotoxicity in Children.

Global longitudinal strain (GLS) is a sensitive predictor of cardiotoxicity in adults with cancer. However, the significance of abnormal GLS during childhood cancer treatment is less well-understood. The objective was to evaluate the use of GLS for predicting later cardiac dysfunction in pediatric cancer survivors exposed to high-dose anthracyclines. This was a retrospective study of pediatric patients exposed to a doxorubicin isotoxic equivalent dose of ≥ 225 mg/m2. Transthoracic echocardiograms (TTE) were obtained prior to chemotherapy (T1), during anthracycline therapy (T2), and following completion of therapy (T3). Cardiotoxicity was defined as meeting at least one of the following criteria after anthracycline therapy: a decrease in left ventricle ejection fraction (LVEF) by 10% from baseline to a value < 55%, fractional shortening < 28%, or a decrease in GLS by ≥ 15% from baseline. Nineteen of 57 (33%) patients met criteria for cardiotoxicity at T3. Cardiotoxicity was associated with a lower LVEF at T2 (p = 0.0003) and a decrease in GLS by ≥ 15% at T2 compared to baseline (p = < 0.0001). ROC analysis revealed that the best predictor of cardiotoxicity at T3 was the percent change in GLS at T2 compared to baseline (AUC 0.87). A subgroup analysis revealed that a decrease in GLS by ≥ 15% from baseline at 0-6 months from completion of anthracycline therapy was associated with cardiotoxicity > 1-year post-treatment (p = 0.017). A decline in GLS during chemotherapy was the best predictor of cardiotoxicity post-treatment. GLS serves as an important marker of cardiac function in pediatric patients undergoing treatment with anthracyclines.

Associations Between Characteristics of Individuals With Fontan Circulation With Blood and Urine Biomarkers of Kidney Injury and Dysfunction.

Background Fontan circulation is associated with kidney injury and dysfunction, often unappreciated until Fontan circulatory failure. We hypothesized that cystatin C-estimated glomerular filtration rate (eGFR) would identify chronic kidney disease more frequently and that urine kidney injury biomarkers would be higher with declining Fontan physiological features. Methods and Results We enrolled 100 ambulatory individuals. Blood and urinary laboratory measurements were compared with demographics and clinically obtained data. Different eGFR equations were used for individuals aged ≥19 years and <19 years. Chronic kidney disease was defined as eGFR <90 mL/min per 1.73 m2. Median (25th-75th percentile) age was 19 (14-26) years, and 43% were female patients. Cystatin C eGFR detected chronic kidney disease (37%) in more patients than creatinine eGFR (11%). Cystatin C eGFR was positively associated, and skeletal muscle mass was negatively associated, with creatinine eGFR in both univariate (cystatin C eGFR ß=0.44±0.12, P=0.0006; skeletal muscle mass ß=-0.72±0.32, P=0.03) and multivariable analysis (cystatin C eGFR ß=0.43±0.12, P=0.0005; skeletal muscle mass ß=-0.69±0.29, P=0.02). Urine neutrophil gelatinase-associated lipocalin concentration correlated with Fontan pressure (r=0.28; P=0.04), ventricular end-diastolic pressure (r=0.28; P=0.04), and body fat mass (r=0.26; P=0.03). Conclusions Cystatin C eGFR identified more kidney dysfunction, likely attributable to creatinine eGFR being confounded by skeletal muscle mass. Elevated urine neutrophil gelatinase-associated lipocalin was associated with worse Fontan hemodynamics and higher percentage body fat, suggesting that higher venous pressure and higher adiposity are associated with ongoing kidney injury.

Isosorbide DiNitrate Effect on Hemodynamic Profile, Liver Stiffness, and Exercise Tolerance in Fontan Circulation (The NEET Clinical Trial).

After Fontan operation, decreased venous capacitance and venoconstriction are adaptive mechanisms to maintain venous return and cardiac output. The consequent higher venous pressure may adversely impact end-organ function, exercise capacity and result in worse clinical outcomes. This pilot study evaluated the safety and effect of isosorbide dinitrate (ISDN), a venodilator, on exercise capacity, peripheral venous pressure (PVP), and liver stiffness in patients with Fontan circulation. In this prospective single-arm trial, 15 individuals with Fontan circulation were evaluated at baseline and after 4 weeks of therapeutic treatment with ISDN. Primary aims were to assess the safety of ISDN and the effect on maximal exercise. We also aimed to evaluate the effect of ISDN on ultrasound-assessed liver stiffness, markers of submaximal exercise, and PVP at rest and peak exercise. Repeated measures t-tests were used to assess change in variables of interest in response to ISDN. Mean age was 23.5 ± 9.2 years (range 11.2-39.0 years), and 10/15 (67%) were male. There was no statistically significant change in peak VO2 (1401 ± 428 to 1428 ± 436 mL/min, p = 0.128), but VO2 at the anaerobic threshold increased (1087 ± 313 to 1115 ± 302 mL/min, p = 0.03). ISDN was also associated with a lower peak exercise PVP (22.5 ± 4.5 to 20.6 ± 3.0 mmHg, p = 0.015). Liver stiffness was lower with ISDN, though the difference was not statistically significant (2.3 ± 0.4 to 2.1 ± 0.5 m/s, p = 0.079). Of the patients completing the trial, mild headache was common (67%), but there were no major adverse events. Treatment with ISDN for 4 weeks is well-tolerated in patients with a Fontan circulation. ISDN is associated with an increase in VO2 at anaerobic threshold, lower peak PVP, and a trend toward lower liver stiffness. Larger, longer duration studies will be necessary to define the impact of ISDN on clinical outcomes in the Fontan circulation.Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT04297241.

Association of Childhood Blood Pressure with Left Atrial Size and Function: Study of High Blood Pressure in Pediatrics-Adult Hypertension in Youth (SHIP AHOY).

OBJECTIVE(S): To evaluate the cross-sectional association of cardiovascular disease risk factors with left atrial (LA) size and function among healthy youth, aged 11-18 years, with a wide range of blood pressures (BPs). STUDY DESIGN: Echocardiographic images of youth enrolled in the Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth study were analyzed for LA measurements. The association of casual BP, ambulatory BP, and other cardiovascular disease risk factors with LA size and function were determined using descriptive statistics and multivariable regression. Regression models adjusting for age, sex, race, and body mass index z score determined the independent association between ambulatory systolic BP indices (mean systolic BP/50th %ile systolic BP) and BP phenotypes with LA outcomes while exploratory analyses investigated for additional predictors of LA outcomes. RESULTS: The study population consisted of 347 youth: median age 15.7 years, 60% male and 40% non-White. Greater-risk casual systolic BP groups had worse cardiometabolic profiles but no differences in LA size and function. Each 0.1 increase in ambulatory systolic BP day or night index was associated with a 9.9 mL/m2 increase in LA volume/body surface area (LAV/BSA; 95th% CI 2.8-17.0, P = .006) and a 6.8 mL/m2 increase in LAV/BSA (95th% CI 0.8-12.8, P = .03), respectively. Ambulatory hypertension was associated with greater odds of abnormal LAV/BSA, defined as >75th %ile (2014 ambulatory BP monitoring criteria: OR 3.2 [95th% CI 1.4-7.2; P = .002]; 2022 ambulatory BP monitoring criteria: OR 2.1 [95th% CI 1.0-4.1; P = .008]). CONCLUSIONS: Increasing ambulatory systolic BP and ambulatory hypertension are independently associated with LAV/BSA.

Association Between Seasonal Fontan Timing, Viral Infection Burden, and Post-Operative Length of Stay.

The Fontan procedure (FP) is typically a semi-elective surgery performed between 2 and 5 years of age to complete staged single ventricle palliation. Optimal timing for the FP, particularly in relation to seasonal infectious burden, remains unclear. We queried the Pediatric Health Information System (PHIS) database for all admissions for viral respiratory infections (VRI) from January 2006 to September 2015 and separately for all admissions with a primary procedure code of FP. The PHIS query generated 2,767,142 admissions for VRI and 6349 admissions for the FP from 45 children's hospitals. Of all FP, 2124 (33.5%) were performed from October through March. The median length of stay after Fontan procedure was 9 days (IQR 7-15). Median length of stay after FP was correlated with VRI burden (correlation coefficient = 0.3, p = 0.03). April through August (weeks 18 through 35) had the lowest VRI admission burden and FP length of stay was significantly shorter during this time (13.6 ± 14.8 days vs 14.9 ± 20.3 days, p = 0.03). The FP is frequently performed during the viral respiratory season. This timing is associated with an increased post-operative length of stay after the FP. For elective FP, ideal timing that avoids the viral respiratory season and minimizes post-operative LOS is April through August.

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review, we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles address the extracardiac anomalies in fetuses with congenital heart disease, post COVID-19 vaccination myocarditis, the use of cardiac magnetic resonance after the Fontan operation, congenitally corrected transposition in adults, robitically assisted congenital heart surgery and the increased risk of congenital heart surgery in patients receiving tracheal surgery during the same admission.

Myocardial Parametric Mapping by Cardiac Magnetic Resonance Imaging in Pediatric Cardiology and Congenital Heart Disease.

Parametric mapping, that is, a pixel-wise map of magnetic relaxation parameters, expands the diagnostic potential of cardiac magnetic resonance by enabling quantification of myocardial tissue-specific magnetic relaxation on an absolute scale. Parametric mapping includes T1 mapping (native and postcontrast), T2 and T2* mapping, and extracellular volume measurements. The myocardial composition is altered in various disease states affecting its inherent magnetic properties and thus the myocardial relaxation times that can be directly quantified using parametric mapping. Parametric mapping helps in the diagnosis of nonfocal disease states and allows for longitudinal disease monitoring, evaluating therapeutic response (as in Thalassemia patients with iron overload undergoing chelation), and risk-stratification of certain diseases. In this review article, we describe various mapping techniques and their clinical utility in congenital heart disease. We will also review the available literature on normative values in children, the strengths, and weaknesses of these techniques. This review provides a starting point for pediatric cardiologists to understand and implement parametric mapping in their practice.

Developing an adolescent and adult Fontan Management Programme.

Patients with single-ventricle CHD undergo a series of palliative surgeries that culminate in the Fontan procedure. While the Fontan procedure allows most patients to survive to adulthood, the Fontan circulation can eventually lead to multiple cardiac complications and multi-organ dysfunction. Care for adolescents and adults with a Fontan circulation has begun to transition from a primarily cardiac-focused model to care models, which are designed to monitor multiple organ systems, and using clues from this screening, identify patients who are at risk for adverse outcomes. The complexity of care required for these patients led our centre to develop a multidisciplinary Fontan Management Programme with the primary goals of earlier detection and treatment of complications through the development of a cohesive network of diverse medical subspecialists with Fontan expertise.

The Severity of Pectus Excavatum Defect Is Associated With Impaired Cardiopulmonary Function.

BACKGROUND: Repair of pectus excavatum has cosmetic benefits, but the physiologic impact remains controversial. The aim of this study was to characterize the relationship between the degree of pectus excavatum and cardiopulmonary dysfunction seen on cardiac magnetic resonance (CMR) imaging, cardiopulmonary exercise testing (CPET), and pulmonary function testing (PFT). METHODS: A single-center analysis of CMR, CPET, and PFT was conducted. Regression models evaluated relationships between pectus indices and the clinical end points of cardiopulmonary function. RESULTS: Data from 345 CMRs, 261 CPETs, and 281 PFTs were analyzed. Patients were a mean age of 15.2 ± 4 years, and 81% were aged <18 years. The right ventricular ejection fraction (RVEF) was <0.50 in 16% of patients, left ventricular ejection fraction (LVEF) was <0.55 in 22%, RVEF Z-score was < -2 in 32%, and the LVEF Z-score was < -2 in 18%. CPET revealed 33% of patients had reduced aerobic fitness. PFT results were abnormal in 23.1% of patients. Adjusted analyses revealed the Haller index had significant (P < .05) inverse associations with RVEF and LVEF. CONCLUSIONS: The severity of pectus excavatum is associated with ventricular systolic dysfunction. Pectus excavatum impacts right and left ventricular systolic function and can also impact exercise tolerance. The Haller index and correction index may be the most useful predictors of impairment.

Relation of Liver Volume to Adverse Cardiovascular Events in Adolescents and Adults With Fontan Circulation.

Elevated central venous pressure in those with Fontan circulation causes liver congestion and hepatomegaly. We assessed if liver volume by magnetic resonance imaging (MRI) is associated with adverse cardiovascular outcomes. Retrospective study of 122 patients with Fontan circulation who were >10 years old and had a liver MRI with magnetic resonance elastography. Liver volume (ml) was measured by manual segmentation from axial T2-weighted images and was indexed to body surface area. The composite outcome included death, heart transplant, ventricular assist device placement, or nonelective cardiovascular hospitalization. The median age at the time of MRI was 18.9 (interquartile range 15.8 to 25.9) years, and 47% of the patients were women. The mean indexed liver volume was 1,133 ± 180 ml/m2. Indexed liver volume was not significantly associated with age, years since Fontan, or with liver stiffness (r = 0.15, p = 0.10), but was positively correlated with Fontan pressure (r = 0.32, p = 0.002). Over a median follow-up of 2.1 (0.8 to 4.2) years, 32 patients (26%) experienced the composite outcome. Higher indexed liver volume was associated with a greater hazard for the composite outcome (hazard ratio per 1 SD increase = 1.74, 95% confidence interval 1.27 to 2.35, p = 0.0004) but increased liver stiffness was not significantly associated with the composite outcome (hazard ratio per 1 SD increase 1.44, 95% confidence interval 0.90 to 2.21, p = 0.11). In conclusion, greater liver volume indexed to body surface area is associated with unfavorable hemodynamics and adverse outcomes in patients with Fontan circulation. Liver volume may be a useful, simple imaging biomarker in adolescents and adults with Fontan circulation.

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles address (1) a summary of a scientific statement of the American Heart Association for diagnosis and treatment of myocarditis, (2) development of a perioperative risk score for in-hospital mortality after cardiac surgery in adults with congenital heart disease, (3) using a machine learning algorithm to predict cardiopulmonary deterioration in patients in the interstage period 1-2 h in advance using hospital monitor generated data, (4) risk factors for reoperation after the arterial switch operation, (5) the effect of mitochondrial transplantation for cardiogenic shock in pediatric patients, (6) comparing outcomes of primary or staged repair in tetralogy of Fallot with pulmonary atresia.

Opportunities, barriers, and recommendations in down syndrome research.

BACKGROUND: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. OBJECTIVE: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. METHODS: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. RESULTS: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. CONCLUSIONS: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review, we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles reviewed in this manuscript address (1) long-term fate of the truncal valve, (2) comparison of combined heart‒liver vs heart-only transplantation in pediatric and young adult Fontan recipients showing non-inferior survival of heart-liver transplant in a small sample, (3) impact of palliation strategy on interstage feeding and somatic growth for infants with ductal-dependent pulmonary blood flow showing no difference in growth between ductal stenting and Blalock-Taussig shunt, (4) biventricular repair in interrupted aortic arch and ventricular septal defect with a small left ventricular outflow tract, (5) a randomized controlled trial comparing controlled reoxygenation and standard cardiopulmonary bypass in pediatric cardiac surgery, and (6) tricuspid valve and right ventricular function throughout the hybrid palliation strategy for hypoplastic left heart syndrome and variants.

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles address (1) The impact of COVID-19 in individuals with congenital heart disease through the life span. Patients with a genetic syndrome and adults at advanced physiological stage were at highest risk for moderate/severe infection. (2) Echocardiographic findings of the multisystem inflammatory syndrome in children showing a high prevalence of myocardial injury and systolic dysfunction that improves in the subacute phase. (3) A score assessment of the Fontan associated liver disease which correlated with the risk for Fontan failure. (4) Grown-up congenital heart surgery in 1093 consecutive cases showed that the 30 day mortality may underestimate the mortaility and that the 6 months mortality is likely a better measure in this population. (5) Cone versus conventional repair for Ebstein's anomaly showed better midterm results and freedom from tricuspid regurgitation after the cone operation. (6) Association between race/ethnicity, illness severity, and mortality in children undergoing cardiac surgery. The study showed that the African American race associated with increased disease severity and thus higher postoperative mortality compared to the caucausian race.

From Other Journals: A Review of Recent Articles in Pediatric Cardiology.

In this review, we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles address (1) developing a risk score to predict adverse outcomes in patients with hypoplastic left heart syndrome using the national pediatric cardiology quality improvement collaborative, (2) outcomes of the Ross procedure in patients with a previous aortic valve surgery showing better outcomes in these patients compared to patients with the primary Ross procedure, (3) the initial experience with continuous flow ventricular assist devices in pediatric patients showing low mortality post implantation, (4) lower socioeconomic status is associated with worse long-term neurodevelopmental outcomes in patients with hypoplastic left heart syndrome, (5) QRS fragmentation is associated with higher incidence of appropriate shock after implantable cardioverter defibrillator implantation in repaired tetralogy of Fallot, (6) atrioventricular valve repair may have better outcomes if performed before the Fontan operation compared to after the Fontan operation.

Timing of Repair in Tetralogy of Fallot: Effects on Outcomes and Myocardial Health.

Early complete repair of tetralogy of Fallot (ToF) prior to 1 year of age has been demonstrated to be safe and has survival benefits over late repair. The age at repair of ToF affects long-term outcomes. This may largely be related to preserved, or comparatively better, myocardial health. Most studies advocate for an age of repair between 3 and 6 months and certainly below the age of 1 year. Patients with severe right ventricular outflow tract obstruction represent an exception to this rule and may require neonatal repair or surgical and catheter-based palliation before surgery. Older age at repair beyond the first birthday leads to unfavorable right ventricular remodeling with increased right ventricular stiffness and hypertrophy and is associated with increased long-term ventricular tachycardia and all-cause mortality. In this article, we review the short- and long-term benefits of early repair, with a focus on long-term morbidity. In conclusion, we emphasize the importance of myocardial health and the relationship to early repair and advocate for the use of magnetic resonance imaging in adult patients with repaired ToF to detect myocardial fibrosis.

Myocardial fibrosis, diastolic dysfunction and elevated liver stiffness in the Fontan circulation.

INTRODUCTION: Single ventricle diastolic dysfunction and hepatic fibrosis are frequently observed in patients with a Fontan circulation. The relationship between adverse haemodynamics and end-organ fibrosis has not been investigated in adolescents and young adults with Fontan circulation. METHODS: Prospective observational study of Fontan patients who had a cardiac catheterisation. Cardiac MRI with T1 mapping was obtained to measure extracellular volume (ECV), a marker of myocardial fibrosis. Hepatic magnetic resonance elastography was performed to assess liver shear stiffness. Serum biomarkers of fibrosis including matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) were measured. Very high ECV was defined as >30% and elevated serum biomarkers as >75th percentile for each biomarker. RESULTS: 25 Fontan patients (52% female) with mean age of 16.3±6.8 years were included. Mean ECV was 28%±5%. There was a significant correlation between ECV and systemic ventricular end-diastolic pressure (r=0.42, p=0.03) and between ECV and liver stiffness (r=0.45, p=0.05). Patients with elevated ECV demonstrated elevations in MMPs and TIMPs. Similarly, patients with elevated MMPs and TIMPs had greater liver stiffness compared with patients with normal levels of these biomarkers. CONCLUSIONS: In Fontan patients, cardiac magnetic resonance evidence of myocardial fibrosis is associated with diastolic dysfunction, increased liver stiffness and elevated circulating biomarkers of fibrosis. These findings suggest the presence of a profibrotic milieu, with end-organ implications, in some patients with Fontan circulation.

The chest wall gender divide: females have better cardiopulmonary function and exercise tolerance despite worse deformity in pectus excavatum.

PURPOSE: Pectus excavatum (PE) is a chest wall deformity of variable severity and symptomatology. Existing female-specific literature highlights breast asymmetry and cosmetic reconstruction. We sought to evaluate gender differences in cardiopulmonary function. METHODS: Cardiac MRIs, pulmonary function tests (PFTs), and cardiopulmonary exercise tests (CPETs) were reviewed in 345 patients undergoing preoperative evaluation for PE. Regression modeling was used to evaluate associations between gender and clinical endpoints of cardiopulmonary function. RESULTS: Mean age was 15.2 years, 19% were female, 98% were white. Pectus indices included median Haller Index (HI) of 4.8, mean depression index (DI) of 0.63, correction index (CI) of 33.6%, and Cardiac Compression Index (CCI) of 2.79. Cardiac assessment revealed decreased right and left ventricular ejection fraction (RVEF, LVEF) in 16% and 22% of patients, respectively. PFTs and CPETs were abnormal in ~ 30% of patients. While females had deeper PE deformities-represented by higher pectus indices-they had superior function with higher RVEF, LVEF Z-scores, FEV1, VO2 max, O2 pulse, work, and breathing reserve (p < 0.05). CONCLUSION: Despite worse PE deformity and symptomatology, females had a better cardiopulmonary function and exercise tolerance than males. Further research is needed to assess the precise mechanisms of this phenomenon and postoperative outcomes in this population.

Imaging of Fontan-associated liver disease.

The Fontan operation has dramatically altered the natural history of functionally single ventricle congenital heart disease. Patients who have undergone the Fontan operation are living longer and, thus, noncardiac morbidity resulting from the Fontan operation is increasingly being recognized. Fontan-associated liver disease (FALD), one of the chief morbidities following the Fontan operation, is believed to be a multifactorial process that manifests as hepatic congestion and fibrosis, portal hypertension, and development of focal liver lesions, including malignant tumors. This article reviews the imaging findings of FALD in the pediatric and young adult population, reviews the literature related to the imaging of FALD and discusses possible screening algorithms for this population. The need for further research to better understand the causes of FALD, to establish if early liver stiffness measurements (or their change over time) predict long-term outcomes and complications, and to define optimal liver screening procedures is highlighted.

Long-Term Kidney Function After the Fontan Operation: JACC Review Topic of the Week.

The Fontan procedure has improved survival and quality of life for patients with single ventricle physiology. Along with extended life expectancy comes a growing population that is experiencing long-term multiorgan adverse effects. Whereas cardiorenal interactions have been extensively studied in patients with a structurally normal heart, these are less well understood in patients with a single ventricle. Several studies have investigated the prevalence of reduced glomerular filtration rate and albuminuria in the Fontan population; however, the long-term implication of renal dysfunction is not well established in this population. This paper provides a concise review of the published reports on the pathophysiology and spectrum of Fontan-associated renal disease. It also identifies gaps in currently available evidence that can guide ongoing and future research.