Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.

BACKGROUND: Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision to vaccinate youth. METHODS: We retrospectively collected data on patients <21 years old presenting before July 4, 2021, with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions. RESULTS: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1-20.3; interquartile range [IQR], 14.5-17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0-22; IQR, 1-3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0-10; IQR, 2-3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50-15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25-1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction <55% on echocardiogram. Of 97 patients who underwent cardiac MRI at a median 5 days (range, 0-88; IQR, 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25). CONCLUSIONS: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.

Birth Location in Infants with Prenatally Diagnosed Hypoplastic Left Heart Syndrome.

There are conflicting data on how delivery location impacts outcomes in neonates with ductal-dependent heart disease. Our goal was to evaluate the impact of delivery location on hospital length of stay and survival in infants with prenatally diagnosed hypoplastic left heart syndrome (HLHS) after stage 1 palliation (S1P). A multicenter cohort study was performed utilizing the National Pediatric Cardiology Quality Improvement Collaborative dataset for infants with prenatally diagnosed HLHS who underwent S1P from August 2016 to December 2018. Univariate comparisons of demographics, clinical, and outcome data were made and multivariable logistic regression was performed between groups stratified by distance from surgical center. A total of 790 patients from 33 centers were analyzed: 85% were born < 5 miles from the surgical center with 72% of those (486/673) born at the surgical center. Infants born < 5 miles from the surgical center were significantly (p < 0.05) more likely to be male, white, full term, have no non-cardiac anomaly, and have commercial health insurance; they were significantly more likely to breastfeed pre-operatively, and less likely to have pre-operative cardiac catheterizations, pre-operative mechanical ventilation, or delayed surgery. There was no significant difference between groups in hospital length of stay, 30-day survival, or survival to hospital discharge. In this multicenter dataset, hospital length of stay and survival after S1P did not differ based on distance from birth location to surgical center. However, neonates born < 5 miles from the surgical center had lower rates of potentially modifiable pre-operative risk factors including mechanical ventilation and delays to surgery.

Fetal Cardiac Intervention for Pulmonary Atresia with Intact Ventricular Septum: International Fetal Cardiac Intervention Registry.

INTRODUCTION: Invasive fetal cardiac intervention (FCI) for pulmonary atresia with intact ventricular septum (PAIVS) and critical pulmonary stenosis (PS) has been performed with small single-institution series reporting technical and physiological success. We present the first multicenter experience. OBJECTIVES: Describe fetal and maternal characteristics of those being evaluated for FCI, including pregnancy/neonatal outcome data using the International Fetal Cardiac Intervention Registry (IFCIR). METHODS: We queried the IFCIR for PAIVS/PS cases evaluated from January 2001 to April 2018 and reviewed maternal/fetal characteristics, procedural details, pregnancy and neonatal outcomes. Data were analyzed using standard descriptive statistics. RESULTS: Of the 84 maternal/fetal dyads in the registry, 58 underwent pulmonary valvuloplasty at a median gestational age of 26.1 (21.9-31.0) weeks. Characteristics of fetuses undergoing FCI varied in terms of tricuspid valve (TV) size, TV regurgitation, and pulmonary valve patency. There were fetal complications in 55% of cases, including 7 deaths and 2 delayed fetal losses. Among those who underwent successful FCI, the absolute measurement of the TV increased by 0.32 (±0.17) mm/week from intervention to birth. Among 60 liveborn with known outcome, there was a higher percentage having a biventricular circulation following successful FCI (87 vs. 43%). CONCLUSIONS: Our data suggest a possible benefit to fetal therapy for PAIVS/PS, though rates of technically unsuccessful procedures and procedure-related complications, including fetal loss were substantial. FCI criteria are extremely variable, making direct comparison to nonintervention patients challenging and potentially biased. More uniform FCI criteria for fetuses with PAIVS/PS are needed to avoid unnecessary procedures, expose only fetuses most likely to sustain a benefit, and to enable comparisons to be made with nonintervention patients.

Impact of standardized prenatal documentation among newborns with ductal-dependent heart disease.

INTRODUCTION: Absent risk stratification, variable physiology of ductal-dependent congenital heart disease (DD-CHD) imparts risk of over-medicalization and unnecessary exclusion from early parental bonding. METHODS: Single-center retrospective cohort study of term infants with isolated prenatally diagnosed DD-CHD expected to require immediate advanced resuscitation/intervention (2005-2017). Standardized documentation (2015 onward) included diagnosis, expected saturations, and allowability of postnatal parental bonding. RESULTS: The study cohort (n = 386) included 289 patients in the pre-standardized documentation era and 97 in the post-era; the groups had similar characteristics. Fewer infants were born by cesarean in the later era (32% vs. 22%; p = 0.049). Decrease in any respiratory intervention (38-26%; p = 0.03) followed standardized documentation. More patients had any bonding time (22-74%; p < 0.0001), without increase in CPAP or intubation in the first two hours of life (6.9% vs. 7.2%; p = 0.92). CONCLUSION: Standardized predelivery documentation for neonates with DD-CHD decreased unnecessary respiratory intervention and increased parental bonding.

Third trimester predictors of interventional timing and accuracy of fetal anticipatory guidance in tetralogy of Fallot: A multi-center study.

OBJECTIVE: The objective was to evaluate and improve accuracy of anticipatory counseling regarding neonatal intervention for prenatally diagnosed tetralogy of Fallot (TOF) by assessing new and previously published predictors of neonatal intervention. METHODS: This is a multi-center, retrospective study from three centers of 112 fetal TOF patients undergoing third trimester fetal echocardiograms from 2004 to 2017. Additional cardiac defects requiring neonatal intervention were excluded. Fetal echocardiographic, clinical, and consultation data were compared between neonatal and late intervention. Optimal echocardiographic values were determined. RESULTS: Twenty-six infants (23%) required neonatal intervention. Those infants had significantly different pulmonary valve (PV) z-scores, PV:aortic valve (AoV) ratios, PV:AoV z-score differences (absolute difference between z-scores), and increased likelihood of abnormal ductal flow. Counseling during fetal echocardiogram regarding interventional timing was accurate for 50% needing neonatal intervention and 86% undergoing late intervention (P = .002). The best neonatal intervention predictors were PV:AoV ratio of <0.6 and counseling for neonatal intervention. PV:AoV z-score difference ≥5 provided 89% negative predictive value for excluding patients from neonatal repair. CONCLUSIONS: Third trimester fetal echocardiograms can predict interventional timing. The best predictors of neonatal intervention are PV:AoV ratio <0.6, PV:AoV z-score difference ≥5, and cardiologist counseling that neonatal intervention was likely.

Cardiac Surgery in Patients With Trisomy 13 and 18: An Analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database.

Background Congenital heart disease is common in patients with Trisomy 13 (T13) and Trisomy 18 (T18), but offering cardiac surgery to these patients has been controversial. We describe the landscape of surgical management across the United States, perioperative risk factors, and surgical outcomes in patients with T13 and T18. Methods and Results Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database with T13 and T18 who underwent cardiac surgery (2010-2017) were included. There were 343 operations (T13: n=73 and T18: n=270) performed on 304 patients. Among 125 hospitals, 87 (70%) performed at least 1 operation and 26 centers (30%) performed ≥5 T13/T18 operations. Operations spanned the full spectrum of complexity with 29% (98/343) being in the highest categories of estimated risk. The operative mortality rate was 15%, with a 56% complication rate. Preoperative mechanical ventilation was associated with an odds ratio of mortality >8 for both patients with T13 and T18 (both P<0.012) while presence of a gastrostomy tube (odds ratio, 0.3; P=0.03) or prior cardiac surgery (odds ratio, 0.2; P=0.02) was associated with better survival in patients with T18 but not patients with T13. Conclusions Data from this nationally representative sample indicate that most centers offer surgical intervention for both patients with T13 and T18, even in highly complex patients. However, the overall mortality rate was high in this select patient cohort. The association of preoperative mechanical ventilation with mortality suggests that this subset of patients with T13 and T18 should perhaps not be considered surgical candidates. This information is valuable to clinicians and families for counseling and deciding what interventions to offer.

Similar Interstage Outcomes for Single Ventricle Infants Palliated With an Aortopulmonary Shunt Compared to the Norwood Procedure.

BACKGROUND: Interstage outcomes for single ventricle infants following Norwood operation have been well studied, showing significant mortality. Other single ventricle infants require only an aortopulmonary shunt. The aim of the study was to describe the interstage outcomes of this group compared to Norwood patients and identify risk factors for mortality. METHODS: A single-center retrospective cohort review was performed in patients who underwent a Norwood operation (Norwood) or aortopulmonary shunt (Shunt) during 2000 to 2011 and survived to discharge. Hybrid or pulmonary artery banding patients were excluded. Univariate comparison was made between Norwood and Shunt patients as well as a Shunt subgroup analysis. RESULTS: A total of 486 patients (368 Norwood and 118 Shunt) were included. Norwood and Shunt patients were similar in terms of preterm birth, surgery weight, and stage 1 complications. Shunt patients were more likely to be female, have an extracardiac or genetic anomaly, and have a shorter hospital length of stay compared to the Norwood patients (all P < .0001). No significant difference in interstage mortality was seen between the Shunt and Norwood patients (6.8% vs 11.1%, respectively; P = .17). Stage 2 mortality was also similar (Shunt 4.6% vs Norwood 7.8%; P = .25). In the Shunt patients, those who died during interstage weighed less at surgery (2.7 [0.7] kg vs 3.3 [0.7] kg, P = .03) and were more likely to have arrhythmias (50% vs 12%, P = .01), compared to survivors. CONCLUSIONS: Shunt patients have an interstage mortality that is not significantly less than Norwood patients. Lower weight at surgery and arrhythmias are risk factors for interstage death in Shunt patients.

Single Ventricle and Total Anomalous Pulmonary Venous Connection: Implications of Prenatal Diagnosis.

BACKGROUND: Single ventricle (SV) patients with total anomalous pulmonary venous connection (TAPVC) are at high risk. Given the limited published data available, we examined outcomes and the implications of a prenatal diagnosis of SV/TAPVC. METHODS: A single-center, retrospective review was performed in neonates with SV/TAPVC from 1998 to 2014, identified through institutional databases. Patient demographic, perioperative, and follow-up data were collected. RESULTS: Thirty-four eligible infants with SV/TAPVC were identified (mean birth weight: 3.0 kg). The TAPVC types were supracardiac (59%), infracardiac (21%), mixed (12%), and cardiac (9%). Heterotaxy syndrome was present in 25 (74%) infants. A prenatal diagnosis of SV was made in 26 (76%) infants, with TAPVC identified in 12 (35%). Seventeen (50%) had obstructed TAPVC within the first 48 hours of life; 7 of these patients had obstructed TAPVC identified prenatally. There were two preoperative deaths. Overall survival for the cohort was 65% at 1 year and 50% at 3 years. Survival in the obstructed group was significantly worse compared to the unobstructed group (47% vs 81% at 1 year; 27% vs 73% at 3 years, P = .01). Obstructed TAPVC and a prenatal prediction of obstructed TAPVC were significantly associated with postoperative mortality ( P = .01 and .03, respectively). CONCLUSIONS: Patients with SV/TAPVC remain a high-risk group, with obstructed TAPVC a significant risk factor for mortality. Prenatal diagnosis of TAPVC in SV patients is challenging, but given those with obstructed TAPVC are especially at high risk, improved prenatal diagnostic techniques in this group may enhance counseling/delivery planning.

Pulmonary Vein Doppler Patterns in Infants with Single Right Ventricle Anomalies After Initial Staged Palliations.

The aim of this study was to describe serial changes in echocardiographic Doppler pulmonary vein flow (PVF) patterns in infants with single right ventricle (RV) anomalies enrolled in the Single Ventricle Reconstruction trial. Measurement of PVF peak systolic (S) and diastolic (D) velocities, velocity time integrals (VTI), S/D peak velocity and VTI ratios, and frequency of atrial reversal (Ar) waves were made at three postoperative time points in 261 infants: early post-Norwood, pre-stage II surgery, and 14 months. Indices were compared over time, between initial shunt type [modified Blalock-Taussig shunt (MBTS) and right ventricle-to-pulmonary artery shunt (RVPAS)] and in relation to clinical outcomes. S velocities and VTI increased over time while D wave was stable, resulting in increasing S/D peak velocity and VTI ratios, with a median post-Norwood S/D VTI ratio of 1.14 versus 1.38 at pre-stage II and 1.89 at 14 months (P < 0.0001 between intervals). MBTS subjects had significantly higher S/D peak velocity and VTI ratios compared to RVPAS at the post-Norwood and pre-stage II time points (P < 0.0001) but not by 14 months. PVF patterns did not correlate with survival or hospitalization course at 1 year. PVF patterns after Norwood palliation differ from normal infants by having a dominant systolic pattern throughout infancy. PVF differences based upon shunt type resolve by 14 months and did not correlate with clinical outcomes. This study describes normative values and variations in PVF for infants with a single RV from shunt-dependent pulmonary blood flow to cavopulmonary blood flow.

Rationale and design of the Children's Oncology Group (COG) study ALTE1621: a randomized, placebo-controlled trial to determine if low-dose carvedilol can prevent anthracycline-related left ventricular remodeling in childhood cancer survivors at high risk for developing heart failure.

BACKGROUND: Anthracyclines are widely used in the treatment of childhood cancer. One of the well-recognized side-effects of anthracycline therapy is dose-dependent cardiomyopathy that may progress to heart failure (HF) years after completion of cancer-directed therapy. This study will evaluate the efficacy of low-dose beta-blocker (carvedilol) for HF risk reduction in childhood cancer survivors at highest risk for HF. The proposed intervention has the potential to significantly reduce chronic cardiac injury via interruption of neurohormonal systems responsible for left ventricular (LV) remodeling, resulting in improved cardiac function and decreased risk of HF. The intervention is informed by previous studies demonstrating efficacy in pediatric and adult non-oncology populations, yet remains unstudied in the pediatric oncology population. METHODS/DESIGN: The primary objective of the trial is to determine impact of the intervention on echocardiographic markers of cardiac remodeling and HF risk, including: LV wall thickness/ dimension ratio (LVWT/D; primary endpoint), as well as LV ejection fraction, volume, and blood biomarkers (natriuretic peptides, galectin-3) associated with HF risk. Secondary objectives are to establish safety and tolerability of the 2-year course of carvedilol using: 1) objective measures: hepatic and cardiovascular toxicity, treatment adherence, and 2) subjective measures: participant self-reported outcomes. Two hundred and fifty survivors of childhood cancer (diagnosed <21 years of age), and previously treated with high-dose (≥300 mg/m2) anthracyclines will be enrolled in a randomized, double-blind, placebo controlled trial. After baseline assessments, participants will be randomized in a 1:1 ratio to low-dose carvedilol (maximum dose: 12.5 mg/day) or placebo. Carvedilol or placebo is up-titrated (starting dose: 3.125 mg/day) according to tolerability. DISCUSSION: When completed, this study will provide much-needed information regarding a physiologically plausible pharmacological risk-reduction strategy for childhood cancer survivors at high risk for developing anthracycline-related HF. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02717507.

International Fetal Cardiac Intervention Registry: A Worldwide Collaborative Description and Preliminary Outcomes.

BACKGROUND: Invasive fetal cardiac intervention (FCI) has been reported in single-institution series, promoting technical and physiologic success. OBJECTIVES: This study describes the creation of an international registry of cases presenting for FCI, intended to compile technical and outcome data from a multicenter cohort. METHODS: For this initial analysis, the entire database of the International Fetal Cardiac Intervention Registry (IFCIR) was queried for details of diagnoses, procedures, and outcomes. Maternal-fetal dyads from January 2001 through June 2014 were included. RESULTS: Eighteen institutions submitted data by data harvest. Of 370 cases entered, 245 underwent FCI: 100 aortic valvuloplasties from a previous single-center report (excluded from additional reporting here), an additional 86 aortic and 16 pulmonary valvuloplasties, 37 atrial septal cases, and 6 unclassified cases. FCI did not appear to affect overall survival to hospital discharge. Among live-born infants with a fetal diagnosis of aortic stenosis/evolving hypoplastic left heart syndrome, more than twice as many were discharged with biventricular circulation after successful FCI versus those meeting institutional criteria but without any or successful FCI (42.8% vs. 19.4%, respectively). When fetal deaths were counted as treatment failures, the percentages were similar: biventricular circulation at discharge was 31.3% versus 18.5% for those discharged with univentricular palliation. Survival to discharge for live-born fetuses with atrial restriction was similar to that of those undergoing technically successful versus unsuccessful FCI (63.6% vs. 46.7%, respectively), although criteria for diagnosis were nonuniform. CONCLUSIONS: We describe the contents of the IFCIR and present post-natal data to suggest potential benefit to fetal therapy among pregnancies considered for possible intervention and support proposals for additional work.

Site of interstage outpatient care and growth after the Norwood operation.

BACKGROUND: Recent efforts have focused on optimising interstage outcomes, including growth, for infants following the Norwood operation. The impact of the site of interstage care remains unclear, and it has been hypothesised that care at the surgical site may be beneficial due to greater access to resources such as nutritional support. This study evaluated the relationship between site of interstage care and weight gain in a large multicentre cohort. METHODS: Infants enrolled in the National Paediatric Cardiology Quality Improvement Collaborative (2008-2013) surviving up to Stage 2 were included. Change in weight-for-age z-score between Norwood discharge and Stage 2 admission was compared in those receiving care at the surgical versus non-surgical site. RESULTS: Of the 487 interstage survivors, 60% received all care at the surgical site, and 40% received care at a non-surgical site. There was no significant difference between groups in change in weight-for-age z-score: +0.36±0.96 for the surgical site group versus +0.46±1.02 for the non-surgical site group, p=0.3. Results were unchanged in multivariable analysis adjusting for differences in important baseline characteristics, duration of interstage, and home surveillance strategy. The proportion of all patients with weight-for-age z-score <-2 decreased from 40% at Norwood discharge to 29% at Stage 2, with no significant difference in change between the two groups (p=0.1). CONCLUSIONS: The site of interstage care was not associated with weight gain during the interstage period. Nearly one-third of patients overall had a weight-for-age z-score <-2 at Stage 2. Further study is required to identify methods to optimise weight gain in these patients.

Echocardiographic factors discriminating biventricular versus univentricular approach in the foetus with borderline left ventricle.

BACKGROUND: The term "borderline left ventricle" describes a small left heart that may be inadequate to provide systemic cardiac output and implies the potential need for a single-ventricle palliation. The aim of this study was to identify foetal echocardiographic features that help discriminate which infants will undergo single-ventricle palliation versus biventricular repair to aid in prenatal counselling. METHODS: The foetal database at our institution was searched to identify all foetuses with borderline left ventricle, as determined subjectively by a foetal cardiologist, from 2000 to 2011. The foetal images were retrospectively analysed for morphologic and physiologic features to determine which best predicted the postnatal surgical choice. RESULTS: Of 39 foetuses identified with borderline left ventricle, 15 were planned for a univentricular approach, and 24 were planned for a biventricular approach. There were significant differences between the two outcome groups in the Z-scores of the mitral valve annulus, left ventricular end-diastolic dimension, aortic valve annulus, and ascending aorta diameter (p<0.05). With respect to discriminating univentricular outcomes, cut-offs of mitral valve Z-score ⩽-1.9 and tricuspid:mitral valve ratio ⩾1.5 were extremely sensitive (100%), whereas a right:left ventricular end-diastolic dimension ratio ⩾2.1 provided the highest specificity (95.8%). CONCLUSION: In foetuses with borderline left ventricle, a mitral valve Z-score ⩾-1.9 or a tricuspid:mitral valve ratio ⩽1.5 suggests a high probability of biventricular repair, whereas a right:left ventricular end-diastolic dimension ratio ⩾2.1 confers a likelihood of single-ventricle palliation.

International fetal cardiac intervention registry: a worldwide collaborative description and preliminary outcomes

BACKGROUND: Invasive fetal cardiac intervention (FCI) has been reported in single-institution series, promoting technical and physiologic success. OBJECTIVES: This study describes the creation of an international registry of cases presenting for FCI, intended to compile technical and outcome data from a multicenter cohort. METHODS: For this initial analysis, the entire database of the International Fetal Cardiac Intervention Registry (IFCIR) was queried for details of diagnoses, procedures, and outcomes. Maternal-fetal dyads from January 2001 through June 2014 were included.RESULTS:Eighteen institutions submitted data by data harvest. Of 370 cases entered, 245 underwent FCI: 100 aortic valvuloplasties from a previous single-center report (excluded from additional reporting here), an additional 86 aortic and 16 pulmonary valvuloplasties, 37 atrial septal cases, and 6 unclassified cases. FCI did not appear to affect overall survival to hospital discharge. Among live-born infants with a fetal diagnosis of aortic stenosis/evolving hypoplastic left heart syndrome, more than twice as many were discharged with biventricular circulation after successful FCI versus those meeting institutional criteria but without any or successful FCI (42.8% vs. 19.4%, respectively). When fetal deaths were counted as treatment failures, the percentages were similar: biventricular circulation at discharge was 31.3% versus 18.5% for those discharged with univentricular palliation. Survival to discharge for live-born fetuses with atrial restriction was similar to that of those undergoing technically successful versus unsuccessful FCI (63.6% vs. 46.7%, respectively), although criteria for diagnosis were nonuniform. CONCLUSIONS: We describe the contents of the IFCIR and present post-natal data to suggest potential benefit to fetal therapy among pregnancies considered for possible intervention and support proposals for additional work.

Screening for cardiac dysfunction in anthracycline-exposed childhood cancer survivors.

PURPOSE: To examine the utility and reliability of obtaining early echocardiographic measurements of left ventricular (LV) remodeling as well as blood biomarkers of cardiac injury in asymptomatic childhood cancer survivors at risk for LV dysfunction and congestive heart failure due to past exposure to anthracycline chemotherapy. EXPERIMENTAL DESIGN: Using a cross-sectional design, anthracycline-exposed childhood cancer survivors with preserved ejection fraction (EF; ≥50%) were evaluated using early echocardiographic indices and blood biomarkers of LV dysfunction. Survivors treated with ≥300 mg/m(2) anthracyclines [high risk (HR): n = 100] were compared with those treated with <300 mg/m(2) anthracyclines [low risk (LR): n = 50] and matched healthy controls (HC: n = 50). All echocardiograms were interpreted by an institutional cardiologist and a study cardiologist blinded to risk status. RESULTS: Time from diagnosis was comparable for HR (12.0 years) and LR (13.2 years, P = 0.8) survivors. Echocardiograms: HR had lower LV thickness-dimension ratio (Z-score: HR: -0.62, LR: -0.03, HC: -0.02; P < 0.001), increased LV wall stress (HR: 66.7 g/cm(2), LR: 56.6 g/cm(2), HC: 54.2 g/cm(2); P < 0.01), and higher myocardial performance index (HR: 0.51, LR: 0.46, HC: 0.46; P < 0.01). Interobserver correlation (clinical/blinded reading) for all echocardiographic indices was excellent (range: R = 0.76-0.97, P < 0.001). Blood biomarkers: With the exception of NT-proBNP (r = 0.28, P < 0.01), there was no correlation between blood biomarkers (B-type natriuretic peptide, Troponin-T, ST-2, Galectin-3) and LV dysfunction. CONCLUSION: Childhood cancer survivors with preserved EF 10+ years from anthracycline exposure had dose-dependent changes in echocardiographic markers of LV dysfunction.

Carnitine and cardiac dysfunction in childhood cancer survivors treated with anthracyclines.

Childhood cancer survivors are at high risk of developing congestive heart failure (CHF) compared with the general population, and there is a dose-dependent increase in CHF risk by anthracycline dose. The mechanism by which this occurs has not been fully elucidated. Metabolomics, the comprehensive profile of small-molecule metabolites, has the potential to provide insight into the pathogenesis of disease states and discover diagnostic markers for therapeutic targets. We performed echocardiographic testing and blood plasma metabolomic analyses (8 pathways; 354 metabolites) in 150 asymptomatic childhood cancer survivors previously treated with anthracyclines. Median time from cancer diagnosis to study participation was 12.4 years (2.6-37.9 years); 64% were treated for a hematologic malignancy; median anthracycline dose was 350 mg/m(2) (25-642 mg/m(2)). Thirty-five (23%) participants had cardiac dysfunction-defined as left ventricular end-systolic wall stress >2SD by echocardiogram. Plasma levels of 15 compounds in three metabolic pathways (carbohydrate, amino acid, and lipid metabolism) were significantly different between individuals with cardiac dysfunction and those with normal systolic function. After adjusting for multiple comparisons, individuals with cardiac dysfunction had significantly lower plasma carnitine levels [relative ratio (RR), 0.89; P < 0.01] in relation to those with normal systolic function. These findings may facilitate the development of primary prevention (treatment of carnitine deficiency before/during anthracycline administration) and secondary prevention strategies (screening and treatment in long-term survivors) in patients at highest risk for CHF. Cancer Epidemiol Biomarkers Prev; 23(6); 1109-14. ©2014 AACR.