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PURPOSE Survivors of childhood cancer treated with anthracyclines and/or chest-directed radiation are at increased risk for heart failure (HF). The International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) recommends risk-based screening echocardiograms, but evidence supporting its frequency and cost-effectiveness is limited. PATIENTS AND METHODS Using the Childhood Cancer Survivor Study and St Jude Lifetime Cohort, we developed a microsimulation model of the clinical course of HF. We estimated long-term health outcomes and economic impact of screening according to IGHG-defined risk groups (low [doxorubicin-equivalent anthracycline dose of 1-99 mg/m2 and/or radiotherapy, 15 Gy], moderate [100 to, 250 mg/m2 or 15 to, 35 Gy], or high [$ 250 mg/m2 or $ 35 Gy or both $ 100 mg/m2 and $ 15 Gy]). We compared 1-, 2-, 5-, and 10-year interval-based screening with no screening. Screening performance and treatment effectiveness were estimated based on published studies. Costs and quality-of-life weights were based on national averages and published reports. Outcomes included lifetime HF risk, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). Strategies with ICERs, $100,000 per QALY gained were considered cost-effective. RESULTS Among the IGHG risk groups, cumulative lifetime risks of HF without screening were 36.7% (high risk), 24.7% (moderate risk), and 16.9% (low risk). Routine screening reduced this risk by 4% to 11%, depending on frequency. Screening every 2, 5, and 10 years was cost-effective for high-risk survivors, and every 5 and 10 years for moderate-risk survivors. In contrast, ICERs were. $175,000 per QALY gained for all strategies for low-risk survivors, representing approximately 40% of those for whom screening is currently recommended. CONCLUSION Our findings suggest that refinement of recommended screening strategies for IGHG high- and low-risk survivors is needed, including careful reconsideration of discontinuing asymptomatic left ventricular dysfunction and HF screening in low-risk survivors.

• Cardiac interdependence in conjoined twins is a rare phenomenon. • Presence of congenital heart disease may be an important prognostic factor. • There is high risk of high-output heart failure and pulmonary hypertension in the donor twin. • If reconstruction is feasible, early separation may improve the chance of survival.

Background: The COVID pandemic necessitated an altered approach to transthoracic echocardiography, especially in COVID cases. Whether this has effected echocardiography lab quality is unknown. Objectives: We sought to determine whether echocardiography lab quality measures during the COVID pandemic were different from those prior to the pandemic and whether quality and comprehensiveness of echocardiograms performed during the pandemic was different between COVID and non-COVID patients. Methods: The four quality measures (diagnostic errors, appropriateness of echocardiogram, American College of Cardiology Image Quality metric and Comprehensive Exam metric in structurally normal hearts) reported quarterly in our lab were compared between two quarters during COVID (2020) and pre-COVID (2019). Each component of these metrics was also assessed in randomly selected echocardiograms in COVID patients and compared to non-COVID echocardiograms. Results: For non-COVID echocardiograms, the image quality metric did not change between 2019 and 2020 and the comprehensive exam metric improved. Diagnostic error rate did not change, and appropriateness of echocardiogram indications improved. When COVID and non-COVID echocardiograms were compared, the image quality metric and comprehensiveness exam metric were lower for COVID cases (image quality mean 21.3/23 for non-COVID, 18.6/23 for COVID, p < 0.001 and comprehensive exam mean 29.5/30 for non-COVID, 27.7/39 for COVID, p < 0.001). In particular, systemic and pulmonary veins, pulmonary arteries and aortic arch were not adequately imaged in COVID patients. For studies in which a follow-up echocardiogram was available, no new pathology was found. Conclusions: At our center, though diagnostic error rate did not change during the pandemic and the proportion of echocardiograms ordered for appropriate indications increased, imaging quality in COVID patients was compromised, especially for systemic and pulmonary veins, pulmonary arteries and arch. Though no new pathology was noted on the small number of patients who had follow-up studies, we are paying careful attention to these structures to avoid diagnostic errors going forward.

TDI–MPI has been shown to predict cardiovascular mortality in adults; there are a paucity of data on its use in children. We sought to determine the prognostic significance of TDI-MPI at time of DCM diagnosis in children. Patients aged ≤18 years diagnosed with DCM were included along with age- and sex-matched controls. Echo at diagnosis was analyzed to obtain standard measures of LV function, PW-MPI, and septal and LV free wall TDI-MPI. Survival analysis was used to assess the time to composite outcome of death, VAD, or transplant, stratified by TDI-MPI z-score. The study included 79 patients with DCM and 79 controls. During a median follow-up of 182 days (IQR 41-815 days), 16 underwent VAD placement, 21 underwent cardiac transplant, 6 died, and 36 had event-free survival. The median septal TDI-MPI for cases was 0.70 for patients with DCM vs 0.45 for controls (P <.001). Those with septal TDI-MPI z-scores ≥2 develop events significantly earlier than those with z-score <2 (P =.014). In multivariable analysis, TDI-MPI z-score ≥2 was significantly associated with poor outcomes (HR 2.12, 95% CI 1.06-4.23). TDI-MPI can be reliably performed in pediatric patients with DCM. A TDI-MPI z-score ≥2 at diagnosis may be associated with earlier poor outcome. Further studies evaluating the use of TDI-MPI in longitudinal follow-up of patients with DCM may be helpful in refining its clinical use.

Background: Retrospective multicenter research using echocardiograms obtained for routine clinical care can be hampered by issues of individual center quality. We sought to evaluate imaging and patient characteristics associated with poorer quality of archived echocardiograms from a cohort of childhood cancer survivors. Methods: A single blinded reviewer at a central core laboratory graded quality of clinical echocardiograms from five centers focusing on images to derive 2D and M-mode fractional shortening (FS), biplane Simpson's ejection fraction (EF), myocardial performance index (MPI), tissue Doppler imaging (TDI)–derived velocities, and global longitudinal strain (GLS). Results: Of 535 studies analyzed in 102 subjects from 2004 to 2017, all measures of cardiac function could be assessed in only 7%. While FS by 2D or M-mode, MPI, and septal E/E′ could be measured in >80% studies, mitral E/E′ was less consistent (69%), but better than EF (52%) and GLS (10%). 66% of studies had ≥1 issue, with technical issues (eg, lung artifact, poor endocardial definition) being the most common (33%). Lack of 2- and 3-chamber views was associated with the performing center. Patient age <5 years had a higher chance of apex cutoff in 4-chamber views compared with 16-35 years old. Overall, for any quality issue, earlier era of echo and center were the only significant risk factors. Conclusion: Assessment of cardiac function using pooled multicenter archived echocardiograms was significantly limited. Efforts to standardize clinical echocardiographic protocols to include apical 2- and 3-chamber views and TDI will improve the ability to quantitate LV function.

Objectives: The purpose of this study was to assess the timing of changes in serial echocardiographic parameters in pediatric cancer survivors and to evaluate their associations with cardiomyopathy development. Background: Pediatric cancer survivors undergo serial echocardiograms to screen for cardiotoxicity. It is not clear whether small longitudinal changes in functional or structural parameters over time have clinical significance. Methods: This is a multicenter, retrospective, case-control study of ≥1-year survivors following the end of cancer therapy. Cardiomyopathy cases (fractional shortening [FS] ≤28% or ejection fraction [EF] ≤50% on ≥2 occasions) were matched to control subjects (FS ≥30%, EF ≥55%, not on cardiac medications) by cumulative anthracycline and chest radiation dose, follow-up duration, and age at diagnosis. Digitally archived clinical surveillance echocardiograms were quantified in a central core laboratory, blinded to patient characteristics. Using mixed models with interaction terms between time and case status, we estimated the least square mean differences of 2-dimensional, M-mode, pulsed wave Doppler, and tissue Doppler imaging–derived parameters over time between cases and control subjects. Results: We identified 50 matched case-control pairs from 5 centers. Analysis of 412 echocardiograms (cases, n = 181; control subjects, n = 231) determined that indices of left ventricular systolic function (FS, biplane EF), diastolic function (mitral E/A ratio), and left ventricular size (end-diastolic dimension z-scores) were significantly different between cases and control subjects, even 4 years prior to the development of cardiomyopathy. Conclusions: Longitudinal changes in cardiac functional parameters can occur relatively early in pediatric cancer survivors and are associated with the development of cardiomyopathy.

Background-The Pediatric Heart Network's Single Ventricle Reconstruction (SVR) trial randomized infants with single right ventricles (RVs) undergoing a Norwood procedure to a modified Blalock-Taussig or RV-to-pulmonary artery shunt. This report compares RV parameters in the 2 groups using 3-dimensional echocardiography. Methods and Results-Three-dimensional echocardiography studies were obtained at 10 of 15 SVR centers. Of the 549 subjects, 314 underwent 3-dimensional echocardiography studies at 1 to 4 time points (pre-Norwood, post-Norwood, pre-stage II, and 14 months) for a total of 757 3-dimensional echocardiography studies. Of these, 565 (75%) were acceptable for analysis. RV volume, mass, mass:volume ratio, ejection fraction, and severity of tricuspid regurgitation did not differ by shunt type. RV volumes and mass did not change after the Norwood, but increased from pre-Norwood to pre-stage II (end-diastolic volume [milliliters]/body surface area [BSA]1.3, end-systolic volume [milliliters]/BSA1.3, and mass [grams]/BSA1.3 mean difference [95% confidence interval]=25.0 [8.7-41.3], 19.3 [8.3-30.4], and 17.9 [7.3-28.5], then decreased by 14 months (end-diastolic volume/BSA1.3, end-systolic volume/BSA1.3, and mass/BSA1.3 mean difference [95% confidence interval]=-24.4 [-35.0 to -13.7], -9.8 [-17.9 to -1.7], and -15.3 [-22.0 to -8.6]. Ejection fraction decreased from pre-Norwood to pre-stage II (mean difference [95% confidence interval]=-3.7 [-6.9 to -0.5]), but did not decrease further by 14 months. Conclusions-We found no statistically significant differences between study groups in 3-dimensional echocardiography measures of RV size and function, or magnitude of tricuspid regurgitation. Volume unloading was seen after stage II, as expected, but ejection fraction did not improve. This study provides insights into the remodeling of the operated univentricular RV in infancy.

Purpose: To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer. Patients and Methods: Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models. Results: Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all Ptrend < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7). Conclusion: Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.

Persistent pressure overload can cause cardiac hypertrophy and progressive heart failure (HF). The authors developed a pressure-overload HF model of juvenile mice to study the cardiac response to pressure overload that may be applicable to clinical processes in children. Severe thoracic aortic banding (sTAB) was performed using a 28-gauge needle for 40 juvenile (age, 3 weeks) and 47 adult (age, 6 weeks) C57BL/6 male mice. To monitor the structural and functional changes, M-mode echocardiography was performed for conscious mice that had undergone sTAB and sham operation. Cardiac hypertrophy, dilation, and HF occurred in both juvenile and adult mice after sTAB. Compared with adults, juvenile HF is characterized by greater impairment of ventricular contractility and less hypertrophy. In addition, juvenile mice had significantly higher rates of survival than adult mice during the early postoperative weeks. Consistent with clinical HF seen in children, juvenile banded mice demonstrated a lower growth rate than either adult banded mice or juvenile control mice that had sham operations. The authors first developed a juvenile murine model of pressure-overload HF. Learning the unique characteristics of pressure-overload HF in juveniles should aid in understanding age-specific pathologic changes for HF development in children.