The Fontan Udenafil Exercise Longitudinal Trial: Subgroup Analysis.

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO2), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO2, work rate at the ventilatory anaerobic threshold (VAT), VO2 at VAT, and ventilatory efficiency (VE/VCO2) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO2, baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115.

Personalized computational heart models with T1-mapped fibrotic remodeling predict sudden death risk in patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is associated with risk of sudden cardiac death (SCD) due to ventricular arrhythmias (VAs) arising from the proliferation of fibrosis in the heart. Current clinical risk stratification criteria inadequately identify at-risk patients in need of primary prevention of VA. Here, we use mechanistic computational modeling of the heart to analyze how HCM-specific remodeling promotes arrhythmogenesis and to develop a personalized strategy to forecast risk of VAs in these patients. We combine contrast-enhanced cardiac magnetic resonance imaging and T1 mapping data to construct digital replicas of HCM patient hearts that represent the patient-specific distribution of focal and diffuse fibrosis and evaluate the substrate propensity to VA. Our analysis indicates that the presence of diffuse fibrosis, which is rarely assessed in these patients, increases arrhythmogenic propensity. In forecasting future VA events in HCM patients, the imaging-based computational heart approach achieved 84.6%, 76.9%, and 80.1% sensitivity, specificity, and accuracy, respectively, and significantly outperformed current clinical risk predictors. This novel VA risk assessment may have the potential to prevent SCD and help deploy primary prevention appropriately in HCM patients.

Ventricular arrhythmia risk prediction in repaired Tetralogy of Fallot using personalized computational cardiac models.

BACKGROUND: Adults with repaired tetralogy of Fallot (rTOF) are at increased risk for ventricular tachycardia (VT) due to fibrotic remodeling of the myocardium. However, the current clinical guidelines for VT risk stratification and subsequent implantable cardioverter-defibrillator deployment for primary prevention of sudden cardiac death in rTOF remain inadequate. OBJECTIVE: The purpose of this study was to determine the feasibility of using an rTOF-specific virtual-heart approach to identify patients stratified incorrectly as being at low VT risk by current clinical criteria. METHODS: This multicenter retrospective pilot study included 7 adult rTOF patients who were considered low risk for VT based on clinical criteria. Patient-specific computational heart models were generated from late gadolinium enhanced magnetic resonance imaging (LGE-MRI), incorporating the individual distribution of rTOF fibrotic remodeling in both ventricles. Simulations of rapid pacing determined VT inducibility. Model creation and simulations were performed by operators blinded to clinical outcome. RESULTS: Two patients in the study experienced clinical VT. The virtual hearts constructed from LGE-MRI scans of 7 rTOF patients correctly predicted reentrant VT in the models from VT-positive patients and no arrhythmia in those from VT-negative patients. There were no statistically significant differences in clinical criteria commonly used to assess VT risk, including QRS duration and age, between patients who did and those who did not experience clinical VT. CONCLUSION: This study demonstrates the feasibility of image-based virtual-heart modeling in patients with congenital heart disease and structurally abnormal hearts. It highlights the potential of the methodology to improve VT risk stratification in patients with rTOF.

Computational Identification of Ventricular Arrhythmia Risk in Pediatric Myocarditis.

Children with myocarditis have increased risk of ventricular tachycardia (VT) due to myocardial inflammation and remodeling. There is currently no accepted method for VT risk stratification in this population. We hypothesized that personalized models developed from cardiac late gadolinium enhancement magnetic resonance imaging (LGE-MRI) could determine VT risk in patients with myocarditis using a previously-validated protocol. Personalized three-dimensional computational cardiac models were reconstructed from LGE-MRI scans of 12 patients diagnosed with myocarditis. Four patients with clinical VT and eight patients without VT were included in this retrospective analysis. In each model, we incorporated a personalized spatial distribution of fibrosis and myocardial fiber orientations. Then, VT inducibility was assessed in each model by pacing rapidly from 26 sites distributed throughout both ventricles. Sustained reentrant VT was induced from multiple pacing sites in all patients with clinical VT. In the eight patients without clinical VT, we were unable to induce sustained reentry in our simulations using rapid ventricular pacing. Application of our non-invasive approach in children with myocarditis has the potential to correctly identify those at risk for developing VT.

Appropriate Use Criteria for paediatric echocardiography in an outpatient practice: a validation study.

BACKGROUND: Although transthoracic echocardiography is the dominant imaging modality in CHD, optimal utilisation is unclear. We assessed whether adherence to the paediatric Appropriate Use Criteria for outpatient transthoracic echocardiography could reduce inappropriate use without missing significant cardiac disease. METHODS: Using the Appropriate Use Criteria, we determined the indication and appropriateness rating for each initial echocardiogram performed at our institution during calendar year 2014 (N=1383). Chart review documented ordering provider training, patient demographics, and study result, classified as normal, abnormal, or abnormal motivating treatment within a 2-year follow-up period. We tested whether provider training level or patient age correlated with echocardiographic findings or appropriateness rating. RESULTS: We found that 83.9% of echocardiograms were normal and that 66.7% had an appropriate indication. Nearly all abnormal results and all results motivating treatment were in appropriate studies, giving an odds ratio of 2.73 for an abnormal result if an appropriate indication was present (95% confidence interval 1.92-3.89, p<0.001). None of the remaining initial abnormal results with less than appropriate indications became significant, resulting in treatment over 2 years. Results suggest a potential reduction in imaging volume of as much as 33% with application of the criteria. Cardiologists ordered nearly all studies resulting in treatment but also more echocardiograms with less appropriate indications. Most examinations were in older patients; however, most abnormal results were in patients younger than 1 year. CONCLUSIONS: The Appropriate Use Criteria can be used to safely reduce echocardiography volume while still detecting significant heart disease.

Classification of the dysmorphology of pectus excavatum.

BACKGROUND/PURPOSE: To describe the dysmorphology of pectus excavatum, the most common congenital chest wall anomaly. METHODS: A stratified sample of 64 patients, representative of a patient population with pectus excavatum of the Children's Hospital of King's Daughters in Norfolk, VA, was described and classified. The sample was stratified by sex to represent a 4:1 male-to-female ratio. The sample was further stratified to represent categories of age (3-10, 11-16, and 17 years and older). Preoperative photos and baseline chest computed tomography scans were examined and categorized according to the chief criteria, including asymmetry/symmetry of the depression, localized vs diffuse morphology, sternal torsion, cause of asymmetric appearance, and the length of the depression. RESULTS: Useful morphologic distinctions in pectus excavatum are localized depressions vs diffuse depressions, short and long length, symmetry, sternal torsion, slope/position of absolute depth, and unique patterns such as the horns of steer depression. CONCLUSIONS: These classifications simplify the diagnosis of pectus excavatum, aid in corrective surgery, and should improve correlation of phenotype and genotype in future genetic analysis.