Niaz, Talha

Introduction: Left and right ventricular systolic dysfunction (LVSD and RVSD respectively) contribute to considerable pediatric morbidity. Both LVSD and RVSD can occur in children before symptom onset, emphasizing the need for early detection. Existing deep-learning algorithms can identify LVSD in adults using 12-lead ECG; however, their efficacy in children is uncertain. Aims: We aimed to create a deep-learning model for LVSD and RVSD detection in pediatric patients using an AI-enabled ECG and compare novel pediatric models to a previously validated adult LVSD model. Methods: We identified 10,214 pediatric patients at the Mayo Clinic with a transthoracic echocardiogram (TTE) and a 10-second, 12-lead surface ECG within 14 days of TTE, performed from 2002 -2022. Our cohort comprised the first TTE-ECG pair from each patient, totaling 138 with EF ≤ 35%, 312 with EF ≤ 50%, 482 with RVSD, and 9,567 without any LVSD or RVSD. The cohort was split into training, validation, and testing datasets to develop neural networks for systolic dysfunction detection. Results: The cohort was 52.3% male, with an average age of 10.3 years. Novel models generated in the pediatric cohort demonstrated excellent performance in systolic dysfunction detection (Figure 1). Pediatric models for EF ≤ 35% and EF ≤ 50% achieved test AUCs of 0.92 (95% CI 0.89, 0.95) and 0.89 (95% CI 0.85, 0.94) respectively. The RVSD model reached a test AUC of 0.91 (95% CI 0.88, 0.94). A combined model for EF ≤ 35% or RVSD exhibited a test AUC of 0.90 (95% CI 0.87, 0.93), sensitivity 0.88, specificity 0.82, PPV 0.20, and NPV 0.95. A combined model for EF ≤ 50% or RVSD exhibited a test AUC of 0.88 (95% CI 0.85, 0.91). The previously validated adult data-derived model achieved an AUC of 0.86 (95% CI 0.83, 0.89) for EF ≤ 50% in children. Conclusions: AI-enabled ECGs demonstrate efficient detection of both LVSD and RVSD in pediatric patients. Future multi-site validation is needed to further establish the reliability of these models.

Introduction: Biologic sex and hormonal concentrations shape ECG parameters due to sex hormone effects on cardiac function. AI-enabled ECGs have previously been shown to accurately predict patient sex in adults and correlate with sex hormone levels. Aims: We aimed to test the ability of AI-enabled ECGs to predict pediatric patient sex and explore the influence of pubertal development. Methods: Two AI-enabled ECG models were created using a convolutional neural network trained on pediatric 10-second, 12-lead surface ECGs. The first model was trained de novo using pediatric data. The second model used transfer learning from a previously validated adult data-derived algorithm. We analyzed the first ECG from 89,063 pediatric patients (aged <19 years) recorded from 1988-2022, and divided the cohort into training, validation, and testing datasets. Subgroup analysis was performed on prepubertal (0-7 years), pubertal (8-14 years), and post-pubertal (15-18 years) patients. Results: The cohort consisted of 46.6% males, with 21,434 prepubertal, 26,300 pubertal, and 41,329 post-pubertal children. No significant performance difference was observed between the two models. Both models demonstrated 81% accuracy and an overall AUC of 0.91 in the testing cohorts, with high discriminatory ability in post-pubertal teenagers (AUC = 0.98). (Figure 1) Conclusions: AI-ECG predicts pediatric patient sex with varying performance across pubertal stages. The highest discriminatory ability is observed post-puberty, decreasing in pubertal and prepubertal children. The results suggest hormonal and physiological changes during puberty may influence cardiac electrophysiology measurably. More research is required to interpret CNN-predicted sex discordance with actual sex and its implications for future cardiovascular risk.

This JAMA Patient Page describes the autosomal dominant genetic disorder of Marfan syndrome and its diagnosis and treatment.

Background Patients with heterotaxy syndromes (right and left atrial isomerism) are at high risk of poor outcomes after single-ventricle palliation. However, the long-term outcomes and specific parameters associated with poor outcomes are incompletely understood. Methods A retrospective review was performed of all patients with atrial isomerism who had a Fontan at our institution from 1973 to 2020. Standard demographic, as well as pre-, peri-, and postoperative parameters were collected. Features and outcomes of patients with polysplenia were compared to asplenia. Outcomes were analyzed for effect during 4 eras: (1: 1973-1984; n = 27), (2: 1985-1994; n = 93), (3: 1995-2004; n = 28), and (4: 2005-2020; n = 10). Results Of the 1176 patients who had a Fontan operation, 158 (14%) had a heterotaxy syndrome. The median age at the time of Fontan was 8 (9) years. Early mortality was 20% and was greater in patients with asplenia compared to polysplenia (27% vs. 12%, p = .019). But it substantially improved over time (61% in era 1 vs. 7%-10% in the more recent eras ( p < .001)), as did transplant-free survival (22% at 10 years in era 1 vs. 88% in era 4, p < .001). Transplant-free survival was significantly lower in patients with asplenia versus those with polysplenia ( p = .014), and patients with heterotaxy had lower survival than nonheterotaxy ( p = .01). This was largely due to the asplenia group ( p < .001) (hazard ratio = 3.05, p = .007). Conclusions After Fontan operation, patients with heterotaxy, particularly asplenia, continue to demonstrate worse transplant-free survival than nonheterotaxy patients. Early mortality and long-term transplant-free survival have improved in more recent eras.

Background: Whole-genome sequencing in families enables deciphering of congenital heart disease causes. A shared genetic basis for familial bicuspid aortic valve (BAV) and hypoplastic left heart syndrome (HLHS) was postulated. Methods: Whole-genome sequencing was performed in affected members of 6 multiplex BAV families, an HLHS cohort of 197 probands and 546 relatives, and 813 controls. Data were filtered for rare, predicted-damaging variants that cosegregated with familial BAV and disrupted genes associated with congenital heart disease in humans and mice. Candidate genes were further prioritized by rare variant burden testing in HLHS cases versus controls. Modifier variants in HLHS proband-parent trios were sought to account for the severe developmental phenotype. Results: In 5 BAV families, missense variants in 6 ontologically diverse genes for structural ( SPTBN1 , PAXIP1 , and FBLN1 ) and signaling ( CELSR1 , PLXND1 , and NOS3 ) proteins fulfilled filtering metrics. CELSR1 , encoding cadherin epidermal growth factor laminin G seven-pass G-type receptor, was identified as a candidate gene in 2 families and was the only gene demonstrating rare variant enrichment in HLHS probands ( P =0.003575). HLHS-associated CELSR1 variants included 16 missense, one splice site, and 3 noncoding variants predicted to disrupt canonical transcription factor binding sites, most of which were inherited from a parent without congenital heart disease. Filtering whole-genome sequencing data for rare, predicted-damaging variants inherited from the other parent revealed 2 cases of CELSR1 compound heterozygosity, one case of CELSR1 - CELSR3 synergistic heterozygosity, and 4 cases of CELSR1 - MYO15A digenic heterozygosity. Conclusions: CELSR1 is a susceptibility gene for familial BAV and HLHS, further implicating planar cell polarity pathway perturbation in congenital heart disease.

Background: There is a paucity of literature regarding systemic semilunar valve (SSLV) dysfunction in patients with Fontan circulation. We sought to describe our center's 47-year experience with systemic semilunar valve replacement or repair (SSLVR) in patients with Fontan circulation. Methods: The Mayo Clinic Fontan Database is a comprehensive institutional database that stores clinical information of 1176 patients from 1973 to 2021. It was reviewed to identify patients who had a SSLV intervention at the time of or after Fontan. A cohort of 15 patients was identified and a retrospective review of their records was performed. Results: Fourteen patients had SSLV replacement (all mechanical) and one had a repair. SSLVR occurred up to 29 years following the Fontan (mean 11.3 ± 9 years, median 14 years). Thirteen of 14 with SSLVR were performed after Fontan and one was done at the time of initial Fontan. This was an older cohort and mean age at the time of Fontan was 8.7 ± 9.4 years (median 4 years). Indication for the operation was > moderate SSLV regurgitation in all patients. Six patients had decreased ventricular function (EF < 50%) prior to SSLVR and 8 had reduced function after SSLVR. Conclusion: Fortunately, the need for SSLV intervention after Fontan was rare, as evidenced by our small cohort extracted from a large single-institution database spanning a 47-year time period. Reduced preoperative and postoperative ejection fraction was common but did not seem to impact the outcome. Optimal timing for SSLV intervention after Fontan remains unclear.

Background: Videoscopic left cardiac sympathetic denervation (LCSD) is an effective antifibrillatory, minimally invasive therapy for patients with potentially life-threatening arrhythmia syndromes like long QT syndrome (LQTS). Although initially used primarily for treatment intensification following documented LQTS-associated breakthrough cardiac events while on beta-blockers, LCSD as 1-time monotherapy for certain patients with LQTS requires further evaluation. We are presenting our early experience with LCSD monotherapy for carefully selected patients with LQTS. Methods: Among the 1400 patients evaluated and treated for LQTS, a retrospective review was performed on the 204 patients with LQTS who underwent LCSD at our institution since 2005 to identify the patients where the LCSD served as stand-alone, monotherapy. Clinical data on symptomatic status before diagnosis, clinical, and genetic diagnosis, and breakthrough cardiac events after diagnosis were analyzed to determine efficacy of LCSD monotherapy. Result: Overall, 64 of 204 patients (31%) were treated with LCSD alone (37 [58%] female, mean QTc 466±30 ms, 16 [25%] patients were symptomatic before diagnosis with a mean age at diagnosis 17.3±11.8 years, 5 had [8%] ≥1 breakthrough cardiac event after diagnosis, and mean age at LCSD was 21.1±11.4 years). The primary motivation for LCSD monotherapy was an unacceptable quality of life stemming from beta-blocker related side effects (ie, beta-blocker intolerance) in 56/64 patients (88%). The underlying LQTS genotype was LQT1 in 36 (56%) and LQT2 in 20 (31%). There were no significant LCSD-related surgical complications. With a mean follow-up of 2.7±2.4 years so far, only 3 patients have experienced a nonlethal, post-LCSD breakthrough cardiac event in 180 patient-years. Conclusions: LCSD may be a safe and effective stand-alone therapy for select patients who do not tolerate beta-blockers. However, LCSD is not curative and patient selection will be critical when potentially considering LCSD as monotherapy.