SOS1-Related Noonan Syndrome and Sudden Cardiac Arrest in the Absence of Cardiomyopathy-An Arrhythmia Phenotype?

Noonan syndrome (NS) is a predominantly autosomal dominant condition with various cardiac and extra-cardiac manifestations. Although it has been linked with atrial arrhythmias, ventricular arrhythmias are extremely rare in the absence of underlying structural cardiac abnormalities. We report an instance of aborted sudden cardiac arrest in a 7-year-old male with a confirmed SOS1 variant and a lack of evidence to support a structural cardiac, metabolic, or infectious etiology. This is the second reported instance of sudden cardiac arrest related to ventricular fibrillation in a child with SOS1-related NS in the absence of any structural cardiac defects. Although no definitive correlation can be ascertained from a limited existing body of knowledge surrounding SOS1 and ventricular fibrillation unrelated to structural heart defects, it provokes the idea of an arrhythmia phenotype and future research is warranted to guide proper clinical treatment, monitoring, and management of such individuals.

Pediatric sex estimation using AI-enabled ECG analysis: influence of pubertal development.

AI-enabled ECGs have previously been shown to accurately predict patient sex in adults and correlate with sex hormone levels. We aimed to test the ability of AI-enabled ECGs to predict sex in the pediatric population and study the influence of pubertal development. AI-enabled ECG models were created using a convolutional neural network trained on pediatric 10-second, 12-lead 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 90,133 unique pediatric patients (aged ≤18 years) recorded between 1987-2022, and divided the cohort into training, validation, and testing datasets. Subgroup analysis was performed on prepubertal (0-7 years), peripubertal (8-14 years), and postpubertal (15-18 years) patients. The cohort was 46.7% male, with 21,678 prepubertal, 26,740 peripubertal, and 41,715 postpubertal children. The de novo pediatric model demonstrated 81% accuracy and an area under the curve (AUC) of 0.91. Model sensitivity was 0.79, specificity was 0.83, positive predicted value was 0.84, and the negative predicted value was 0.78, for the entire test cohort. The model's discriminatory ability was highest in postpubertal (AUC = 0.98), lower in the peripubertal age group (AUC = 0.91), and poor in the prepubertal age group (AUC = 0.67). There was no significant performance difference observed between the transfer learning and de novo models. AI-enabled interpretation of ECG can estimate sex in peripubertal and postpubertal children with high accuracy.

Pediatric Quadricuspid Aortic Valve: Morphology, Characteristics, Clinical Outcomes, and Literature Review.

BACKGROUND: Quadricuspid aortic valve (QAV) is an exceedingly rare congenital heart defect (CHD) which has not been well-defined in a pediatric population. METHODS: The Mayo Clinic echocardiography database was retrospectively analyzed to identify patients ≤18 years diagnosed with QAV from January 1990 to December 2023. Patients with truncus arteriosus were excluded. All images were independently reviewed to define morphology of the QAV by using the Hurwitz and Roberts classification. RESULTS: Fourteen patients with QAV were identified with a median age at time of diagnosis being 10.5 years (interquartile range [IQR] 6-14 years). Male-to-female ratio was 3:1. Associated CHDs were present in 50% (n = 7) patients. The most common morphological subtypes of QAV were Type D in 43% (n = 6) and Type B in 29% (n = 4). Aortic regurgitation was the most frequently associated valvular abnormality affecting 86% (n = 12) cases, with greater than moderate regurgitation in only two patients. Aortic valve stenosis was observed in 14% (n = 2) patients. Ascending aortic dilatation was present in 21% (3/14) of the cohort, but only 14% (1/7) of isolated QAV patients. At a mean follow up of 11 ± 6.6 years and a median follow-up age of 22 years (IQR 14-27 years), survival was 100% with no primary interventions on the aortic valve or aorta. However, four patients required surgical interventions for associated CHDs. CONCLUSION: Among children with QAV, almost half of the patients had additional CHD. Aortic regurgitation was the predominant hemodynamic abnormality. Long-term survival was excellent with minimal progression during childhood and adolescence.

Perforated posterior mitral valve leaflet in mitral annular disjunction and infective endocarditis.

We herein presented a 17-year-old female with history of mild mitral valve prolapse who was admitted for methicillin-sensitive Staphylococcus aureus endocarditis and diagnosed with mitral annular disjunction and perforated posterior mitral valve leaflet on two-dimensional and three-dimensional echocardiography (P1-P2). A perforation in the posterior leaflet was confirmed and repaired during surgical intervention. This is a rare presentation of leaflet perforation in the area of mitral annular disjunction.

What Is Marfan Syndrome?

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

Outcomes of Biventricular and Single Ventricle Heterotaxy Patients: A Single Center Five-Decade Experience.

BACKGROUND: Surgical palliation of patients with heterotaxy syndrome has proven challenging. Long-term outcomes have historically been poor. Factors contributing to these outcomes are not completely understood. METHODS: The institutional databases were queried for patients with heterotaxy syndrome from 1973 to 2021. Comparisons were made between patients managed with single ventricle physiology and biventricular physiology. RESULTS: Heterotaxy syndrome was identified in 230 patients (polysplenia, 47%; asplenia, 53%). In all, 199 patients had single ventricle physiology; 180 (78%) had undergone Fontan palliation. Thirty-one patients had biventricular physiology, including 20 (9%) with surgical intervention and 11 (5%) without surgical intervention. Median age at Fontan was 7.5 years (interquartile range, 8.8). Median follow-up was 20 years (interquartile range, 21). Kaplan-Meier analysis showed decreased survival with single ventricle physiology (53% ± 4%, vs biventricular 93% ± 5% at 30 years; P = .001), as well as asplenia compared with polysplenia (49% ± 5% vs 68% ± 5% at 30 years; P < .001). Polysplenia patients with biventricular physiology demonstrated the best survival (100% alive, vs 53% ± 25% of asplenia biventricular at 30 years; P < .001). Overall, 8 patients (3.5%) underwent cardiac transplantation at a median age of 17 years. On multivariable analysis, risk factors associated with mortality included single ventricle physiology (odds ratio [OR] 7.2; 95% CI, 2.4-21.7), no prior Glenn (OR 3.6; 95% CI, 1.9-6.7), need for permanent pacemaker (OR 2.3; 95% CI, 1.2-4.6), and asplenia (OR 2.7; 95% CI, 1.5-5.0). CONCLUSIONS: Overall, patients with asplenia demonstrated decreased survival compared with patients with polysplenia; and single ventricle physiology had decreased survival compared with biventricular. Patients with biventricular physiology and polysplenia had the best survival.

Fontan Palliation in Patients with Heterotaxy Syndrome: A Five Decade Experience.

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.

Massive pulmonary embolism treated with low-dose thrombolysis on the geriatric ward during the COVID-19 pandemic.

A man in his 70s was admitted to hospital due to a fall, urinary tract infection and delirium. The patient had a 'do not attempt cardiopulmonary resuscitation' order in place and a ward-based ceiling of care was agreed. He tested positive for COVID-19 while on a geriatric ward and subsequently developed bilateral pulmonary emboli with haemodynamic instability. The patient had a significant bleeding risk; however, the expected morbidity and mortality risk from the pulmonary emboli was high. A decision was made to give the patient low-dose thrombolysis on the geriatric ward, following which he made a full recovery. Acute thrombolysis is normally performed in emergency department, high dependency unit (HDU) or intensive care unit (ICU) settings; however, this was not possible in this case due to the burden the COVID-19 pandemic had placed on HDU/ICU services and bed capacity. Adaptation of treatment guidelines allowed for emergency life-saving treatment to be delivered to this patient.

CELSR1 Risk Alleles in Familial Bicuspid Aortic Valve and Hypoplastic Left Heart Syndrome.

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.

Acute Kidney Injury and Renal Replacement Therapy After Fontan Operation.

Fontan circulation leads to chronic elevation of central venous pressure. We sought to identify the incidence, risk factors, and survival among patients who developed acute kidney injury (AKI) after the Fontan operation. We retrospectively reviewed 1,166 patients who had Fontan operation/revision at Mayo Clinic Rochester from 1973 to 2017 and identified patients who had AKI (defined by AKI Network criteria) within 7 days of surgery. A total of 132 patients (11%) developed AKI after the Fontan operation with no significant era effect. Of those who developed AKI, severe (grade 3) kidney injury was present in 101 patients (76.5%). Multivariable risk factors for AKI were asplenia (odds ratio [OR] 4.2, p <0.0001), elevated preoperative pulmonary artery pressure (per 1 mm Hg increase, OR 1.04, p = 0.0002), intraoperative arrhythmias (OR 1.9, p = 0.02), and elevated post-bypass Fontan pressure (per 1 mm Hg increase, OR 1.12, p = 0.0007). Renal replacement therapy (RRT) was used in 72 patients (54%), predominantly through peritoneal dialysis (n = 56, 78%). Multivariable risk factors for RRT were age ≤3 years (OR 9.7, p = 0.0004), female gender (OR 2.6, p = 0.02), and aortic cross-clamp time >60 minutes (OR 3.1, p = 0.01). Patients with AKI had more postoperative complications, including bleeding, stroke, pericardial tamponade, low cardiac output state and cardiac arrest, than those without AKI. This resulted in longer intensive care unit stay (39 vs 17 days, p = 0.0001). In-hospital mortality was exceedingly higher among patients with AKI versus no AKI (58%, 76 of 132 vs 10%, 99 of 1,034, p <0.0001); however, there was no significant difference based on the need for RRT. Recovery from AKI was observed in 56 patients (42%). Over 20-year follow-up, patients with AKI had a distinctly higher all-cause-mortality (82%) than those without AKI (35%). It is prudent to identity patients at a higher risk of developing postoperative AKI after Fontan operation to ensure renal protective strategies in the perioperative period. Postoperative AKI leads to substantial short and long-term morbidity and mortality, but the need for RRT does not affect the outcomes.

Systemic Semilunar Valve Repair/Replacement With Fontan Circulation: The Mayo Clinic Experience.

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.

Adaptations of paediatric cardiology practice during the COVID-19 pandemic.

During the initial surge of the COVID-19 pandemic in the spring and summer of 2020, paediatric heart centres were forced to rapidly alter the way patient care was provided to minimise interruption to patient care as well as exposure to the virus. In this survey-based descriptive study, we characterise changes that occurred within paediatric cardiology practices across the United States and described provider experience and attitudes towards these changes during the pandemic. Common changes that were implemented included decreased numbers of procedures, limiting visitors and shifting towards telemedicine encounters. The information obtained from this survey may be useful in guiding and standardising responses to future public health crises.

Chromogenic Factor X Assay for Monitoring Warfarin Anticoagulation in a Child With a Prosthetic Mitral Valve.

Mechanical mitral valve replacement in infants and young children is associated with substantial morbidity and mortality. Lifelong anticoagulation is required, with all the accompanying challenges of maintaining levels in infants and children whose dietary input continually changes. Even with careful control of all aspects that can perturb the coagulation cascade, these patients have a substantial lifelong risk of thrombotic and hemorrhagic complications that can also affect the durability of the valve. Anticoagulation is usually achieved utilizing warfarin with the degree of anticoagulation measured via the international normalized ratio (INR). Unfortunately, in some cases, the INR can be falsely elevated and lead to inappropriate reassurance. We describe a 4-year-old patient with complex congenital heart disease palliated via a single ventricular pathway with a mechanical atrioventricular valve replacement. The patient experienced acute valvular thrombosis while receiving warfarin with INR at target levels. Chromogenic factor X (CFX) levels were discordant with INR measurements, suggesting a subtherapeutic level of anticoagulation despite maintaining the standard INR target. Therefore, CFX levels were used to interpret INR measurements and guide an individualized approach to anticoagulation. We propose a new role of CFX: to verify and guide warfarin anticoagulation in high-risk pediatric patients including those undergoing mechanical mitral valve replacement.

Sex Differences in Children and Young Adults With Bicuspid Aortic Valve Disease in First Two Decades of Life.

OBJECTIVE: To elucidate sex differences in valve morphology, disease phenotype, progression, and outcomes among children and young adults with bicuspid aortic valve (BAV). PATIENTS AND METHODS: This is a retrospective cohort study examining all children and young adults (aged ≤22 years) with isolated BAV diagnosed, by excluding patients with concomitant congenital heart defects or genetic syndromes, from January 1, 1990, through December 1, 2016, at Mayo Clinic in Rochester, Minnesota. RESULTS: Of 1010 patients with BAV, 558 had isolated BAV. Distributions of morphology were right-left in 65.8% (n=367), right-noncoronary in 34% (n=190), and left-noncoronary cusp fusion in 0.2% (n=1) of patients; with no sex differences. Male to female ratio was 3:1. At the first echocardiographic evaluation in the study, there were no sex differences in terms of frequency of aortic valve stenosis or regurgitation. However, males had significantly higher grades of aortic valve regurgitation at 17 years of age onward (P<.0001). Males had significantly larger mid-ascending aorta (P=.01) and sinus of Valsalva dimensions (z score; P=.0001) as compared with females, with a novel finding of peak aortic dimensions around 8 years of age. Males also had more than 2-fold higher risk for sinus of Valsalva dilation (z score >2) as compared with females (odds ratio, 2.3; 95% CI, 1.2 to 4.2; P=.01). There were no significant sex differences in the primary cardiac outcomes of interventions on aortic valve and/or aorta, aortic dissection, or death. CONCLUSION: In children and young adults with BAV, males have a higher grade of aortic regurgitation in late adolescence, significantly larger aortic dimensions, different patterns of aortic growth, and more frequent sinus of Valsalva dilation as compared with females. Overall, the rate of primary cardiac events is lower in young patients, with no significant sex differences.

Role of a Pediatric Cardiologist in the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) has affected patients across all age groups, with a wide range of illness severity from asymptomatic carriers to severe multi-organ dysfunction and death. Although early reports have shown that younger age groups experience less severe disease than older adults, our understanding of this phenomenon is in continuous evolution. Recently, a severe multisystem inflammatory syndrome in children (MIS-C), with active or recent COVID-19 infection, has been increasingly reported. Children with MIS-C may demonstrate signs and symptoms of Kawasaki disease, but also have some distinct differences. These children have more frequent and severe gastrointestinal symptoms and are more likely to present with a shock-like presentation. Moreover, they often present with cardiovascular involvement including myocardial dysfunction, valvulitis, and coronary artery dilation or aneurysms. Here, we present a review of the literature and summary of our current understanding of cardiovascular involvement in children with COVID-19 or MIS-C and identifying the role of a pediatric cardiologist in caring for these patients.

Left Cardiac Sympathetic Denervation Monotherapy in Patients With Congenital Long QT Syndrome.

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.