Pediatric Cardiology

Outcomes of Dilated Cardiomyopathy in Japanese Children - A Retrospective Cohort Study. Mori H, Yoshikawa T, Kimura H, Ono H, Kato H, Ono Y, Nii M, Shindo T, Inuzuka R, Horigome H, Miura M, Ogawa S, Shiono J, Furutani Y, Ishido M, Nakanishi T. Circ J. 2021 Dec 24;86(1):109-115. doi: 10.1253/circj.CJ-20-1239. Epub 2021 Sep 28. PMID: 34588404    Take Home Points: Pediatric DCM continues to carry significant morbidity and mortality resulting in death or transplantation in about half of patients by 10 years from diagnosis. Of note, LV dysfunction was defined as a FS below 20% per the WHO criteria. Age at diagnosis is not a predictor of outcome in Japanese children, unlike prior reports from the US and Australia. The most significant risk factor for death or transplant is a FS <10% at diagnosis. Family history of DCM was not associated with outcome- that may be related to the specific genetic mutations found in Japan. This study includes patients starting in the early 90s, therefore not all patients were started on ACE inhibitors or beta blockers. The initiation of ACE inhibitors but not beta blockers seemed to be protective in this population Prospective multicenter studies are needed to further delineate the course of pediatric dilated cardiomyopathy in the current era. Commentary from Dr. Anna Tsirka (Connecticut, USA), Section editor of Pediatric & Fetal Cardiology Journal Watch. Introduction Idiopathic dilated cardiomyopathy (DCM) reportedly carries worse prognosis in children than in adults. The outcome may vary by country and health care systems. This represents a retrospective nationwide observational study of children with DCM in Japan between January 2010 and December 2014.   Methods 18 institutions across participated. Children younger than 18 years of age were included. Secondary cardiomyopathies (neuromuscular, metabolic disease or known myocarditis) were excluded. LV dilation was defined as LVIDd z score >2 (adjusted to BSA) by M Mode. Systolic dysfunction was defined as FS by M mode < 20%.   Results: 106 patients were included in the study. 42% were younger than 1 year of age. 9% had a first or second degree relative with DCM. 12% were asymptomatic at the time of presentation while 80% presented with symptoms of CHF, and 4% with arrhythmia or aborted sudden death.   Echocardiographic parameters at diagnosis are presented below:     Median follow up was 3.3 years. At last follow up alive, 98% were receiving medical treatment as shown below:     In patients During the period of the study, 15% of patients underwent heart transplantation and 29% died without transplantation.   Freedom from death or transplantation at 1,3,5,10 and 20 years from diagnosis was 76%, 66%, 61%, 54%, and 43%, respectively. Overall survival rates (with or without transplantation) were 81%, 75%, 72%, and 53%, respectively, as shown below:     On multivariate analysis, the only predictor of death or transplant was a FS at presentation < 10%. Age at diagnosis was not a risk factor. There was no significant difference in freedom from death or transplantation between patients treated with and those without β-blocker treatment as shown below:     

An International Multicenter Cohort Study on β-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia. Peltenburg PJ, Kallas D, Bos JM, Lieve KVV, Franciosi S, Roston TM, Denjoy I, Sorensen KB, Ohno S, Roses-Noguer F, Aiba T, Maltret A, LaPage MJ, Atallah J, Giudicessi JR, Clur SB, Blom NA, Tanck M, Extramiana F, Kato K, Barc J, Borggrefe M, Behr ER, Sarquella-Brugada G, Tfelt-Hansen J, Zorio E, Swan H, Kammeraad JAE, Krahn AD, Davis A, Sacher F, Schwartz PJ, Roberts JD, Skinner JR, van den Berg MP, Kannankeril PJ, Drago F, Robyns T, Haugaa K, Tavacova T, Semsarian C, Till J, Probst V, Brugada R, Shimizu W, Horie M, Leenhardt A, Ackerman MJ, Sanatani S, van der Werf C, Wilde AAM. Circulation. 2022 Feb;145(5):333-344. doi: 10.1161/CIRCULATIONAHA.121.056018. PMID: 34874747   Take Home Points: Children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk. β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol.Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT. Commentary from Dr. Manoj Gupta (New York City, NY, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch. These findings are supported by similar studies - JAMA Cardiol. 2022;7(5):504-512; selective β-blockers were associated with a higher risk of “Life threatening arrhythmia event [LTAE]” as compared with nadolol. Independently from treatment, LTAE and syncope before diagnosis and C-terminal domain variants identified patients at higher risk of β-blocker failure, and the ICD was associated with reduced mortality in high-risk patients with CPVT.   HRS PRACTICE GUIDELINES| VOLUME 14, ISSUE 1, E41-E44, JANUARY 01, 2017: There is strong consensus among the authors that nadolol is the preferred antiarrhythmic, antiadrenergic therapy for CPVT patients. Whereas the conventional dosage is that of 1 mg/kg per day, data that support the safety of the highest tolerated dosage indicate the potential to double the standard recommended regimen. Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm Volume 13, Issue 2, February 2016, Pages 433-440   2017 AHA Guidelines     Introduction: CPVT is a rare inherited cardiac arrhythmia syndrome in which bidirectional or polymorphic ventricular arrhythmias (VAs) induced by exercise or emotional stress can trigger syncope, sudden cardiac arrest (SCA), or sudden cardiac death. Results from several small studies have suggested that nadolol, a nonselective β-blocker, may be superior to other types of β-blocker, in particular, β1-selective β-blockers, in the treatment of patients with CPVT.2,7 However, this evidence is limited because of the small size of these cohorts. In addition, nadolol is currently unavailable in many countries. Therefore, there is a compelling need for a large-cohort study comparing the efficacy of the different types of β-blocker in patients with CPVT.1,13 Here, data from 2 large international multicenter CPVT patient registries were used to evaluate the association of nonselective versus β1-selective β-blockers and of specific β-blockers with arrhythmic event rates in a high risk CPVT population of symptomatic children. Results:   A total of 329 symptomatic children with CPVT were included. During a median follow-up duration of 6.7 years (IQR, 2.8–12.5), 99 patients (30.1%) experienced an arrhythmic event and 74 (22.5%) experienced a near-fatal arrhythmic event. Appropriate ICD shock was the most frequent arrhythmic event.     The risk for an arrhythmic event in patients treated with atenolol, bisoprolol, and metoprolol was higher than in patients treated with nadolol (Table 2) after multivariable adjustment.     DISCUSSION β-Blockers vary in elimination half-life, with a half-life of 20 to 24 hours for oral nadolol compared with 3 to 6 hours for propranolol, 9 to 12 hours for bisoprolol, 6 to 7 hours for atenolol, and 3 to 7 hours for metoprolol. Lipophilic β-blockers, such as metoprolol and propranolol, can pass the blood-brain barrier and might therefore be more likely to induce central nervous system–related side effects. This could potentially result in nonadherence and subsequently a higher risk for events. Hydrophilic β-blockers, such as atenolol and nadolol, in general, show a lower pharmacokinetic variability. Food enhances the bioavailability of metoprolol and propranolol, whereas it reduces the bioavailability of atenolol. Nadolol has a low pharmacokinetic variation, which may explain the apparent benefit of nadolol over the other types of β-blocker as is shown in these results. Propranolol affects both the peak and late sodium current, whereas nadolol solely blocks the peak sodium current and metoprolol has no effect on these currents.   Clinical Implications The authors believe that nadolol should be the preferred initial β-blocker for treatment of this population. Even though propranolol did not reach statistical significance over β1-selective β-blockers in terms of a lower risk for arrhythmic events, we would recommend remaining with a nonselective β-blocker, such as propranolol, in situations where nadolol is either unavailable or not tolerated. Furthermore, the rate of nonadherence and suboptimal dosages at the time of an event in this population is high. Clinicians should be aware of this to treat and counsel their patients appropriately.   

Genomic Autopsy of Sudden Deaths in Young Individuals. Webster G, Puckelwartz MJ, Pesce LL, Dellefave-Castillo LM, Vanoye CG, Potet F, Page P, Kearns SD, Pottinger T, White S, Arunkumar P, Olson R, Kofman A, Ibrahim N, Ing A, Brew C, Yap KL, Kadri S, George AL Jr, McNally EM. JAMA Cardiol. 2021 Nov 1;6(11):1247-1256. doi: 10.1001/jamacardio.2021.2789. PMID: 34379075   Take Home Points: Whole genome sequencing effectively identified P/LP variants in cases of sudden death in young individuals, implicating both arrhythmia and cardiomyopathy genes. Genomic analyses and familial phenotype association suggest potentially additive, oligogenic risk mechanisms for sudden death in this cohort. In multivariate analysis, rare variants in cardiac genes (pathogenic/likely pathogenic/uncertain significance) were associated with younger age at death, and with potentially additive effect. Commentary from Dr. Manoj Gupta (New York City, NY, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch. Introduction: Postmortem genetic testing discovers pathogenic or likely pathogenic (P/LP) variants in genes affecting heart rhythm and function among 10% to 25% of people who have sudden unexplained death (SUD) before age 40 years. Family screening for P/LP monogenic variants can identify and reduce risk in relatives. The authors considered a model associating rare variants in a small number of genes with phenotypes (an oligogenic approach).   Methods: A prospective study. Recruited from May 2015 to March 2019. Decedents aged between 1 and 45 years at death were included. Genomic Analysis: Whole-genome sequencing was completed and analyzed. We constructed a consensus arrhythmia and cardiomyopathy gene panel.   Results: In total, 103 individuals with sudden death were included for analysis. The mean (SD) age at death was 23.7 (11.9) years, and 33 individuals (32%) were 18 years or younger (Table 1). Most decedents were male (77 of 103 [75%]). Activity at time of death included sleep (42 [41%]), awake but at rest (27 [26%]), strenuous activity (15 [15%]), light activity (11 [11%]), and other or not documented (8 [8%]). A heart weight exceeding the 95% of normal for height, weight, age, and sex (cardiomegaly)30 was present in 21 of 103 decedents (20%). Cardiomegaly was present in 8 of 10 decedents with hypertrophic cardiomyopathy, 2 of 6 with dilated cardiomyopathy, and 2 of 10 with arrhythmogenic ventricular cardiomyopathy. Isolated cardiomegaly was present in 4 of 23 decedents (17%) with an FUS and in 1 with SUD (1 of 44 [2%]).     Abbreviations: FUS, findings of uncertain significance; NA, not applicable; SUD, sudden unexplained death. Hispanic and Asian decedents were clustered along the Euro-Asian line of the genetic principal component analysis   P/LP Genetic Variants: We assembled a cardiac panel of 118 genes implicated in inherited cardiomyopathy and arrhythmia conditions. Using this cardiac panel, we identified P/LP variants in 13 of 103 decedents (12.6%). A P/LP variant was present in 6 of 36 decedents (17%) with a postmortem clinical diagnosis, 2 of 23 (9%) with an FUS, and 5 of 44 (11%) classified as SUD. P/LP variants were distributed uniformly across the ages in this cohort.   VUS in Cardiac Genes For initial VUS analysis, we considered the 118 genes on the cardiac panel. We identified 292 variants from 80 of these genes. At least 1 P/LP/VUS variant was present in 93 of 103 individuals (90%), with a mean (SD) of 3.0 (1.7) variants per decedent. We identified 205 VUSs among 89 decedents (86%; mean [SD], 2.3 [1.4] VUS per decedent). Almost all variants were heterozygous (204 of 205 [99.5%]). There was 1 hemizygous variant in DMD. We identified 41 rare variants of interest in 30 preliminary evidence genes, present within 32 of 103 decedents (31.1%) (e-Table 2)   Transmitted P/LP Variants Associated with a Range of Clinical Findings We obtained DNA from 31 parent-decedent trios and 14 parent decedent dyads. From these data, 9 P/LP variants were captured; 8 were inherited and 1 was de novo.   Genotype-Phenotype Analysis Suggests Oligogenic Risks: P/LP genotypes did not fully predict phenotype; therefore, we assessed genetic features across all decedents that may promote risk of death, as manifested by an association between variant burden and age at death. For this analysis, we examined all P/LP/VUS variants in the 118 gene cardiac panel and the 41 rare variants of interest in 30 preliminary evidence genes. We found that having more variants was associated with a younger age at death. For decedents older than 2 years at death, a younger age was associated with a greater number of rare cardiac variants.   Multiple Genetic Variants May Contribute to Sudden Death Risk: We identified a quantitative association between risk of sudden death and a multiple-gene model of cardiac disease, in which each variant provides a small contribution to sudden cardiac death risk (an oligogenic approach). In current practice, P/LP variants are clinically actionable and VUSs are not. The demonstration of oligogenic effects does not elevate any individual VUS to a clinically actionable status. However, the refinement of oligogenic models may complement the efforts of ClinGen and others to adjudicate highly penetrant cardio-rhythm gene variants, leading to improved classification and improved clinical care.   Conclusions: Both genotype and phenotype analyses implicated additional, oligogenic risk factors in sudden death in young individuals.    

Association of Preoperative Diuretic Use With Early Acute Kidney Injury in Infants With Biventricular Hearts Following Cardiac Surgery. Rathgeber SL, Chakrabarti A, Kapravelou E, Hemphill N, Voss C, Mammen C, Skippen P, Harris KC.J Am Heart Assoc. 2021 Oct 19;10(20):e020519. doi: 10.1161/JAHA.120.020519. Epub 2021 Oct 8. PMID: 34622667   Take Home Points: Preoperative diuretic use does not increase the risk of Cardiac Surgery associated acute kidney injury (CS-AKI) in infants early after surgery. A diagnosis of tetralogy of Fallot was the only risk factor for CS-AKI identified using multivariate analysis in the author’s cohort. Furthermore, a diagnosis of tetralogy of Fallot and longer cardiopulmonary bypass time are risk factors for moderate to severe CS-AKI.   Commentary from Dr. Manoj Gupta (New York City, NY, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch.   Introduction Diagnosis of cardiac surgery associated acute kidney injury (CS-AKI) is recognized as a significant complication in both pediatric and adult populations that is associated with increased morbidity and mortality. Diuretic therapy is a mainstay in pre-operative medical management of congenital heart disease to control the symptoms of congestive heart failure.   Methods: AKI was defined as a rise in serum creatinine (SCr) >50% from preoperative baseline or < 0.5 ml/kg per hour of urine output for any 6-hour period postoperatively as defined by the Kidney Disease Improving Global Outcomes Guidelines (KDIGO) classification, which is recommended for use in pediatric populations. Urine output was measured over 6-hour intervals for the first 18 hours postoperatively in the cardiac intensive care unit while an indwelling catheter was in place. Patients who met the KDIGO criteria to have CS-AKI based on either the SCr or urine output criteria were further classified to have either mild (stage 1), moderate (stage 2), or severe (stage 3) AKI according to the KDIGO classification system. Preoperative diuretic use in this study refers to any patient taking the loop diuretic furosemide as this was the preferential mode for management of infants with CHF at our center. The dose range of furosemide was between 1 and 3 mg/ kg per day divided 1 to 3 times per day and was administered orally in all cases. Most patients were concurrently taking spironolactone 1 to 2 mg/kg per day divided 1 or 2 times daily.     Results: Table 1 showing patient Demographics and Preoperative, Intraoperative, and Postoperative Parameters for the Entire Cohort According to Exposure to Preoperative Diuretics     Preoperative Diuretic Use and Impact on CS-AKI The incidence of CS-AKI in infants within 24 hours after CS was 49.7% (149/300) with 122 (41%) patients meeting the SCr criteria, 17 (6%) patients meeting the oliguric criteria, and 10 patients satisfying both criteria, among the patients who developed CS-AKI, the severity was stage 1 in 53.7% (80/149), stage 2 in 38.2% (57/149), and stage 3 in 8.1% (12/149). Both older age and weight at the time of surgery were associated with an increased incidence of CS-AKI. Tetralogy of Fallot was the only diagnosis with a significantly increased risk of AKI among those operated on in our cohort (CS-AKI 43 [72%], no CS-AKI 17 [28%], P=0.0005). Exposure to diuretics preoperatively did not increase the risk of AKI post operatively early after cardiac surgery.   Risk Factors for Moderate to Severe CS-AKI A total of 69 patients were diagnosed with moderate to severe CS-AKI. Univariate analysis demonstrated that the diagnosis of moderate to severe CS-AKI relative to no AKI or stage 1 AKI is significantly associated with Aristotle Complexity Score, CPB time, cross-clamp time, heart block, cardiac arrest, postoperative extracorporeal life support, and mortality. Preoperative diuretic use was significantly associated with mild or no CS-AKI. Multiple logistic regression showed that a diagnosis of TOF and longer CPB time are associated with an increased risk of moderate to severe CS-AKI   DISCUSSION Operative factors such as surgical complexity, CPB time, cross-clamp time, and use of inotropes have been described to contribute to the risk of postoperative AKI along with an increased risk of developing chronic kidney disease (CKD). The incidence of AKI in this population of infants undergoing CS was found to be 49.7%. This represents a high proportion of AKI cases in this population. Results suggest that preoperative diuretics do not increase the risk of postoperative AKI early after CS in infants with no history of renal dysfunction. The authors assessed early AKI only within this first 24 hours after CS and the onset of AKI beyond the first postoperative day was not assessed.   CONCLUSIONS The authors have found that preoperative use of diuretics in infants with no history of renal dysfunction for management of CHF does not increase the risk of postoperative CS-AKI early after CS. The only independent variable that increases the risk of CS-AKI is a diagnosis of TOF. With respect to CS-AKI severity, a diagnosis of TOF and longer CPB time are both risk factors for moderate to severe CS-AKI.   

Accuracy of the Apple Watch iECG in Children With and Without Congenital Heart Disease. Kobel M, Kalden P, Michaelis A, Markel F, Mensch S, Weidenbach M, Riede FT, Löffelbein F, Bollmann A, Shamloo AS, Dähnert I, Gebauer RA, Paech C.Pediatr Cardiol. 2022 Jan;43(1):191-196. doi: 10.1007/s00246-021-02715-w. Epub 2021 Sep 1.PMID: 34468775   Take Home Points: Apple watch 4 iECG showed good quality as compared to lead I of a standard ECG in pediatric patients with and without congenital heart disease Automatic rhythm classification of the Apple watch software was poor Apple watch iECG may be a good product for detection of normal sinus rhythm, but a formal interpretation by a pediatric cardiologist would be necessary Adequacy for determination of an arrhythmia on the iECG is still unknown Commentary from Dr. Jared Hershenson (Greater Washington DC), section editor of Pediatric Cardiology Journal Watch: Over the past 5 years, use of smartwatches such as the Apple watch have exploded in popularity, and there have been increasing technologic advances of the software to allow for determination of abnormal heart rhythms. Currently, the iECG function of the Apple watch is FDA approved for detection of arrhythmias in adults > 22 years of age. Its utility and accuracy in the pediatric age population though is not yet known. This study compared the iECG of the Apple watch with a lead I rhythm strip of a standard 12-lead ECG in pediatric patients with and without congenital heart disease (CHD).   Methods: Patients aged 0-16 years presenting to a single cardiac center were eligible. An iECG and lead I rhythm strip were obtained within 10 minutes apart, and the cardiac rhythm, amplitudes and timing intervals were measured blindly by 2 pediatric cardiologists. The Apple watch was placed on the left wrist and a finger from the right hand placed on the knob. Parents or a nurse held the finger of the younger aged patients on to the knob to allow for recording.   Results: 215 patients, with a mean age of 8 +/- 4.33 years were enrolled, and an iECG was able to be obtained in all of them. 134 patients did not have CHD; the others had various diagnoses including shunt lesions (VSD/ASD), TGA, TOF, or single ventricles. Heart rate, P wave duration, QRS duration, QT interval, P wave amplitude, QRS amplitude, and T wave amplitude were compared and plotted via Bland-Altman analysis, showing a highly significant correlation of all values except for P wave duration and P wave amplitude which showed a weaker, yet still significant correlation. See Table 2. Multivariate analysis suggested that weight and BMI did affect the accuracy of the iECG. The majority of the rhythms were classified as sinus rhythm by the pediatric cardiologists (90%) while the automated Apple watch algorithm classified only 55% as sinus rhythm. Additionally, ~38% of iECGs were labeled as inconclusive by the algorithm, but when reviewed by the pediatric cardiologist, only ~5% of the tracings could not be assessed for rhythm, with those usually due to motion artifact/low quality. See Figure 3. There was no significant influence of the presence of CHD on heart rhythm classification.   Conclusions: Overall, there was good compatibility and quality of the iECG, but poor automated classification of the heart rhythm by the Apple watch. However, since sinus rhythm was the most common rhythm, and arrhythmias were limited in this sample, it remains to be seen whether the iECG will be accurate as a mobile event monitor in that scenario. As many practicing pediatric cardiologists know, it can be difficult to document and diagnose arrhythmias in young patients when they occur intermittently or last short durations. However, when possible, a pediatric cardiologist review of a tracing that shows sinus rhythm can potentially alleviate parental anxiety and possibly decrease unnecessary urgent care and ER visits.     

Progression in Fontan conduit stenosis and hemodynamic impact during childhood and adolescence. Patel ND, Friedman C, Herrington C, Wood JC, Cheng AL. J Thorac Cardiovasc Surg. 2021 Aug;162(2):372-380.e2. doi: 10.1016/j.jtcvs.2020.09.140. PMID: 33220959   Take Home Points: The minimum Fontan CSA/BSA was not associated with cardiac index or pulmonary artery size but did correlate with % predicted peak oxygen consumption. Smaller minimum CSA/BSA was associated with decreased exercise capacity. Commentary from Dr. Manoj Gupta (New York City, NY, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch.   Introduction While most children receive an 18- or 20-mm conduit, the optimal size is not known. The authors sought to characterize changes in Fontan conduit size over time in single-ventricle population and determine if a decrease in conduit CSA affects cardiac output, pulmonary artery growth, and exercise capacity.     RESULTS The authors observed a significant reduction in both minimum and average Fontan conduit CSA in the majority of patients. The median percentage decrease in minimum conduit CSA was 33% and in average conduit CSA was 24%.     Pulmonary Artery Size Nakata index was not associated with minimum Fontan conduit CSA/BSA (p = 0.09, P = .29) when combining the cardiac catherization and MRI data. Nakata index based on initial Fontan conduit size, the difference in median Nakata index did not differ (175.4 mm2 /m2 [153.3, 191.2] for 16 mm vs 185.0 mm2 /m2 [150.7, 212.3] for 18 mm, 149.3 mm2 /m2 [112.6, 176] for 20 mm, P = .10). Interestingly, the patients with the 18-mm conduit on average had a greater Nakata index than patients with both smaller and larger conduits.   Hemodynamic Measurements Cardiac index was not associated with minimum Fontan conduit CSA/BSA whether the cardiac MRI and cardiac catheterization data were considered together (p = – 0.003, P = .97) or separately. Pulmonary blood flow distribution measured by cardiac MRI, quantified as percentage of flow to the RPA, was not associated with minimum Fontan conduit CSA/BSA (p = 0.10, P = .44), average Fontan conduit CSA/BSA (p = 0.09, P = .50), or time from Fontan (p –0.11, P = .39).   Exercise Performance: The minimum Fontan CSA indexed to BSA at CPET had a weakly positive correlation with % predicted peak VO2 (r - 0.31, P = .013). By multiple regression analysis, % predicted peak VO2 was greater in patients with a larger Fontan conduit minimum CSA/BSA. Among patients with a 20-mm conduit, % predicted peak VO2 was lower when compared with those with a 16-mm conduit. % predicted VO2 was not influenced by time from Fontan, cardiac index, or sex. % predicted VO2 at anaerobic threshold was also greater in patients with a larger Fontan conduit minimum CSA/BSA.   DISCUSSION The authors observed a significant decrease in Fontan conduit CSA over a mean follow-up period of 10 years. By both cardiac MRI and cardiac catheterization, Fontan conduit size did not appear to affect cardiac index at rest or pulmonary artery growth; however, it did correlate with exercise capacity.   Lee and colleagues determined that a Fontan CSA of 12.5 mm/m2 (18- or 20-mm diameter conduit in an adult sized patient) was associated with the greatest exercise capacity, with both smaller and larger conduits being associated with lower exercise capacity.   CONCLUSIONS The authors observed a significant decrease in Fontan conduit CSA over a mean follow-up period of 10 years. These changes in CSA were observed as early as 6 months after surgery. Percentage CSA loss was also independent of initial conduit size. Conduit CSA indexed to BSA was not associated with cardiac index or pulmonary artery size but did correlate with exercise capacity.   

Pediatric athletes' ECG and diagnostic performance of contemporary ECG interpretation criteria Geza Halasz, Mattia Cattaneo, Massimo Piepoli, Silvio Romano, Vincenzo Biasini, Andrea Menafoglio, Alessio Gasperetti, Matteo Badini, Michele Villa, Lorenzo Dall'Ara, Marco Roberto, Tiziano Cassina, Bruno Capelli; International Journal of Cardiology 335 (2021) 40–46   Take Home Points: Electrocardiographic (ECG) pre-participation screening (PPS) can prevent sudden cardiac death (SCD) but the Interpretation of the athlete's ECG is based on specific criteria addressed for adult athletes while few data exist about the pediatric athlete's ECG. The incidence of sudden cardiac death (SCD) among adolescent soccer players was approximately 6.8 per 100,000 athletes Therefore, there is need for the development of specific and sensible diagnostic ECG criteria for PPS in pediatric athletes aged ≤16. Commentary from Dr. Manoj Gupta (New York City, NY, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch.   Study details A prospective study in 886 consecutive pediatric athletes aged≤16 years undergoing PPS. Furthermore, the authors tested the diagnostic accuracy of the 2010 European Society of Cardiology recommendation (2010-ESC), the 2013 Seattle-criteria-(2013-Seattle) and the 2017-International-ECG-recommendation (2017-International) in identifying pathologies at risk of SCD in this cohort of athletes.   According to the 2017-international the most common normal ECG pattern in pediatric athletes were isolated left ventricular hypertrophy criteria (LVH)(26.9%), juvenile T-wave pattern(22%) and ERP(13.2%). Among borderline abnormalities the most frequent were left axis deviation (1.8%) and right axis deviation (0.9%) while T wave inversion (TWI) (0.8%) especially located in inferior leads (0.7%) was the most prevalent abnormal ECG changes.   Table 1 showing the demographic and clinical characteristics   Results Seven athletes (0.79%) were diagnosed with a condition potentially related to SCD: three of them were diagnosed with Wolf-Parkinson-White syndrome (WPW), one with type-1 long-QT syndrome (LQTS-1), two with Ebstein's anomaly and one with Botallo's duct (PDA) and LV dilation. The two reported cases of Ebstein's anomaly were both asymptomatic with moderate tricuspid regurgitation one of them presented also frequent supraventricular arrhythmias on 24-h Ecg Holter. Among these athletes, nobody demonstrated abnormal findings on physical examination while six athletes (0.85%) showed an abnormal ECG according to both 2010-ESC and Seattle criteria whereas four (0.68%) according to the 2017-International (Table 2).     Thirty-three (4%) athletes presented echocardiographic findings not associated to SCD: four bicuspid aortic valve, three interatrial septum aneurysm, two mitral valve prolapses with mild regurgitation, two aortic valve mild regurgitation, one Patent Foramen Ovale, one muscular interventricular septum defect, two coronary sinus dilation, two pulmonary valve stenosis, one patent Botallo's duct without LV dilation. None of these athletes showed an abnormal ECG according to the 2017- international and 2013-Seattle while one male subjects with coronary sinus dilation showed a QTc > 440 msec considered abnormal according to ESC-2010.   Comparison of diagnostic performance of the three ECG interpretation criteria   The 2017-International led to a significant improvement in specificity (98%) compared with 64% and 95% for the 2010-ESC and 2013- Seattle, respectively. However, the last two criteria offered 86% sensitivity compared with 57% for the 2017-International criteria. All criteria failed to identify one patient with patent ductus arteriosus and mild LV dilation, while the 2017-International did not identify two patients with Ebstein's anomaly and complete RBBB. The false positive rate for pathologies at risk of SCD was 36% for the 2010-ESC, 5% for the 2013-Seattle criteria and 2% for the 2017-International (Table 3).     Applying the 2010-ESC the highest numbers of false positives were related to long QT criteria (10.6%), left axis deviation(1.8%) and right ventricular hypertrophy (RVH) criteria(1.1%) while using the Seattle-criteria which adjusted the long QTc cut-off value, the majority of false positives was related to Left and right axis deviation. The introduction of borderline findings in 2017-International has made that the number of false positives results were mainly related to inferior TWI(0.7%) and Complete Right Bundle Branch Block (CRBBB) (0.7%).   DiscussionECG abnormalities representing training-related ECG adaptation; the false positive rate was significantly reduced to 2.2% when using the 2017-International compared with 5.1% of the 2013-Seattle and 36% of the 2010-ESC respectively; the 2017-International showed the lower sensitivity failing to identify two athletes with Ebstein anomaly and CRBBB on ECG. This higher specificity was largely attributable to re-classification of left and right axis deviation, left and right atrial enlargement as normal ECG pattern not requiring further investigations when observed in isolation or in association with a recognized training-related ECG finding.   Conclusion and Implications for pre-participation screening The ECG can provide valuable information when interpreted properly, accounting for the electrical and structural changes that are common results of regular training. The European Society of Cardiology and the Association of European Pediatric Cardiology recommend initiation of ECG based screening to coincide with the onset of competitive athletic activity that is under 12 years for the majority of sports. We confirmed that the QTc-interval in pediatric athletes seems to be longer than in the general pediatric population [20]. Stratification of QTc interval showed that increasing the cut-off for long-QTc from>440 to ≥470 ms and from >460 to ≥480 ms in male and female respectively, as suggested by the 2013-Seattle criteria and the 2017-International, considerably reduce the prevalence of long-QT in the pediatric group from 10.2% to 0.7%, thus supporting the use of a higher cut-off in the pediatric athletes as suggested in adult athletes   As suggested by our study among the currently available recommendations for the ECG interpretation the Seattle criteria demonstrated the best balance between improvement in specificity and loss of sensitivity. In this context, the classification of isolated CRBBB as a normal finding in pediatric asymptomatic athletes could lead to not diagnose diseases at risk of SCD. Therefore, there is need for the development of specific and sensible diagnostic ECG criteria for PPS in pediatric athletes aged ≤16.   International criteria for electrocardiographic interpretation in athletes: Consensus statement http://dx.doi.org/10.1136/bjsports-2016-097331     The Seattle Criteria

Risk Factors for Severe Primary Graft Dysfunction in Infants Following Heart Transplant. Tajinder P. Singh, MD, MSc; Elizabeth L. Profita, MD; Peter Rycus, MPH; Ravi Thiagarajan, MD, MPH; Kimberlee Gauvreau, ScD; PMID: 34184543, PMCID: PMC8403271, DOI: 10.1161/JAHA.121.021082               Commentary from Dr. Manoj Gupta (New York City, NY, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch Take Home Points: Infant heart transplant (HT) recipients are at higher risk of developing severe primary graft dysfunction (PGD) than older children. Severe PGD was identified in 7.8% of infant HT recipients in the United States during 1996 to 2015 with no significant change in incidence over time. Possible risk factors based on this study are recipient congenital heart disease, ECMO, or biventricular assist device support at transplant, recipient blood type AB, donor‐recipient weight ratio <0.9, and graft ischemic time ≥4 hours. Left ventricular assist device support at HT was not associated with increased risk of severe primary graft dysfunction. Hearts from donors with donor: recipient weight ratio <0.9 and with expected ischemic time ≥4 hours should be avoided in candidates with high‐risk recipient profile. Although some recipient‐level risk factors are nonmodifiable, avoiding modifiable risk factors may mitigate further risk in infants at high risk of developing severe PGD. Introduction Based on a recent expert consensus statement endorsed by the International Society for Heart and Lung Transplantation, primary graft dysfunction (PGD) after heart transplant (HT) is defined as the development of left ventricular or biventricular systolic dysfunction within 24 hours of HT which is of primary cardiac origin and not secondary to causes such as acute rejection, pulmonary hypertension, or surgical complications. While HT recipients with milder forms of PGD may be managed with inotropes, those with severe PGD require mechanical circulatory support such as ventricular assist device or extracorporeal membrane oxygenation (ECMO).   Aim of the study: The aim for the current study was to describe risk factors for developing severe PGD in US infants aged <1 year at HT during 1996 to 2015. Using the subject‐level variables of HT center, date of birth, and date of HT in the OPTN data and the date of initiating ECMO in the ELSO registry, we identified infants initiated on ECMO for cardiac support within 2 calendar days following HT. Exclusion criteria included infants at risk of secondary graft dysfunction, ie, those with a positive cross‐match attributable to the potential risk of acute antibody‐mediated rejection and those with pulmonary vascular resistance >6 wood units attributable to a risk of posttransplant acute right heart failure.   Results Incidence of Severe PGD The overall incidence of severe PGD was 7.8% (95% CI, 6.6%‒9.2%). The incidence was 4% in infants with dilated cardiomyopathy, 10% in infants with CHD, 15% in those supported on ECMO or biventricular assist device (BIVAD) at HT, 2% in those supported on a left ventricular assist device (LVAD) and 21% in those supported on dialysis. A higher incidence of severe PGD was also noted in association with donor ischemic time ≥4 hours and with donor: recipient weight ratio <0.9 or >2.3 but not with donor left ventricular ejection fraction <0.45 or donor support using multiple inotropes.   The remaining 134 infants required veno‐arterial ECMO for cardiac support and thus met the criteria for severe PGD. Of these, 95 (71%) were initiated on ECMO support on the day of HT, 34 (25%) the following day, and 5 (4%) on the second posttransplant day. Their median age was 120 days, 52 (39%) were <90 days old, 42 (31%) were 91 to 180 days old and 40 (30%) were >180 days old. Cardiac diagnosis was CHD in 81% (46% with prior surgery, 35% unrepaired) and cardiomyopathy in 19%. A majority of patients with PGD (77%) were supported using a single ECMO run whereas 18% were supported using 2 ECMO runs. Median duration of ECMO support was 105 hours (interquartile range, 65−173 hours).   Independent Risk Factors for Severe PGD   Figure 2A illustrates the observed incidence of severe PGD with different combinations of recipient‐level risk factors if they received an HT using low‐risk donor criteria as defined by the multivariable model (donor: recipient weight ratio 0.9–2.3 and donor ischemic time <4 hours). The effect of a higher risk donor (either donor: recipient weight ratio <0.9 or ischemic time ≥4 hours) to corresponding recipient risk profiles is illustrated in Figure 2B, showing a disparate effect of higher risk donor on recipients with different risk profiles.   Posttransplant Survival Death (or graft loss) before hospital discharge occurred in 42.5% of infants with PGD (55 deaths, 2 retransplants) and 8.8% of infants without severe PGD (P<0.001). Discussion In this study, we identified severe PGD in 7.8% of infant HT recipients in the United States during 1996 to 2015 with no significant change in incidence over time when assessed in consecutive 5‐year periods. The finding that 3‐month survivors of severe PGD remained at increased risk of death or graft loss was surprising and not previously noted in the larger pediatric cohort. Infants are known to have worse first‐year survival after HT than older children but have the best conditional survival of all age‐groups if they survive the first posttransplant year.   Because LVAD support is being increasingly used to support infants awaiting HT, whether it is truly associated with lower incidence of severe PGD will be of high interest in future analyses of more recent recipients.   Conclusions Severe PGD was identified in 7.8% of infant HT recipients in the United States during 1996 to 2015. The risk of developing severe PGD was heterogeneous, however, with independent recipient‐ and donor‐level risk factors identified in this study. Identifying and avoiding modifiable risk factors may mitigate further risk in infants at high risk of developing severe PGD.    

Longitudinal Assessment of Right Ventricular Function in Hypoplastic Left Heart Syndrome. Balasubramanian S, Smith SN, Srinivasan P, Tacy TA, Hanley FL, Chen S, Wright GE, Peng LF, Punn R. Pediatr Cardiol. 2021 May 13. doi: 10.1007/s00246-021-02624-y. PMID: 33987707   Take home points: Right ventricular (RV) function in the long term affects prognosis in hypoplastic left heart syndrome patients. RV fractional area change (FAC) and Tricuspid annular systolic excursion (TAPSE) decreased after all surgical staged palliation procedure. Patients with RV FAC ≤ 35% and TAPSE Z-score ≤ -5 had a significantly lower transplant-free survival (p<0.0001). Commentary from Dr. Manoj Gupta (New York City, NY, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch: Introduction Failure of RV function remains a significant cause of mortality or transplantation in patients with hypoplastic left heart syndrome (HLHS). In addition to identifying patients who are susceptible to RV failure, understanding the mechanism and timing of decline may allow for closer surveillance and early optimization of medical therapy.   Results Of the echocardiographic indices, RV FAC showed significant decrease from post-Norwood to all subsequent stages (p < 0.001). In contrast, TAPSE Z-score showed a gradual decrement when pre-Norwood, pre-Glenn and pre-Fontan measures were compared (p < 0.0001).   Interestingly, FAC increased immediately post-Norwood while TAPSE Z-score decreased (Fig. 1). Neo-aortic valve VTI, global longitudinal strain, myocardial performance index and RV sphericity index did not show any trends over the course of the three surgeries.   Figure 1   Fig. 1 Box and Whisker plot comparing echocardiographic measures over the three stages of surgical palliation. Right ventricular FAC showed a statistically significant difference (n=43, p < 0.001). Post-hoc, pairwise comparison revealed differences between post-Norwood and other time points (p < 0.001) as well as between pre- and post-Glenn (p=0.01). TAPSE Z-score showed a statistically significant difference (n=47, p<0.001). Posthoc analysis pre-Norwood, pre-Glenn and pre-Fontan measures were compared (p < 0.0001) and when post-Norwood, post-Glenn and post-Fontan measures were compared (p < 0.0001).   Univariate analysis of serial echocardiographic markers showed post-Norwood RV FAC, TAPSE Z-score, global longitudinal strain, and dichotomized variables RV FAC≤35% and TAPSE Z-score≤-5 to be predictors of transplant-free survival. Using discrete variables, factors independently associated with death or transplant were presence of either RV FAC≤35% or TAPSE Z-score≤-5   RV end-diastolic dimension indexed to body surface area showed a statistically significant decrease following each of the surgeries with the greatest decrease noted following the Glenn operation.   Discussion This study showed a decrement in RV function longitudinally as measured by TAPSE and FAC for the whole cohort. In multivariable analysis, post-Norwood lower RV FAC and lower TAPSE Z-score independently predicted death or transplant. The presence of RV FAC≤35% or TAPSE Z-score≤-5 or a combination of the two were associated with a 2-3 fold higher likelihood of death or transplant. TAPSE is a measure of longitudinal shortening of the RV but there are only limited reports on the applicability of TAPSE to single ventricle patients.   Conclusions Patients undergoing staged palliation for HLHS continue to have significant disease burden. Detection of RV dysfunction measured by FAC≤35% or TAPSE Z-score≤-5 were found to be early predictors of poor outcome of death or transplant. Using these easily obtainable echocardiographic measures may allow early identification of the most vulnerable subset of HLHS patients and alter the intensity of their medical management and longitudinal care.   

Impact of Major Residual Lesions on Outcomes After Surgery for Congenital Heart Disease. Nathan M, Levine JC, Van Rompay MI, Lambert LM, Trachtenberg FL, Colan SD, Adachi I, Anderson BR, Bacha EA, Eckhauser A, Gaynor JW, Graham EM, Goot B, Jacobs JP, John R, Kaltman JR, Kanter KR, Mery CM, LuAnn Minich L, Ohye R, Overman D, Pizarro C, Raghuveer G, Schamberger MS, Schwartz SM, Narasimhan SL, Taylor MD, Wang K, Newburger JW; Pediatric Heart Network Investigators.J Am Coll Cardiol. 2021 May 18;77(19):2382-2394. doi: 10.1016/j.jacc.2021.03.304.PMID: 33985683   Take Home Points: Major residual lesions after CHD repair impact in-hospital outcomes for both mortality and length of stay> Future studies looking at greater granularity within the Residual Lesion Score (RLS) should be undertaken to help determine which lesions should be addressed prior to initial discharge Commentary from Dr. Jared Hershenson (Greater Washington DC), section editor of Pediatric and Fetal Cardiology Journal Watch: Of the many factors that affect outcomes after surgical repair of congenital heart defects, residual lesions would logically be significant for in-hospital morbidity, length of stay (ICU and total), as well as mortality. Past studies have looked at the Technical Performance Score TPS), but the generalizability is poor due to single center retrospectively collected data. This multicenter group met to refine the TPS using a modified RAND-Delphi technique and renamed it the Residual Lesion Score (RLS). This was prospectively collected data based on the discharge echo or need for unplanned reintervention during index hospitalization. They characterized each procedure by multiple subcomponents as measures of completeness of repair and then voted on whether this would be part of the RLS.   Infants age < 1 year with one of five common CHD of increasing complexity were studied, tetralogy of Fallot (TOF), complete AVSD, arterial switch (ASO) with/without VSD, coarctation/interrupted arch, and Norwood. No or trivial lesions were classified as RLS1, minor residual lesions RLS2, and major residual lesions or unplanned reinterventions RLS3. They also used RSL4 for patients with incomplete echocardiograms and RLS5 for those that did not have any pre-discharge echo. Primary outcome measures included number of days alive and out of hospital within 30 days of surgery (60 days for Norwood). Multiple secondary outcomes mostly related to morbidity were also assessed.   1149 patients were enrolled. Table 2 (central illustration) shows the numbers and percentages of patients with residual lesions. RLS3 was associated with worse primary outcomes for all types of surgeries (Figure 1A). There was no difference between RLS1 and RLS2. For secondary outcomes, RSL3 was associated with longer stay for all operations in bivariate and multivariate analysis. Notably, and likely obviously, when RLS3 was assigned for an unplanned reintervention (vs. discharge echo finding), outcomes were worse. This was most common in the Norwood group (usually shunt or arch intervention). For the other secondary outcomes, this varied by operation. RSL3 was significant for all outcomes after the Norwood. Other operations have a few significant findings for RSL3 and other lacking statistical significance. There was no consistent effect of RLS2 vs. RLS1 on any outcomes. When trying to determine the impact of RLS3 vs. other patient or pre-operative variables, the authors found a 20% R^2. In TOF, the R^2 was only 5%.   Overall, RLS1 and RLS2 had limited impact, but RLS3 significantly impacted morbidity and mortality even after controlling for other variables. However, the authors do note that no model explained more than 50% of the variance in outcomes, suggesting other as yet unidentified factors having an important impact. There are a few other important limitations to this study as identified by the authors and mentioned in an accompanying editorial. First, this analysis was only for children ages < 1 year. Also, since RLS was derived by pre-discharge echo, and not by earlier inpatient echo or post-operative TEE, how to intervene based on this data to prevent the poor outcomes in RLS3 is not clear. There may be multiple levels within RLS3 that may better predict the impact of inadequate repair on the outcomes, e.g. perhaps some lesions should be addressed and others left alone. Finally, there are some residual lesions that cannot be repaired or should not be repaired due to risk, and RLS does not discriminate whether an attempted repair did occur or when the care team decides lesions should not be repaired. This study was an important step in hopefully helping clinicians make decisions that can improve morbidity and mortality when residual lesions are present. Since the ultimate goal is to improve outcomes, further studies using the RLS should be done, with a goal of identifying and acting upon those truly modifiable lesions during the index hospitalization.      

Dobutamine stress cardiac MRI is safe and feasible in pediatric patients with anomalous aortic origin of a coronary artery (AAOCA). Doan TT, Molossi S, Sachdeva S, Wilkinson JC, Loar RW, Weigand JD, Schlingmann TR, Reaves-O'Neal DL, Pednekar AS, Masand P, Noel CV.Int J Cardiol. 2021 Apr 20:S0167-5273(21)00667-7. doi: 10.1016/j.ijcard.2021.04.031. Online ahead of print.PMID: 33892043 Take home points: Dobutamine stress cardiac MRI (DSCMR) is feasible and safe in pediatric patients with AAOCA, with very low risk of major or minor adverse events Inducible hypoperfusion was present in a small percentage of patients, along with wall motion abnormalities, suggesting that detection of myocardial ischemia with this modality may be helpful in the management of these patients Commentary from Dr. Jared Hershenson (Greater Washington DC), section editor of Pediatric Cardiology Journal Watch:  Testing to reliably risk stratify patients with AAOCA has not yet been fully elucidated. It is well known that exercise stress testing, stress echo and nuclear perfusion imaging have a low negative predictive valve in detecting myocardial ischemia. This is especially true in patients with anomalous origin of the right coronary artery (AAORCA). This single center study from Texas Children’s Hospital prospectively enrolled all patients < 20 years old with AAOCA. DSCMR and dobutamine administration was performed via the following protocol showed in Figure 1. First pass imaging was added to the protocol due to previous research studies showing reversible ischemia preceding wall motion abnormalities. Dobutamine increases heart rate and contractility, decreases systemic vascular resistance and increases coronary vasodilation which makes it a useful agent to increase oxygen consumption. Atropine was added to achieve the target HR of at least 150 bpm. They also targeted a calculated rate pressure product (RPP) of greater than 20x10^3 bpm*mmHg, which was considered an indirect estimate of high intermediate myocardial oxygen consumption. Inducible hypoperfusion predicts adverse outcomes in adults with ischemic heart disease, so this study was done to assess the feasibility and safety in the pediatric population and to help decision making with their cohort (eg. surgery vs. observation). 221 DSCMRs were completed on 182 patients. 14% had AAOLCA, 9% had intraseptal AAOLCA, and 77% had AAORCA.  Maximum dobutamine dose of 40 mcg/kg/min was given in 94% of studies, and atropine was given in 63%. Sedation was provided in 17% of patients primarily due to younger age. 86% achieved the target RPP. Heart rate did not affect first pass perfusion image quality and only HR > 85% age-predicted maximum reduced cine image quality, which was still adequate in all patients. Intraobserver agreement was very good. No major events (ventricular arrhythmia, MI, cardiac arrest) occurred, and 12.5% had minor events (severe HTN, chest pain, nausea/vomiting, paradoxical bradycardia, rash, anxiety, dizziness, or dyspnea) with none associated with sedation.   Inducible hypoperfusion was detected in 31/221, with 13/31 having wall motion abnormalities. See Table 2. Of the 161 first time DSCMR, 80% had AAORCA, 10% AAOLCA, and 10% intraseptal AAOLCA. Symptoms of exertional chest pain or exertional syncope were associated with inducible hypoperfusion. 13% of AAORCA, 18% AAOLCA, and 44% intraseptal had inducible hypoperfusion (total 27/161). 70% of those underwent successful surgical intervention, 15% were pending, and 15% were medically managed. Post-surgery, only 1 had inducible hypoperfusion on DSCMR that resolved on a follow up study and no patients with a negative DSCMR had any concerning symptoms or events during the time of the study. Figure 4 shows the distribution of regional inducible hypoperfusion seen in AAOLCA and AAORCA. While this study was mostly observational/feasibility, it is important to mention a few caveats. First, it was not clear which patients received surgery, although this may be published elsewhere. Many centers will operate on all patients with AAOLCA regardless of stress testing or MRI, so the utility of DSCMR in this subgroup may be less relevant. Additionally, there was no mention of any patients who had exertional symptoms but a negative DSCMR.  There was no discussion on whether any assessment of the RV could be done on MRI, a known limitation of all stress imaging tests, including MRI, and potentially more important in AAORCA. The authors discuss the lack of an evidence-based target hemodynamic response in the assessment of FPP, so it could be possible that this is not providing the same hemodynamics as exercise or in the pathophysiology of sudden cardiac death. All pediatric and sports cardiologist hope that we can find better testing to risk assess this challenging population, specifically those with AAORCA, where many are diagnosed incidentally and are asymptomatic. This study was not designed to assess negative predictive value so longer term studies will be necessary. Overall though, it is very helpful to know that this test can be done with good quality, and with more centers adding this to the arsenal of testing, hopefully we will have more meaningful data in the future.  

Left atrial strain and function in pediatric hypertrophic cardiomyopathy. Jhaveri S, Komarlu R, Worley S, Shahbah D, Gurumoorthi M, Zahka K.J Am Soc Echocardiogr. 2021 Apr 26:S0894-7317(21)00431-4. doi: 10.1016/j.echo.2021.04.014. PMID: 33915246 Take home points: Left atrial (LA) strain and dysfunction are markers of diastolic dysfunction, associated with poor exercise capacity in hypertrophic cardiomyopathy patients. Children with phenotype positive hypertrophic cardiomyopathy have reduced LA function, measurable by both volumetric and strain analysis. LA conduit function, LA reservoir function and LA reservoir strain were lower in Phenotype positive hypertrophic cardiomyopathy than in Genotype positive and phenotype negative patients. Children with phenotypic HCM have lower left atrial strain values. Altered LA mechanics are associated with poor exercise capacity. Lower LA conduit function is associated with worsened aerobic capacity in pediatric HCM.         Commentary from Dr. Manoj Gupta (New York, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch Introduction Literature on the assessment of diastolic dysfunction in pediatric HCM has focused primarily on the use of tissue Doppler indices, left atrial (LA) size, and inflow patterns. Research in adult HCM has shown that LAS values are independently associated with adverse outcomes, including heart failure, worsened exercise capacity, arrhythmias, stroke, and death. Left atrial Parameters Volumetric analysis of the left atrium was performed from apical four-chamber and two chamber views and was indexed to body surface area. LA volume (LAV) was collected at three points in the cardiac cycle as follows: (1) maximum LAV just before mitral valve opens (LAV max), (2) minimal LAV at the end of diastole when the mitral valve closes (LAV min), and (3) LAV just before atrial systole, before the p wave on electrocardiography (LAV pre-A). Reservoir function = LAV max - LAV min/ LAV min Conduit function = LAV max - LAV pre-A/LAV max Booster pump function = LAV pre-A - LAV min/LAV pre-A RESULTS The HCM cohort consisted of 78 subjects with a median age of 16 years (range, 3–25 years), of whom 60 (64%) were male). Phenotypic criteria for HCM were present in 59% patients (P+ group, n = 46) whereas the remaining carried the genotype but lacked phenotypic characteristics (G+P- group, n = 32). (Table 1) Diastolic Parameters The maximal LA volume index (LAVI) was higher in patients with P+ HCM compared with the G+P- and control groups (median, 28 vs 20 vs 19 mL/m2 , respectively; P < .001). Nearly one third of the P+ group (32% [n = 14]) had LAVI > 34 mL/m2 , which is the adult cutoff for LA dilation. Higher LAVI was associated with higher NTproBNP (r = 0.43; 95% CI, 0.05–0.71; P = .029). DISCUSSION Left atrial strain and volumetric function parameters were significantly lower in patients with phenotypic (P+) HCM compared with those with a positive genotype but without significant hypertrophy (G+P-). On the basis of these results and known literature, it can be concluded that children with HCM have impaired reservoir and conduit function, similar to their adult counterparts. However, given that they have preserved contractile pump function in childhood years, it can be speculated that changes in their atrial contractile function probably take place as they age. CONCLUSION Altered atrial mechanics, as measured by volumetric and strain analysis, are present even in the pediatric population with phenotypic HCM.

Delivery room oxygen physiology and respiratory interventions for newborns with cyanotic congenital heart disease. Thomas AR, Ma AL, Weinberg DD, Huber M, Ades A, Rychik J, Foglia EE. J Perinatol. 2021 Mar 23. doi: 10.1038/s41372-021-01029-2. PMID: 33758390     Take-Home Points: In a single-center retrospective study of neonates born with cyanotic congenital heart disease, a comparison was made of the trends of oxygen saturations for the first ten minutes after birth between three physiologies – single ventricle physiology with critical aortic obstruction, single or double ventricle physiology with pulmonary outflow obstruction, and those with transposition of great arteries physiology (TGA) Infants with TGA physiology had lower pulse oximetry levels at all recorded time points (up to 10 min) when compared to those with ductal dependent systemic and pulmonary circulation. Infants with TGA physiology received supplemental oxygen therapy and respiratory interventions more frequently than the other groups. Majority of the infants had stable cardiovascular status with initially recorded heart rates of more than 100 beats per minute.     Commentary from Dr. Venu Amula (Salt Lake City, UT, USA), section editor of Pediatric & Fetal Cardiology Journal Watch:  Newborns with cyanotic congenital heart disease differ from normal neonates concerning oxygen saturations(SpO2). Their transition from fetal to neonatal physiology at birth is also different, and reference oxygen saturation trajectories and respiratory interventions needed have not been well established. In this study by AR Thomas et al., the authors characterize and trend SpO2 values at birth in neonates with cyanotic congenital heart disease. They also report the frequency and intensity of delivery room respiratory interventions in neonates during the birth transition. This single-center, retrospective study of all infants born at > or = 32 weeks GA with a prenatal diagnosis of cyanotic congenital heart disease at a quaternary pediatric care center with a Level IV neonatal care nursery. Based on fetal echocardiogram – the infants were grouped into three categories – those with single ventricle physiology with critical aortic obstruction (SV-CAO )leading to ductal dependent systemic circulation, those with critical pulmonary outflow obstruction ( CPO) with either single ventricle or two ventricles but ductal dependent pulmonary flow and the third group with transposition physiology (TGA) where the systemic and pulmonary circulations are in parallel. At birth for all infants, the standardized institution neonatal resuscitation guidelines were followed with anticipated goal saturations of 75-85% for neonates given their cyanotic heart lesion. The saturations were measured on the right hand to obtain preductal measurements. Interventions were indicated to maintain saturations in the goal range and provide supplemental oxygen therapy, continuous positive airway pressure, positive pressure ventilation, and endotracheal intubation. Delivery room interventions and minute-to-minute SpO2 values were compared across and between three diagnostic groups using standard statistical tests. Of 208 infants ≥32 weeks gestation with eligible prenatally diagnosed cardiac lesions born during the study period, 196 infants were included in the analyses of oxygen saturation and respiratory intervention data. The TGA group had lower pulse SpO2 values at each time point. Comparing each group separately to TGA showed significant differences in SpO2 values at each minute (all p < 0.01 for CPO v TGA and all p < 0.02 for SV-CAO v TGA). No significant differences were found in pairwise comparison of the SV-CAO group to CPO group (p > 0.05) in SpO2 values at each minute after birth. Infants with TGA physiology received supplemental oxygen and non-invasive respiratory interventions more frequently than the infants in the SV-CAO and the CPO groups (Table 3). Significantly more infants with TGA physiology underwent endotracheal intubation in the resuscitation suite (53%) and occurred at a median of 24 (IQR 18–35) minutes after birth.         This study attempts to analyze the trends of target oxygen saturation in children with cyanotic congenital heart disease immediately after birth. These infants represent a heterogeneous group of neonates, and even within the same physiology group, the spectrum of disease dictates the target oxygen saturation achieved. The interventions were performed to achieve the goal target oxygen saturations of 75-85% - and represent the current practice in most institutions, although the optimal saturations are not well known. The goal is to accept some degree of hypoxia to maintain adequate systemic perfusion. Though the study represents a single-center practice, this information is valuable to guide physicians in providing resuscitation to babies with known cyanotic heart disease. Smoothed conditional curves of the 25th, 50th, and 75th percentiles for pre-ductal SpO2 values for minutes 3–10 after birth were plotted for each diagnostic group and for comparison, the 25th, 50th, and 75th percentile values for SpO2 at each minute reported for infants without CCHD by Dawson et al.(1)             Dawson JA, Kamlin COF, Vento M, Wong C, Cole TJ, Donath SM, et al. Defining the reference range for oxygen saturation for infants after birth. Pediatrics. 2010;125:e1340–7.

Goldstein BH, Petit CJ, Qureshi AM, McCracken CE, Kelleman MS, Nicholson GT, Law MA, Meadows JJ, Zampi JD, Shahanavaz S, Mascio CE, Chai PJ, Romano JC, Batlivala SP, Maskatia SA, Asztalos IB, Kamsheh AM, Healan SJ, Smith JD, Ligon RA, Pettus JA, Juma S, Raulston JEB, Hock KM, Pajk AL, Eilers LF, Khan HQ, Merritt TC, Canter M, Juergensen S, Rinderknecht FA, Bauser-Heaton H, Glatz AC. J Am Coll Cardiol. 2021 Mar 2;77(8):1093-1106. doi: 10.1016/j.jacc.2020.12.048. PMID: 33632484 Take-Home Points: In children with symptomatic Tetralogy of Fallot, needing neonatal intervention, a comparison made between those managed with staged repair (SR) vs. primary repair (PR) showed balanced results. Upon adjusting for patient factors, early mortality risk was higher in the PR group; however, the overall risk of death did not differ between treatment groups. Lesser neonatal morbidity was reported in the SR group. In contrast, the overall cumulative morbidity burden (combining the initial palliation and complete repair in the SR group) favored the primary repair group. Reintervention risk was higher in the SR group, but late reintervention risk (>3 months) and reintervention burden following definitive repair did not differ between groups. Both strategies have potential benefits, and hence an individualized case-based approach is warranted based on patient, procedural and institutional factors. Commentary from Dr. Venu Amula (Salt Lake City, UT, USA), section editor of Pediatric & Fetal Cardiology Journal Watch:  Tetralogy of Fallot (TOF) is a congenital heart disease with a spectrum of cyanosis based on the degree of right ventricular outflow tract obstruction. Neonates can be symptomatic early, with cyanosis needing an intervention. Early intervention in symptomatic neonates can be palliative – both surgical and transcatheter procedures to provide additional pulmonary blood flow, or some may consider primary repair of the intracardiac defect. In this study by Goldstein et al., the investigators seek to compare the two treatment strategies of staged repair (SP) ( initial palliation [IP] followed by complete repair [CP])  and Primary repair (PR). The authors performed a retrospective cohort study using a multicenter collaborative with good sample size and practice variability to compare outcomes adjusted for patient-level differences and reduce confounding by indication. Study subjects included all neonates with tetralogy of Fallot who underwent an initial intervention  < or = 30 days at the nine centers of the Congenital Cardiac Research Collaborative. The indication of intervention was cyanosis, ductal dependent pulmonary blood flow, or hyper cyanotic episodes. Cases with discontinuous pulmonary arteries, TOF associated with Atrioventricular canal, Absent Pulmonary Valve, and Major Aortopulmonary Collaterals were excluded. The index procedure ( Initial Palliation or Primary Repair ) was the exposure, with the primary outcome being death or heart transplantation. Secondary outcomes included in-hospital mortality, procedural and hospital complications, reinterventions, and other measures of morbidity. The five variables most likely associated with treatment strategy ( SR vs. PR) – center, preintervention mechanical ventilation, prematurity, DiGeorge syndrome, and presence of antegrade blood flow were used in a logistic regression model to estimate propensity scores. Inverse probability of treatment weighting using propensity scores was used to adjust for potential confounders between groups. The effect of treatment strategy on dichotomous outcomes was evaluated by logistic regression weighted by propensity score. Time-dependent outcomes were analyzed with survival analysis. The overall study cohort consisted of 572 patients, 230 treated with primary repair and 345 with initial palliation.     Adjusted comparison of the primary outcome of death ( none got transplanted in this cohort)  showed no difference in the overall hazard of death (HR: 0.82; 95% CI: 0.49 to 1.38; p = 0.459), although early mortality hazard (<4 months post-intervention) was lower in the SR group (HR: 0.5; 95% CI: 0.25 to 0.97; p =0.041). Propensity score-adjusted differences in continuous secondary outcomes of neonatal morbidities, including procedural complications, duration of mechanical ventilation and inotrope use, procedural support times (CPB, cross-clamp, anesthesia), and ICU LOS, remained lower in the SR group at the index procedure. As was the case in the observed data, the adjusted cumulative burden of the SR strategy was associated with greater exposure to procedural, ICU, and post-procedural secondary outcomes than in the PR group. Adjusted differences in the outcomes of in-hospital mortality and complications showed that the risk of in-hospital mortality was lower in the SR group at the index procedure (OR: 0.37; 95% CI: 0.15 to 0.88; p = 0.025) and again at definitive repair (OR: 0.25; 95% CI: 0.09 to 0.69; p = 0.008), but when the entirety of the SR strategy was compared with PR, there was no difference in the risk of in-hospital mortality between groups (OR: 0.57; 95% CI: 0.26 to 1.24; p = 0.16). Similarly, although components of the SR pathway demonstrated lower rates of complications, there were no differences in the rate of procedural complications (OR: 0.84;95%CI:0.6to1.19; p = 0.33) or hospital complications (OR: 1.13; 95% CI: 0.79 to 1.61; p =0.51) between the treatment groups when the cumulative therapeutic pathways were compared.   The authors tried to address the vital issue of comparing staged repair vs. primary repair in the setting of symptomatic neonates with tetralogy of Fallot. While a well-designed  Randomized Controlled Trial would make the treatment groups well balanced to make an unbiased comparison of two treatment strategies – the large sample size from a research collaborative gave the authors unique opportunity to apply statistical methodology to adjust patient differences and provide a meaningful comparison of outcomes.  Given that early mortality, neonatal morbidity, and procedural complications were lower in the SR group, whereas cumulative morbidity and reinterventions favored the PR group, the authors conclude that an individualized, case-based approach to the initial interventional strategy is warranted.

Increases in oxygen saturation following discharge from Fontan palliation - an indicator of resolution of pulmonary arteriovenous malformations? Van Galder H, Schaal AM, Feng M, Pan AY, Frommelt MA, Ginde S, Spearman AD. Cardiol Young. 2021 Mar 11:1-7. doi: 10.1017/S1047951121000913. PMID: 33691814   Take Home Points:   Pulmonary arteriovenous malformations in single ventricle congenital heart disease are poorly understood. Pulmonary arteriovenous malformations are variably diagnosed prior to Fontan palliation; however, all study groups had increased oxygen saturations after Fontan discharge, potentially indicating resolution of pulmonary arteriovenous malformations in all groups. The prevalence of pulmonary arteriovenous malformations pre-Fontan is likely underestimated.   Commentary from Dr. Manoj Gupta (New York, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch   Introduction: In single ventricle patients, intrapulmonary shunting through pulmonary arteriovenous malformations may develop, worsen, or regress after Fontan palliation and can variably impact oxygen saturation. The prevalence of pulmonary arteriovenous malformations in single ventricle CHD is variably reported – ranging from 15 to 100% depending on the specific cohort, diagnostic criteria, and follow-up duration.   The primary objective of this study was to determine whether pulmonary arteriovenous malformations are diagnosed more frequently before Fontan palliation in patients with heterotaxy syndrome compared to matched non-heterotaxy patients. Secondarily the authors sought to compare oxygen saturation changes after Fontan discharge as a clinical marker of resolution of pulmonary arteriovenous malformations.   Diagnosis of pulmonary arteriovenous malformations pre-Fontan was obtained by contrast echocardiogram using agitated saline (“bubble study”) or during cardiac catheterization. Severity of shunting was classified as negative (no bubbles entering the single ventricle), mild (occasional or few bubbles filling of the single ventricle), moderate (moderate filling of the single ventricle), or severe (complete opacification of the single ventricle)   Results   A total of 124 patients with single ventricle CHD and previous Fontan palliation were included in this study with 62 heterotaxy patients and 62 non-heterotaxy hypoplastic left heart syndrome controls. Of the 62 heterotaxy patients, 14 (22.6%) had an interrupted inferior cava vein.   Patients with heterotaxy and interrupted inferior cava vein were more likely to have a documented diagnosis of pulmonary arteriovenous malformations in their medical record prior to Fontan palliation (85.7%) compared to patients with heterotaxy and intact inferior caval vein (20.8%) and non-heterotaxy control (24.2%) (p < 0.01).  Using a linear mixed model, there was no difference in Pre-Fontan oxygen saturations among the three groups (heterotaxy: intact inferior caval vein 82.0 (78.0, 85.0)%, interrupted inferior caval vein 80.5 (77.0, 85.0)%; non-heterotaxy control 82.0 (79.0, 85.0)%   At Fontan discharge, the non-heterotaxy control group (90.0 (86.0, 94.0)%) increased their oxygen saturations more than both heterotaxy sub-groups (intact inferior caval vein 87.0 (83.0, 92.0)%, p < 0.01; interrupted inferior caval vein 84.0 (82.0, 86.0)%, p < 0.01), but there was no difference in oxygen saturation between the two heterotaxy sub-groups (p = 0.18).   At 3, 6, and 12 months post-Fontan, there was no difference in oxygen saturation among the three groups at each time point.   Discussion   In this study, patients with heterotaxy syndrome and non-heterotaxy hypoplastic left heart syndrome had variable diagnostic rates of pulmonary arteriovenous malformations pre-Fontan, yet all study groups had increases in oxygen saturation after Fontan discharge. This data indicate that pulmonary arteriovenous malformations are present prior to Fontan palliation and resolve after Fontan palliation for patients with and without heterotaxy syndrome. The specific patient factors that increase susceptibility to pulmonary arteriovenous malformations remain unknown. Despite a lack of consensus on the prevalence and optimal diagnostic criteria for pulmonary arteriovenous malformations, studies have repeatedly used increased oxygen saturations after Fontan discharge as a surrogate for resolution of pulmonary arteriovenous malformations.   In conclusion, our data indicate that pulmonary arteriovenous malformations are variably diagnosed prior to Fontan palliation. It remains unclear, though, if there are true differences in susceptibility to pulmonary arteriovenous malformations because patients with and without heterotaxy syndrome have increases in oxygen saturations throughout the first year after Fontan discharge. A quantitative, systematic approach to diagnosis and follow-up pulmonary arteriovenous malformations is needed to better understand pulmonary microvascular remodeling in single ventricle CHD.

Higher efficacy of infliximab than immunoglobulin on Kawasaki disease, a meta-analysis. Li X, Tang Y, Ding Y, Chen Y, Hou M, Sun L, Qian G, Qin L, Lv H. Eur J Pharmacol. 2021 Feb 27;899:173985. doi: 10.1016/j.ejphar.2021.173985. Online ahead of print. PMID: 33652059   Take Home Points: Infliximab was more effective than the control group, with the total summary odds ratio (OR) of 0.34 (95% confidence interval (CI): 0.19–0.62). The treatment resistance of the infliximab group was lower than the IVIG group (0.36 [95% CI: 0.14–0.92]) when infliximab was combined with IVIG as the initial treatment. Infliximab treatment for IVIG resistant KD was more effective than the IVIG group (0.28 [95% CI: 0.12–0.66]). Infliximab improved clinical course in IVIG resistant KD patients. Infliximab treatment did not reduce the incidence of coronary artery lesions and did not show any significant increase in the incidence of adverse events. Commentary from Dr. Manoj Gupta (New York, USA), section editor of Pediatric & Fetal Cardiology Journal Watch:   Introduction Kawasaki disease (KD) is a systemic immune vasculitis disease affecting the small and medium arteries. Coronary artery lesions (CALs) are one of the most severe complications in KD patients. A high dose of intravenous immunoglobulin (IVIG) is the mainstream treatment of KD. However, about 10–20% of KD patients show resistance to IVIG treatment. A good number of studies in recent days have shown that infliximab could be an effective treatment for IVIG-resistant KD. This is a meta-analysis for the comprehensive evaluation of infliximab’s efficacy and safety as initial therapy for patients with KD and IVIG resistant KD by including both prospective and high-quality retrospective studies. Eight studies were included in this meta-analysis study. These studies covered 713 patients, with 327 cases in the infliximab treated group and 386 in the control group.     Effective of infliximab on KD The total summary OR was 0.34 (95% CI: 0.19 to 0.62) with low heterogeneity (I2 = 30.1%), which showed that infliximab was more effective than the control group. The summary OR of infliximab treatment of IVIG resistant group was 0.28 (95% CI: 0.12 to 0.66), with low heterogeneity (I2 = 0). The results revealed that infliximab treatment was as effective as the initial treatment of KD as well as for IVIG resistant KD.   Coronary artery lesions (CAL) Six studies reported the CALs complication. The summary OR of infliximab treatment on the IVIG resistant group was 0.88 (95% CI: 0.48 to 1.62), with low heterogeneity (I2 = 0). The summary OR was 0.64 (95% CI: 0.23 to 1.74) for infliximab as initial treatment group, with low heterogeneity (I2 = 0), the summary OR of infliximab as treatment of IVIG resistant group was 1.06 (95% CI: 0.49 to 2.28), with low heterogeneity (I2 = 7.9)   Adverse events (AEs) Six studies reported the AEs. Analysis revealed that the incidence of AEs between both groups was not significant. The summary OR was 0.71 (95% CI: 0.44 to 1.16), with low heterogeneity (I2 = 45.3%   Infusion reaction Infusion reaction was regarded as fever with or without chill requiring transient interruption of infusion. The results showed that the infusion reaction incidence in the infliximab group was significantly lower compared to the IVIG group. The summary OR was 0.11 (95% CI: 0.03 to 0.43), with low heterogeneity (I2 = 0).   Other adverse events Patients treated with infliximab had a prevalence of transient hepatomegaly of 19% (6/31) versus 1.5% (1/68) in patients who never received infliximab, with an odds ratio of 16.1 (95% CI, 1.8 to 140.3; P = 0 0.004).   A: Comparison of treatment effectiveness between the infliximab group and control group   B: Comparing the treatment effectiveness of infliximab between prospective and retrospective studies, in the retreatment group.     Discussion The meta-analysis demonstrated that infliximab, a TNF-α blocker is useful either as a first-line treatment in KD or as a treatment for IVIG resistant KD. This analysis has shown that infliximab is potently effective in reducing fever; however, it failed to reduce CALs. Infliximab might also increase the risk of TB and hepatitis when infection occurred. Nevertheless, physicians need to confirm the absence of TB lesions before the use of infliximab. It is highly recommended that pediatricians consider early use of infliximab in cases with refractory KD due to its safety and efficacy.   Conclusion When infliximab combined with IVIG had been used in the primal treatment of patients with KD, it could reduce the rate of resistance compared with conventional IVIG therapy. However, there was no advantage of reducing the incidence of the coronary artery lesions. Infliximab can improve treatment efficiency in treating children resistant to IVIG. There was no increase in adverse events in the treatment of infliximab. Infliximab might reduce the infusion reaction of IVIG. When patients with IVIG contraindicated or exhibited IVIG resistance, infliximab might be useful.   

The mid-term outcome of Fontan conversion compared with primary total cavopulmonary connection. Kato A, Sato J, Yoshii K, Yoshida S, Nishikawa H, Ohashi N, Sakurai T, Sakurai H, Hata T, Yoshikawa T. J Cardiol. 2021 Feb 26:S0914-5087(21)00042-3. doi: 10.1016/j.jjcc.2021.02.005. PMID: 33648806   Take Home Points: The indication of Fontan conversion (FC) from atriopulmonary connection (APC) to total cavopulmonary connection (TCPC) is unclear. Fontan conversion is a safe and feasible procedure to bring APC patients back onto the same track of primary TCPC patients in terms of hemodynamics as well as arrhythmia. The antiarrhythmic procedure should be carefully chosen because sinus node dysfunction can frequently occur and FC itself would reduce the risk of arrhythmia.     Commentary from Dr. Manoj Gupta (New York, USA), section editor of Pediatric & Fetal Cardiology Journal Watch:   Introduction The Fontan procedure, which is the treatment of choice for patients with functionally univentricular hearts, has been modified by the Bjork, lateral tunnel, and extracardiac total cavopulmonary connection (TCPC) procedures since the introduction of its initial version—the atriopulmonary connection (APC)—by Fontan et al. in the 1970s.   Fontan conversion, which entails connecting the inferior vena cava to the pulmonary artery using an artificial conduit, combined with arrhythmia surgery has been introduced. Possible benefits of prophylactic Fontan conversion in asymptomatic APC patients are improving cardiac output as well as preventing new onset of atrial tachyarrhythmia. On the other hand, the long-term hemodynamic outcome of patients after Fontan conversion compared with that of patients after primary TCPC is unknown. In this study, the sought to compare the midterm outcomes after prophylactic and therapeutic Fontan conversion with those after primary TCPC.   A total of 54 consecutive patients undergoing either Fontan conversion (n = 30) or primary TCPC (n = 24), followed by cardiac catheterization for postoperative hemodynamic evaluation at over 18 years of age between July 2005 and April 2019, were included in the study The included 52 patients were divided into three groups: p-FC, consisting of 15 asymptomatic APC patients who underwent prophylactic Fontan conversion; t-FC, consisting of 13 symptomatic APC patients who received therapeutic Fontan conversion [including arrhythmia (n = 11), heart failure (n = 1), and protein-losing enteropathy (n = 1)]; and p-TCPC, consisting of 24 patients who underwent primary TCPC.   Tricuspid atresia turned out to be the most frequent diagnosis in patients receiving Fontan conversion procedure and the majority of patients in the t-FC (69%) and p-FC (93%) groups were found to have a dominant left ventricle (p = 0.71).   The initial Fontan procedure was performed at the ages of 7.5 (2.3–18.7), 4.7 (1.4– 10.1), and 6.7 (2.9–26.3) years in the t-FC, p-FC, and p-TCPC groups, respectively. The patients in the t-FC and p-FC groups underwent Fontan conversion at 24.4 (14.1–37.7) and 20.3 (8.0–25.6) years of age, respectively.   Overall outcome     Arrhythmia Before Fontan conversion, nine cases of atrial tachycardia (69%), one case of ventricular tachycardia (8%), and one case of sick sinus syndrome (SSS; 8%) were found in the t-FC group, all of which were managed with concomitant antiarrhythmic surgery.   Overview of the patients who underwent therapeutic Fontan conversion (t-FC). The second row indicates pre-operative rhythm (the dotted boxes); the third row indicates anti-arrhythmic surgeries performed at the time of the Fontan conversion (the bold boxes); the fourth and fifth rows indicate cardiac rhythm and devices required post-operatively, respectively. APC, aortopulmonary connection; AT, atrial tachycardia; AVB, atrioventricular block; CRT-P, cardiac resynchronization therapy pacing; JR, junctional rhythm; RA, right atrium; SSS, sick sinus syndrome; VT, ventricular tachycardia.   Hemodynamics No difference in central venous pressure, aortic pressure, and cardiac index was observed across the three groups. Similarly, the levels of brain natriuretic protein (BNP)—which were found to be 34.3 (9.7–93.5), 10.4 (4.9–59.2), and 21.7 (4.9–365.5) in the t-FC, p-FC, and p-TCPC groups, respectively—exhibited no significant difference (p = 0.22).     Discussion Fontan conversion with the Maze procedure has emerged as a tertiary prevention strategy for those with previous APCs and tachyarrhythmia. The present study revealed that this procedure is both prophylactically and therapeutically feasible and effective and that it can yield the same outcomes in conventional APC patients as those observed with the contemporary primary extracardiac TCPC patients.   Tachyarrhythmia in patients with univentricular hearts is known to be a predictor of worse outcomes, especially in APC patients. Thus, antiarrhythmic interventions, such as the Maze procedure, combined with Fontan conversion, are likely to change the deleterious clinical course in these patients. In this cohort, arrhythmia was very well controlled following Fontan conversion that nearly half of the patients in the t-FC group experienced no recurrence without antiarrhythmic medications. Moreover, no newly developed case of tachyarrhythmia was observed in the p-FC group, suggesting the strategy, Fontan conversion +/- antiarrhythmic procedure, can exert both primary and secondary preventative effects against atrial tachyarrhythmias. Aggressive prophylactic Maze procedure appeared to be more harmful than beneficial in our study since three patients (20%) developed sinus node dysfunction postoperatively.   The strategy utilized in this study turned out to have limited efficacy in the prevention of thromboembolism, as 11% of the patients developed a thromboembolic event following Fontan conversion. Although whether antiplatelet therapy or anticoagulation is more effective has yet to be elucidated, lifelong thromboprophylaxis seems essential even after the TCPC procedure or Fontan conversion is performed —probably more in older age.   Conclusions Fontan conversion is a safe and feasible procedure that helps APC patients keep up with primary TCPC patients with respect to hemodynamics and arrhythmia. It is recommended that this procedure be performed before patients become symptomatic. However, the Maze procedure should be limited to those with a history of significant arrhythmia, as it can frequently result in sinus node dysfunction, whereas Fontan conversion itself could lower the risk of arrhythmia.   

Angiotensin-converting enzyme inhibition and pre-superior cavopulmonary connection haemodynamics in infants with single-ventricle physiology. Al Balushi A, Averin K, Hsu DT, Mackie AS. Cardiol Young. 2021 Feb 16:1-5. doi: 10.1017/S1047951121000305. PMID: 33588974   Take Home Points: ACE inhibitors did not impact mean pulmonary artery pressure or transpulmonary gradient amongst infants with single-ventricle physiology prior to Superior Cavo-pulmonary connection (Glenn) palliation. The pathophysiology of pulmonary vascular remodeling in these infants is complex, and this study suggests that enalapril plays no role in that process in this population.     Commentary from Dr. Manoj Gupta (New York, USA), section editor of Pediatric & Fetal Cardiology Journal Watch: Introduction: Angiotensin-converting enzyme inhibitors have been used in pediatric heart failure associated with left-to-right shunts or chronic valvular regurgitation because they reduce systemic vascular resistance and left-to-right shunt. Amongst single-ventricle patients, ACEi have been shown to decrease ventricular filling pressure in older children with Fontan physiology while pulmonary hypertension therapies aimed at modulating the pulmonary vascular resistance in this patient population have yielded mixed results. Adults with chronic heart failure treated with ACEi have been shown to have lower PA pressure with short term use.   Material and methods: Using the Pediatric Heart Network Infant Single Ventricle trial (ISV trial) dataset, the original ISV trial showed that enalapril in the first year of life was not associated with improved somatic growth, ventricular function, or heart failure severity, but the ISV trial did not explore the impact of ACEi on measures of pulmonary vascular health. The authors hypothesized that infants enrolled in the ISV trial who received enalapril would have lower mean PA pressure compared to those who received placebo.   The study enrolled infants at 10 centers in the United States of America and Canada from August 2003, to May 2007. Inclusion criteria were infants with single ventricle physiology between 1 week and 45 days of age with stable systemic and pulmonary blood flow in whom a superior Cavo pulmonary connection (SCPC) was planned.   The primary outcome of this analysis was: Invasively measured mean PA pressure at the time of the pre-SCPC catheterization. If the mean PA pressure was not recorded in the catheterization dataset, a pulmonary venous wedge pressure was taken as a representative of mean PA pressure if < 18 mmHg. Transpulmonary gradient and pulmonary-to-systemic blood flow ratio recorded during pre-SCPC catheterization and oxygen saturation post-SCPC (7 days after surgery) were secondary outcomes. The initial enalapril dose prescribed in the ISV trial was 0.1 mg/kg/day. The dose was up titrated as tolerated over a period of 2 weeks to the target dose of 0.4 mg/kg/day, given in two divided doses per day. Patients on enalapril were grouped into low- and high dose, based on a cut-off of 0.3 mg/kg/day.   Within the ISV trial, 179 of 230 patients underwent pre-SCPC cardiac catheterization and were included in the current analysis. There were 94 patients (53%) in the placebo group and 85 (47%) in the enalapril group. Baseline patient characteristics were similar between the two groups.  Results are provided as n (%) unless otherwise specified.DKS = Damus–Kaye–Stansel. PAB = pulmonary artery band. SD = standard deviation. *No direct measurement of pulmonary artery pressure and pulmonary vein wedge pressure > 18 mmHg   Hemodynamic outcomes The primary analysis showed no difference in the mean PA pressure between the enalapril and placebo groups (13.1 ± 2.9 versus 13.7 ± 3.4 mmHg, p = 0.31).     Secondary outcome variables also did not differ between study groups. There was no difference in the enalapril versus placebo groups for any of the outcome measures according to the morphology of the ventricle.     Pre-specified subgroup analysis was also performed according to the type of shunt. In infants who had a Sano shunt (Table 4), the mean PA pressure was 13.0 ± 2.5 in the enalapril group versus 14.0 ± 3.6 in the placebo group (p = 0.25). In the Sano shunt patients, the post-SCPC oxygen saturation was 84 ± 4% in the enalapril group versus 82 ± 5% in the placebo group (p = 0.007). In infants who received an aortopulmonary shunt, the mean PA pressure was 14.0 ± 3.2 in the enalapril group versus 14.0 ± 3.4 in the placebo group (p = 0.75), and post-SCPC oxygen saturation was similar in the enalapril and placebo groups (83 ± 6 versus 82 ± 6, respectively, p = 0.96).     Impact of high-dose enalapril: The mean PA pressure was 13.2 ± 3.6 in the high-dose enalapril group (0.3–0.4 mg/kg/day) versus 13.2 ± 3.5 in the low-dose group (0.1–0.2 mg/kg/day) (p = 0.98).   Conclusion: ACE inhibitors did not impact mean pulmonary artery pressure or transpulmonary gradient amongst infants with single-ventricle physiology prior to Glenn palliation.   

Comparison Between Currently Recommended Long-Term Medical Management of Coronary Artery Aneurysms After Kawasaki Disease and Actual Reported Management in the Last Two Decades. Osborne J, Friedman K, Runeckles K, Choueiter NF, Giglia TM, Dallaire F, Newburger JW, Low T, Mathew M, Mackie AS, Dahdah N, Yetman AT, Harahsheh AS, Raghuveer G, Norozi K, Burns JC, Jain S, Mondal T, Portman MA, Szmuszkovicz JR, Crean A, McCrindle BW; International Kawasaki Disease Registry Pediatr Cardiol. 2021 Jan 13. doi: 10.1007/s00246-020-02529-2. PMID: 33439285   Take Home Points: This is an observational registry study. In the 2017 American Heart Association (AHA) Kawasaki disease (KD) guidelines, risk levels (RLs) risk stratification was added for long-term management. Generally, past practice was consistent with the latest AHA guidelines. However, the important exception was that 35% of patients with persistent giant coronary artery aneurysms were not on anticoagulants. Physician education could improve guideline compliance and patient outcomes.   Commentary from Dr. Manoj Gupta (New York, USA), section editor of Pediatric & Fetal Cardiology Journal Watch: Introduction: Kawasaki disease (KD) is a self-limiting, systemic vasculitis of unclear etiology that mostly occurs in children. Coronary artery aneurysms form in approximately 25% of untreated patients and in approximately 4% of patients treated within 10 days of the onset of illness. The long-term consequences of KD may include myocardial infarction and death. In 2017, the American Heart Association (AHA) updated the approach to risk stratification and long-term management of KD patients (https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000484). This manuscript compared the Kawasaki disease management practice from 1999 to 2016 with the most recent AHA 2017 recommendations for thromboprophylaxis and medical therapy based on the new risk stratification. The study included the eligible patients from registry who were diagnosed with Kawasaki disease under the age of eighteen years from 1999 to 2016 and had coronary artery aneurysms (Defined as at least one coronary artery diameter with a maximum z-score ≥ 2.5 at any point in their initial work up and subsequent follow -up). Figure 1: Risk level (RL) classification of coronary artery aneurysms per the 2017 AHA guidelines using maximum z-score, luminal dimension, and amount of regression. Risk Level 1: No involvement Risk Level 2: Dilation only     Results: Prevalence of medication use by risk levels (RL) was explored across 3 eras (1999–2004, 2005–2010, and 2011–2016). Acetylsalicylic Acid (ASA): Use of ASA/aspirin ranged from 88 to 96% for RLs for which use was “indicated” (RLs 3.1, 4.1, 4.2, 5.1, 5.2, and 5.3); this represents patients with coronary artery aneurysms of any size that have not regressed to normal luminal dimensions or dilation only (z-score <2.5)   Systemic anticoagulation is only “recommended” for patients for RL 5.1 (persistent large/giant coronary artery aneurysms). Despite this, only 65% of patients in RL 5.1 were receiving anticoagulation and there was no trend toward increased usage over the different year groups.   Dual antiplatelet therapy (ASA and clopidogrel) was in use at 16% of patient visits for RL 5.2 where use was “reasonably indicated.” For visits for RLs 5.3 and 5.4, dual antiplatelet therapy was used for 11% and 9%, respectively (“not indicated”).   There was an increase in ASA use for RL 3.2 from 54% in 1999–2004 to 73% in 2011–2016 and there was increased single antiplatelet (ASA only) use from 43% in 1999–2004 to 67% in 2011–2017. Conclusions and Implications for Clinical Practice:   The management of patients with Kawasaki disease and coronary artery aneurysms from 1999 to 2016 was generally similar to 2017 AHA Kawasaki disease guidelines.   Physician education could improve guideline compliance and patient outcomes, and knowledge translation efforts are needed to further optimize practice in anticoagulation KD patients. Additionally, more research is needed to advance future recommendations, particularly for statins, beta-blockers, and direct oral anticoagulants.   

Long-term experience with the one-and-a-half ventricle repair for simple and complex congenital heart defects. Cabrelle G, Castaldi B, Vedovelli L, Gregori D, Vida VL, Padalino MA. Eur J Cardiothorac Surg. 2021 Jan 4;59(1):244-252. doi: 10.1093/ejcts/ezaa289. PMID: 32888295   Take Home Points: Long-term (median 13 years) results in patients with a single RV and a 1 ½ ventricle repair are good in this relatively small group. There was no significant difference in survival or freedom from adverse events between simple and complex patients. When planned, a 1.5V repair may be beneficial in a very specific subset of patients and possibly lead to better outcomes than single ventricle (Fontan) palliation?   Commentary from Dr. Jared Hershenson (Greater Washington DC), section editor of Pediatric Cardiology Journal Watch: One and a half ventricle (1 ½ V) repair has been proposed for those with borderline/small right ventricles with hypothetical advantages over single ventricle palliation/Fontan such as ability to increase cardiac output and adapt to exercise, maintain pulsatile pulmonary blood flow, and low venous pressure in the IVC. This single center study retrospectively evaluated 29 patients who underwent 1 ½ V staged or primary repair between 1994-2018. Inclusion criteria were hypoplastic tricuspid valve (z-score < -3) and hypoplastic RV (< 2/3 predicted normal volume). Patients were divided into simple (CHD confined to right heart lesions) and complex anatomy (including other than right heart lesions and more challenging surgical repair). Echo data, cath data (PVR), and metabolic stress test data were followed. See table 2.   Median follow up was 12.5 years. Specific surgical details were discussed in the results section. Most common post-operative complications included pericardial and pleural effusions and arrhythmias. There were 3 late deaths with 2 considered non-cardiac related. 6 required a cardiac cath after a median time of 2.8 years, most commonly to address branch pulmonary artery stenosis. 3 patients required subsequent re-operation; 1 underwent transplant and the other 2 underwent biventricular conversion due to interval RV growth. Survival at 25 years was 89%; all had normal kidney and liver function (based on lab tests). Median O2 sat was 98%. Freedom from any late adverse event was 57% (16/28) and freedom from reoperation or re-intervention was 82.1% (23/28) and 78.6% (22/28) respectively. The complex patients had a much more significant initial post-operative course as would be expected. None of the “late” deaths occurred in the first year of follow up. 5 patients had neurological AEs which possibly contributed the most to the late AE rate, but the paper does not define this well. See tables 3 and 4. Comparison between the complex and simple group found no significant differences in survival, freedom from AE, or freedom from reintervention. See figure 1. Only 10 patients had MRIs and only 12 patients had metabolic stress testing. Mean VO2 was higher than compared to a control group of Fontan patients (33 +/- 5 vs. 24 +/- 1.6 ml/kg/min).   This surgical center planned for 1.5V repair after birth and show overall good results, with a few patients even being able to undergo biventricular conversion. No patients had PLE or chronic liver congestion, known complications of the Fontan. Important limitations include low total number of patients, lack of MRI data, and limited stress test data. When planned, a 1.5V repair may be beneficial in a very specific subset of patients and possibly lead to better outcomes than single ventricle (Fontan) palliation.            

Six-Year Neurodevelopmental Outcomes for Children With Single-Ventricle Physiology. Sananes R, Goldberg CS, Newburger JW, Hu C, Trachtenberg F, Gaynor JW, Mahle WT, Miller T, Uzark K, Mussatto KA, Pizarro C, Jacobs JP, Cnota J, Atz AM, Lai WW, Burns KM, Milazzo A, Votava-Smith J, Brosig CL; PHN investigators. Pediatrics. 2021 Feb;147(2):e2020014589. doi: 10.1542/peds.2020-014589. Epub 2021 Jan 13. PMID: 33441486   Take Home Points: There is an increase in externalizing behavioral problems and decreased adaptive skills in school age children with HLHS. Many children with HLHS who have low adaptive skills at 6 years of age will not be identified by screening at earlier ages. Serial neurodevelopmental evaluations will be necessary to diagnose deficits as these single ventricle patients get older and advance in school.   Commentary from Dr. Jared Hershenson (Greater Washington DC), section editor of Pediatric Cardiology Journal Watch: Neurodevelopmental deficits are one of the most common long term issues that face children with HLHS. Early identification could theoretically allow for implementation of therapies that could improve long-term educational and behavioral outcomes. This extension study to the Single Ventricle Reconstruction (SVR) Trial studied the original cohort who had a 14-month mental development index (MDI) and psychomotor development index (PDI) via annual developmental (ASQ) and behavioral (externalizing and internalizing)/adaptive assessments (BASC-2) based on parental questionnaires from ages 3-6. The ASQ measures the child’s development in communication, gross motor, fine motor, problem solving and personal social skills, and the BASC-2 measures adaptive skills and problem behaviors in the community and home settings. Adaptive functioning refers to how a child copes with demands of everyday life and their personal independence. Scores were compared to population norms and classified as at least average (< 1 SD), at risk (< 1-2 SC) and impaired (< 2 SD). 249 patients completed the assessments.   The greatest change in proportion of children at being at risk or impaired occurred between ages 3 and 4, but this was largely due to a lower rate of reported problem behaviors at age 3 than the population norms. However, by age 6, many more had externalizing behavior challenges (e.g. hyperactivity, aggression, and rule breaking). There was not an increase in internalizing behaviors or differences compared to population norms. The most significant deviations were noted on the adaptive skills portion of BASC-2, with most differences occurring between ages 5 and 6. At age 3, 87% were age-appropriate, but by age 6, this dropped to only 71%. 22% (vs. 14% expected) were classified as at risk and 7% (vs. 2%) as impaired. See figure 1 and table 2. The authors note that this finding may not be a regression, but rather the parents now having increased opportunities for social comparison now that the children are in school and begin to act more independently. Parent ratings of deficits in problem solving skills and communication were strongly related to future poor adaptive skills, with ~44% of children at risk/impaired on the 14 month MDI and ~ 36% of children at risk/impaired on the 14 month PDI having impaired adaptive skills at age 6. As a “half glass full” observation, the authors highlight that a significant proportion (77-85%) who do not show early impairments remain unimpaired at age 6.   Limitations of the study were that only parental assessments were made, a selection bias was possibly present given that participants had fewer risk factors for impaired neurodevelopment and higher socioeconomic status than non-participants, and the inability to measure impact of access to early intervention services on outcome scores. A follow up study at 10-12 years is already underway to allow for further understanding of a relationship with later school age outcomes and standardized testing.       

Low-dose prostaglandin E1 is safe and effective for critical congenital heart disease: is it time to revisit the dosing guidelines? Daniel Vari 1, Wendi Xiao 2, Shashank Behere 3, Ellen Spurrier 3, Takeshi Tsuda 3, Jeanne M Baffa 3 Cardiol Young. 2021 Jan;31(1):63-70. doi: 10.1017/S1047951120003297. Epub 2020 Nov 3. PMID: 33140712; DOI: 10.1017/S1047951120003297   Take Home Points: Prostaglandin E1 at an initial and maintenance dose of 0.01 μg/kg/minute was sufficient to maintain ductal patency in 83% in this study, instead of the standard starting dose of prostaglandin E1 is 0.05 μg/kg/minute. Starting low-dose prostaglandin E1 at 0.01 μg/kg/minute is a safe and effective therapy for critical CHD. Patients with pulmonary obstruction were more likely to require higher doses than patients with systemic obstruction. Postnatally diagnosed patients with systemic obstruction are also at a higher risk of dose escalation than prenatally diagnosed infants. The incidence of respiratory depression requiring mechanical ventilation was low and was mostly seen in premature infants.      Commentary from Dr. Manoj Gupta (New York, USA), section editor of Pediatric & Fetal Cardiology Journal Watch: Of the 153 eligible patients, 127 (83%) were started and maintained on a prostaglandin E1 dose of 0.01 μg/kg/minute until the end- point. Of the 26 patients who had their doses increased, the final dose was less than 0.05 μg/kg/minute in 15, 0.05 μg/kg/minute in five, and greater than 0.05 μg/kg/minute in two patients. 15 patients had their dose increased due to both echocardiographic findings and clinical factors suggesting ductal constriction. In systemic obstruction patients, these factors included blood pressure gradients, pulse abnormalities between upper and lower extremities, and elevated serum lactate levels. In pulmonary obstruction and inadequate mixing patients, the primary clinical factor driving dose increase was hypoxemia. In six patients, there was an echocardiographic finding of ductal constriction without corresponding clinical signs.   Of the 137 patients analyzed for respiratory depression, 38 (28%) had documented respiratory depression at a dose of 0.01μg/kg/ minute. In 10 of these patients, the respiratory depression was transient and did not merit initiation of respiratory support although four were started on caffeine. Fourteen patients (10%) were started on nasal cannula or high-flow nasal cannula, three patients (2%) were placed on continuous positive airway pressure, and 11 patients (8%) were mechanically ventilated via endotracheal intubation as a result of respiratory depression. Premature infants were more likely to experience respiratory depression (12/18, 67%) than term infants (26/117, 22%, p < 0.001). Mechanical ventilation was also more frequent in premature infants (6/18, 33%) than in term infants (5/117, 4%, p = 0.001).