Connecting Transcriptomics with Computational Modeling to Reveal Developmental Adaptations in the Human Pediatric Myocardium.

Background: Nearly 1% or 1.3 million babies are born with congenital heart disease (CHD) globally each year - many of whom will require palliative or corrective heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate cardiovascular drug therapies, and inform clinical care decisions related to surgical repair, myocardial preservation, or postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is largely limited to animal models. Methods: Right atrial tissue samples were collected from n=117 neonatal, infant, and pediatric patients undergoing correct surgery due to (acyanotic) CHD. Patients were stratified into five age groups: neonate (0-30 days), infant (31-364 days), toddler to preschool (1-5 years), school age (6-11 years), and adolescent to young adults (12-32 years). We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. Results: Enrichment of differentially expressed genes (DEG) was explored, revealing age-dependent changes in several key biological processes (cell cycle, cell division, mitosis), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited both linear trends and sudden shifts across developmental stages, with changes in calcium handling ( I NCX ) and repolarization ( I K1 ) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We also note a shift in repolarization reserve, with lower I Kr expression in younger patients, a finding likely tied to the increased amplitude of I Ks triggered by elevated sympathetic activation in pediatric patients. Conclusion: This study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology among patients with CHD, shedding light on molecular mechanisms underlying cardiac development and function across different developmental stages.

Exercise Capacity and Reoperation Late After Transatrial Fallot Repair.

BACKGROUND: The exercise capacity long after repair of tetralogy of Fallot, when performed exclusively with a transatrial repair, is unclear. It is also unknown whether echocardiography and cardiopulmonary exercise testing can predict the risk of reoperation in this patient group. METHOD: We retrospectively reviewed the clinical records of 59 patients who underwent cardiopulmonary exercise testing after transatrial Fallot repair at a single centre. Patients underwent cardiopulmonary exercise testing at a mean age of 16.6±4.4 years, and at 15.3±4.1 years after Fallot repair. RESULTS: At testing, the volume of oxygen consumption at maximal exercise (VO2 max) was 71%±13% and the oxygen pulse was 80%±17% of predicted values. Seventeen (17) patients (29%) had a VO2 max superior to 80% of the predicted value. Thirty-two (32) patients (56%) had severe pulmonary regurgitation, three (5%) had moderate pulmonary regurgitation, and 12 (21%) had mild pulmonary regurgitation. After a mean of 7.8±3.9 years following cardiopulmonary exercise testing (23±5.3 years after the repair), 21 (40%) patients underwent reoperation. Right ventricular dilation and systolic function on echocardiography were both significantly associated with subsequent reoperation rates. Patients who had severe right ventricular dilation were eight times more likely to undergo subsequent reoperation (hazard ratio 8.67; 1.82-41.3; p=0.007). No cardiopulmonary exercise testing variable independently predicted reoperation. CONCLUSIONS: The exercise capacity at adolescence following transatrial repair of tetralogy of Fallot is maintained at around 70% of predicted values. Only the patients with normal right ventricular size and normal right ventricular function seemed to be protected from reoperation over the subsequent decade. We found no exercise variables which predicted reoperation.

Survival benefits of the wait-and-grow approach in small babies (≤2000 g) requiring heart surgery.

Objective: The best approach to minimize the observed higher mortality of newborn infants with low birth weight who require congenital heart surgery is unclear. This retrospective study was designed to review outcomes of newborn infants weighing <2000 g who have undergone cardiovascular surgery to identify patient parameters and clinical strategies for care associated with higher survival. Methods: A retrospective chart review of 103 patients who underwent cardiovascular surgery from 2010 to 2021 who were identified as having low birth weight (≤2000 g). Patients who underwent only patent ductus arteriosus ligation or weighing >3500 g at surgery were excluded. Results: Median age was 24 days and weight at the time of surgery was 1920 g. Twenty-six (25%) operative mortalities were recorded. Median follow-up period was 2.7 years. The 1- and 3-year overall Kaplan-Meier survival estimate was 72.4% ± 4.5% and 69.1% ± 4.6%. The 1-year survival of patients who had a weight increase >300 g from birth to surgery was far superior to the survival of those who did not achieve such a weight gain (81.4% ± 5.6% vs 64.0% ± 6.7%; log-rank P = .04). By multivariable Cox-hazard regression analysis, the independent predictor of 1-year mortality was genetic syndrome (hazard ratio, 3.54; 95% CI, 1.67-7.82; P < .001), whereas following a strategy of increasing weight from birth to surgery resulted in lower mortality (hazard ratio, 0.49; 95% CI, 0.24-0.90; P = .02). Conclusions: A strategy of wait and grow for newborn infants with very low birth weight requiring heart surgery results in better survival than immediate surgery provided that the patient's condition allows for this waiting period.

Excellent Survival With a Focus on Pulmonary Artery Reinterventions After the Arterial Switch Operation.

Background: We sought to evaluate the outcomes in patients who underwent the arterial switch operation (ASO) over a 20-year period at a single institution. Methods: The current study is a retrospective review of 180 consecutive patients who underwent the ASO for biventricular surgical correction of dextro-transposition of the great arteries (d-TGA) between 2002 and 2022. Results: Among 180 patients, 121 had TGA-intact ventricular septum, 47 had TGA-ventricular septal defect and 12 had Taussig-Bing Anomaly (TBA). The median follow-up time was 6.7 years (interquartile range: 3.9-8.7 years). There were five early (2.8%) and one late (0.6%) mortality. Survival was 96.6% at one year and beyond. Reoperations were performed in 31 patients (17%). Taussig Bing Anomaly was found to increase the risk of reoperation by 17 times (P < .0001). A total of 37 (21%) patients underwent 53 reinterventions (14 surgical procedures, 39 catheter interventions) specifically addressing pulmonary artery (PA) stenosis. Freedom from PA reintervention was 97%, 87%, 70%, and 55% at 1, 5, 10, and 15 years, respectively. By bivariable analysis, TBA (P = .003, odds ratio [OR]: 6.4, 95% confidence interval [CI]: 1.9-21.7), mild PA stenosis at discharge (P ≤ .001, OR: 6.1, 95% CI: 2.7-13.6), and moderate or severe PA stenosis at discharge (P ≤ .001, OR: 12.7, 95% CI: 5-32.2) were identified as predictors of reintervention on PA. In the last follow-up of 174 survivors, 24 patients (14%) had moderate or greater PA stenosis, two (1%) had moderate neoaortic valve regurgitation, and 168 were New York Heart Association status I. Conclusions: Our results demonstrated excellent survival and functional status following the ASO for d-TGA; however, patients remain subject to frequent reinterventions especially on the pulmonary arteries.

Alarming rate of liver cirrhosis after the small conduit extracardiac Fontan: A comparative analysis with the lateral tunnel.

BACKGROUND: The association between the prevalence of cirrhosis and the types of Fontan operations remains unclear. METHODS: We conducted a retrospective chart review of 332 patients who underwent the Fontan procedure at our institution. Four patients who underwent the atriopulmonary connection Fontan were excluded from the analysis. Patients who had intracardiac-extracardiac conduit (126) between 1989 and 2021 were pooled with those having extracardiac conduit (ECC) (134). The 260 patients who underwent the ECC and the 68 patients who had the lateral tunnel (LT) Fontan constitute the core of the study. RESULTS: Median age at the Fontan procedure was 23.7 months (interquartile range [IQR], 20.8-32.6) in the LT group, compared with 28.8 months (IQR, 24.6-39.5) in the ECC group (P < .01). The median follow-up was 14.8 years (IQR, 12.5-16.5) in the LT group and 7 years (IQR, 2.8-10.4) in the extracardiac conduit group. During the follow-up period, 3 patients (4.4%) with LT and 17 patients (6.5%) with ECC (11 patients with 16 mm or less conduit size) were diagnosed with cirrhosis. The prevalence of cirrhosis at 1, 5, 10, and 15 years was 0%, 0%, 0%, and 4.4% in the LT group, respectively, and 0%, 0.9%, 7.7%, and 29.8% in the ECC group (P < .01) Rates of mortality, Fontan revision, Fontan takedown, transplant, and complications were comparable between the 2 groups. CONCLUSIONS: The extracardiac conduit Fontan seems to be associated with faster development of cirrhosis.

Repair of the complete atrioventricular septal defect-impact of postoperative moderate or more regurgitation.

OBJECTIVES: To study the risk factors for mortality, moderate or more left atrioventricular valve regurgitation (LAVVR) and reoperation after the surgical repair of complete atrioventricular septal defect (cAVSD) in a single centre. METHODS: The current study is a retrospective review of patients who underwent surgical repair of cAVSD between 2000 and 2021. Patients with unbalanced ventricles not amenable to biventricular repair, double outlet right ventricle and malpositioned great arteries were excluded. The clinical predictors of outcome for end points were analysed with univariate and multivariable Cox regression analysis or Fine-Gray modelling for competing risks. Time-dependent end points were estimated using the Kaplan-Meier curve analysis and cumulative incidence curves. RESULTS: The median follow-up time was 2.3 years. Among 220 consecutive patients were 10 (4.6%) operative and 21 late mortalities (9.6%). A total of 26 patients were identified to have immediate postoperative moderate or more regurgitation and 10 of them ultimately died. By multivariable analysis prematurity and having more than moderate regurgitation immediately after the operation were identified as predictors of overall mortality (P = 0.003, P = 0.012). Five- and ten-year survival rates were lower for patients with immediate postoperative moderate or more LAVVR {51.9% [confidence interval (CI): 27.5-71.7%]} when compared to patients without moderate or more regurgitation [93.2% (CI: 87.1-96.4%) and 91.3% (CI: 83.6-95.5%)]. CONCLUSIONS: The patients who undergo cAVSD repair remain subjected to a heavy burden of disease related to postoperative residual LAVVR. Immediate postoperative moderate or more LAVVR contributes significantly to overall mortality. Whether a second run of bypass can decrease this observed mortality should be investigated.

Reconstruction of Fibrous Skeleton of the Heart for Double-Valve Replacement in A Pediatric Patient - Modified Commando Procedure.

The so-called Commando procedure, initially described by David and colleagues, consists in the reconstruction of the mitro-aortic fibrous lamina by a patch that enlarges both annuli. Its use has been described to upsize the aortic and mitral annulus for double valve replacement in adolescents. We describe a modified technique of this reconstruction of the fibrous skeleton of the heart, combined with Konno procedure to further enlarge the aortic annulus. In modified Commando procedure, following the reconstruction of aortomitral continuity with a bovine pericardium CardioCel patch (Admedus Regen Pty Ltd, Perth, WA, Australia), an aortic valved conduit that was made on the bench in order to have bottom skirt that enabled the suturing of the composite conduit far inside the left ventricle outflow tract. Coronary buttons were implanted at the supra-commissural level. The advantages of this modified Commando procedure are (1) the creation of a new aortic annulus when the integrity of this annulus has been compromised, (2) the upsizing of both annuli to any possible size of aortic and mitral prostheses, and (3) the relief of any residual left ventricular outflow tract obstruction.

Brain injury and neurodevelopmental outcomes in children undergoing surgery for congenital heart disease.

Objectives: Brain injury is commonly seen on magnetic resonance imaging in infants with complex congenital heart disease. The impact of perioperative brain injury on neurodevelopmental outcomes is not well understood. We evaluate the association of brain injury and other markers on neurodevelopmental outcomes in patients undergoing surgery for congenital heart surgery during infancy. Methods: Term newborns with infant cardiac surgery performed between 2008 and 2019 at a single tertiary center, and both preoperative and postoperative brain magnetic resonance imaging were included. Those with underlying genetic conditions were excluded. Brain injury was characterized using an magnetic resonance imaging scoring system. Neurodevelopmental outcomes were assigned using the Pediatric Stroke Outcome Measure and Glasgow Outcome Scale Extended. Independent risk factors for poor neurodevelopmental outcomes were determined by multivariable Cox regression. Results: A total of 122 patients were included. New or progressive postoperative brain injury was noted in 69 patients (57%). A total of 101 patients (83%) had at least 1 neurodevelopmental assessment (median age 36 months) with an early assessment (5-24 months) performed in 95 children. Multivariable Cox regression analysis of early neurodevelopmental outcomes identified new stroke on postoperative magnetic resonance imaging to be an independent predictor of poor neurodevelopmental outcome. Postoperative peak lactate was an independent predictor of poor outcome assessed by the Pediatric Stroke Outcome Measure and Glasgow Outcome Scale Extended. Conclusions: Our study reveals that evidence of new stroke on magnetic resonance imaging after infant congenital heart surgery is a predictor of poor neurodevelopmental outcomes in early childhood. Postoperative lactic acidosis is associated with poor neurodevelopmental outcome and may be a surrogate biomarker for ischemic brain injury.

Cerebral autoregulation monitoring using the cerebral oximetry index after neonatal cardiac surgery: A single-center retrospective cohort study.

OBJECTIVE: To investigate whether cerebral autoregulation is impaired after neonatal cardiac surgery and whether changes in autoregulation metrics are associated with different congenital heart defects or the incidence of postoperative neurologic events. METHODS: This is a retrospective observational study of neonates undergoing monitoring during the first 72 hours after cardiac surgery. Archived data were processed to calculate the cerebral oximetry index (COx) and derived metrics. Acute neurologic events were identified by an electronic medical record review. The Skillings-Mack test and the Wilcoxon signed-rank test were used to analyze the evolution of autoregulation metrics over time; the Mann-Whitney U test was used for comparison between groups. RESULTS: We included 28 neonates, 7 (25%) with hypoplastic left heart syndrome and 21 (75%) with transposition of the great arteries. Overall, the median percentage of time spent with impaired autoregulation, defined as percentage of time with a COx >0.3, was 31.6% (interquartile range, 21.1%-38.3%). No differences in autoregulation metrics between different cardiac defects subgroups were observed. Seven patients (25%) experienced a postoperative acute neurologic event. Compared to the neonates without an acute neurologic event, those with an acute neurologic event had a higher COx (0.16 vs 0.07; P = .035), a higher percentage of time with a COx >0.3 (39.4% vs 29.2%; P = .017), and a higher percentage of time with a mean arterial pressure below the lower limit of autoregulation (13.3% vs 6.9%; P = .048). CONCLUSIONS: COx monitoring after cardiac surgery allowed for the detection of impaired cerebral autoregulation, which was more frequent in neonates with postoperative acute neurologic events.

Are dynamic measurements of central venous pressure in Fontan circulation during exercise or volume loading superior to resting measurements?

BACKGROUND: The main objective measure to assess the health of the Fontan circulation is the pressure measurement of the superior vena cava or pulmonary arteries. We reviewed the literature for benefits of measuring resting pressure in the Fontan circuit and explored whether dynamic measurement by volume loading or exercise has the potential to refine this diagnostic tool. METHODS: PubMed was searched for articles showing a relationship between resting post-operative central venous pressure or pulmonary artery pressure and Fontan failure. Relationships between post-operative central venous pressure or pulmonary artery pressure and volume loading changes, such as during exercise or volume loading during cardiac catheterization, were also queried. RESULTS: A total of 44 articles mentioned relationships between resting central venous pressure or pulmonary artery pressure and Fontan failure. Only 26 included an analysis between the variables and only seven of those articles found pressure to be predictive of Fontan failure. Ten articles examined the relationship between exercise or volume loading and outcomes and demonstrated a large individual variation of pressures under these dynamic conditions. CONCLUSIONS: Based on current literature, there is not a lot of strong evidence to show that elevated resting central venous pressure or pulmonary artery pressure is predictive of Fontan failure. Some individuals experience dramatic increases in central venous pressure or pulmonary artery pressure under increased loading conditions with exercise or bolus fluid infusion, while others experience increases closer to that of a healthy control population. Further studies are needed to examine whether more dynamic and continuous monitoring of systemic venous pressures might better predict outcomes in patients with Fontan circulation.

T-Remodeling of the Pulmonary Artery Bifurcation for Pulmonary Artery Origin Stenosis.

BACKGROUND: Various surgical techniques are utilized for reconstructing hypoplastic pulmonary arteries (PAs) in patients with conotruncal anomalies and at times, may be susceptible to restenosis and reoperation. We reviewed our experience with a simple technique of T-shaped remodeling of the PA bifurcation. METHODS: Between 2005 and 2019, 31 patients underwent T-remodeling of central PAs by a single cardiac surgeon. The PA bifurcation was opened cranially, and the opening was augmented with an oval-shaped patch effectively transforming the V-shaped bifurcation into a T-shaped bifurcation. Both origins of the PAs were enlarged, even in the instance of single PA origin stenosis. RESULTS: Median age at time of T-remodeling was 17 months (range: 7 weeks to 14 years). The following cardiac morphologies were observed: tetralogy of Fallot (n = 12, 39%), pulmonary atresia with ventricular septal defect (VSD) and major aortopulmonary collateral arteries (n = 8, 26%), truncus arteriosus (n = 6, 19%), pulmonary atresia with VSD (n = 3, 9.7%), and transposition of the great arteries (n = 2, 6.5%). Thirteen patients (42%) had previous central shunt, and eight patients (26%) had previous modified Blalock-Taussig shunt. There were no operative mortalities. Immediately after T-remodeling, echocardiographic estimates of right ventricle to PA gradient decreased from 42 [interquartile range 28-58] mm Hg to 20 [12-36] mm Hg (P = .03). Freedom from reoperation on the PA bifurcation for the entire cohort was 100% at one year, 88% (95% CI 68%-96%) at five years and 82% (57%-93%) at ten years. CONCLUSIONS: T-remodeling for PA origin stenosis is a safe procedure with excellent freedom from reoperation that is easily reproducible and applicable to patients with all cardiac morphologies.

O2 pulse slope correlates with stroke volume during exercise in patients with a Fontan circulation.

BACKGROUND: Peak oxygen pulse (O2pulse=oxygen consumption/heart rate) is calculated by the product of stroke volume (SV) and oxygen extraction. It has been shown to be reduced in patients with a Fontan circulation. However, in the Fontan population, it may be a poor marker of SV. We propose that the slope of the O2 pulse curve may be more reflective of SV during exercise. METHODS: We analysed cardiopulmonary exercise test data in 22 subjects with a Fontan circulation (cohort A) and examined the association between peak SV during exercise (aortic flow measured on exercise cardiac MRI), and O2 pulse parameters (absolute O2 pulse and O2 pulse slopes up to anaerobic threshold (AT) and peak exercise). In a separate Fontan cohort (cohort B, n=131), associations between clinical characteristics and O2 pulse kinetics were examined. RESULTS: In cohort A, peak aortic flow was moderately and significantly associated with O2pulseslopePEAK (r=0.47, p=0.02). However, neither absolute O2pulseAT nor O2pulsePEAK was significantly associated with peak aortic flow. In cohort B, O2pulseslopePEAK and O2pulseslopeAT were not significantly associated with clinical parameters, apart from a weak association with forced vital capacity. CONCLUSION: The slope of the O2 pulse curve to peak exercise may be more reflective of peak SV in the Fontan population than a single peak O2 pulse value.

A uniform strategy of primary repair of tetralogy of Fallot: Transventricular approach results in low reoperation rate in the first decade.

OBJECTIVES: To review outcomes after a uniform strategy of transventricular repair of tetralogy of Fallot. METHODS: A total of 244 consecutive patients underwent transventricular primary repair of tetralogy of Fallot from 2004 to 2019. Median age at operation was 71 days; 57 (23%) patients were premature; 57 (23%) patients had low birth weight (<2.5 kg), and 40 (16%) had genetic syndromes. The diameter of pulmonary valve annulus, right pulmonary artery (PA), and left PA were 6.0 ± 1.8 mm (z score, -1.7 ± 1.3), 4.3 ± 1.4 mm (z score, -0.9 ± 1.2) and 4.1 ± 1.5 mm (z score, -0.5 ± 1.3). RESULTS: Three (1.2%) operative deaths were recorded. Ninety patients (37%) underwent transannular patching. Postoperative echocardiographic peak right ventricular outflow tract gradient decreased from 72 ± 27 mm Hg to 21 ± 16 mm Hg. Median intensive care unit and hospital stay were 3 and 7 days. The survival rate at 10 years was 94.6% ± 1.8%. Reintervention was required 86 times (55 catheter interventions) in 56 patients following tetralogy of Fallot repair. The freedom from all-cause reintervention rate at 10 years was 70.5% ± 3.6%. Cyanotic spells (hazard ratio, 2.14; 95% CI, 1.22-3.90; P < .01) and smaller pulmonary valve annulus z score (hazard ratio, 1.26; 95% CI, 1.01-1.59; P = .04) were associated with increasing risk of all reinterventions. Freedom from redo surgery for right ventricular outflow tract obstruction and right ventricular dilatation at 10 years were, respectively, 85.0% ± 3.1% and 98.7% ± 0.9%. Freedom from valve implantation was 96.7% ± 1.5% at 10 years. CONCLUSIONS: A uniform strategy of primary repair of tetralogy of Fallot through a transventricular approach resulted in low reoperation rate in the first decade. The need of pulmonary valve implantation was limited to <4% at 10 years.

Aortic valve-sparing procedure in the pediatric population.

Background: Aortic valve-sparing procedures have been established as a mainstream treatment option for adult patients with aortic root aneurysms. However, data regarding their use in the pediatric population is limited. This study reports on our experience with aortic valve-sparing procedures in children. Methods: A retrospective review was conducted of all patients who underwent an aortic valve-sparing procedure at the Royal Children's Hospital, Melbourne, Australia between April 2006 and April 2016. Clinical and echocardiographic data were analyzed. Results: The study included 17 patients, with a median age of 15.7 years and a majority of patients being male (82.4%). The most common diagnosis was transposition of great arteries after arterial switch operation, followed by Loeys-Dietz syndrome and Marfan syndrome. Preoperative echocardiography showed more than moderate aortic regurgitation in 94.1% of the patients. The David procedure was performed in all 17 patients, with no mortality during follow-up. Reoperation was required in 29.4% of patients, and 23.5% required aortic valve replacement. Freedom from reoperation for aortic valve replacement at 1, 5, and 10 years was 93.8%, 93.8% and 68.2% respectively. Conclusions: Aortic valve-sparing surgery can be successfully performed in the pediatric population. However, it requires a highly skilled surgeon due to the often dysplastic or distorted nature of these valves and the need for additional procedures on the aortic valve leaflets.