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Coronary sinus ostial obstruction is an exceedingly rare anomaly that is particularly important to diagnose in patients with single-ventricle heart disease before surgical palliation. We present 2 cases, an infant and an adult, diagnosed with coronary sinus ostial obstruction, with different clinical outcomes due to timing of diagnosis. (Level of Difficulty: Intermediate.), Central Illustration

We report the first successful implantation in the United States of a novel mitral valve (MITRIS RESILIA by Edwards Lifesciences) in a patient with history of mitral valve replacement at a young age. This new bioprosthetic valve offers a unique profile and innovative option for mitral valve replacement in patients who are at risk of left ventricular outflow tract obstruction.

Objectives To explore relationships between the training background of cardiac critical care attending physicians and self-reported perceived strengths and weaknesses in their ability to provide clinical care. Design Cross-sectional observational survey sent worldwide to ~550 practicing cardiac ICU attending physicians. Setting Hospitals providing cardiac critical care. Subjects Practicing cardiac critical care physicians. Interventions None. Measurements and main results We received responses from 243 ICU attending physicians from 82 centers (14 countries). The primary training background of the respondents included critical care (62%), dual training in critical care and cardiology (16%), cardiology (14%), and other (8%). We received 49 responses from medical directors in nine countries, who reported that the predominant training background for attending physicians who provide cardiac intensive care at their institutions were critical care (58%), dual trained (18%), cardiology (12%), and other (11%). A greater proportion of physicians trained in either critical care or dual-training reported feeling confident managing multiple organ failure, neurologic conditions, brain death, cardiac arrest, and performing procedures like advanced airway placement and inserting chest- and abdominal-drains. In contrast, physicians with cardiology and dual-training reported feeling more confident managing intractable arrhythmias, understanding cardiopulmonary interactions, and interpreting echocardiogram, electrocardiogram, and cardiac catheterization. Overall, only 57% of the respondents felt comfortable based on their current training background to manage patients with complex cardiac issues without collaboration with other specialists. Conclusions Our survey demonstrates that intensivists trained in critical care are more comfortable with critical care skills, cardiology-trained intensivists are more comfortable with cardiology skills, and dual-trained physicians are comfortable with both critical care skills and cardiology skills. These findings may help inform future efforts to optimize the educational curriculum and training pathways for future cardiac intensivists. These data may also be used to shape continuing medical education activities for cardiac intensivists who have already completed their training.

OBJECTIVES Caring for a child with gastrostomy and/or tracheostomy can cause measurable parental stress. It is generally known that children with 22q11.2 deletion syndrome are at greater risk of requiring gastrostomy or tracheostomy after heart surgery, although the magnitude of that risk after complete repair of tetralogy of Fallot has not been described. We sought to determine the degree to which 22q11.2 deletion is associated with postoperative gastrostomy and/or tracheostomy after repair of tetralogy of Fallot. DESIGN Retrospective cohort study. SETTING Pediatric Health Information System. PATIENTS Children undergoing complete repair of tetralogy of Fallot (ventricular septal defect closure and relief of right ventricular outflow tract obstruction) from 2003 to 2016. Patients were excluded if they had pulmonary atresia, other congenital heart defects, and/or genetic diagnoses other than 22q11.2 deletion. MEASUREMENTS AND MAIN RESULTS Two groups were formed on the basis of 22q11.2 deletion status. Outcomes were postoperative tracheostomy and postoperative gastrostomy. Bivariate analysis and Kaplan-Meier analysis at 150 days postoperatively were performed. There were 4,800 patients, of which 317 (7%) had a code for 22q11.2 deletion. There were no significant differences between groups for age at surgery or sex. Patients with 22q11.2 deletion had significantly higher rates of gastrostomy (18% vs 5%; p < 0.001) and higher rates of tracheostomy (7% vs 1%; p < 0.001); there was no difference for mortality. Kaplan-Meier analyses also showed higher rates of gastrostomy (p = 0.024) and tracheostomy (p = 0.037). CONCLUSIONS The present study establishes rates of postoperative gastrostomy and tracheostomy in children with 22q11.2 deletion after complete repair of tetralogy of Fallot. These data are useful to clinicians for providing families with preoperative counseling.

The phenotypic spectrum of congenital heart defects (CHDs) is contributed by both genetic and environmental factors. Their interactions are profoundly heterogeneous but may operate on common pathways as in the case of hypoxia signaling during postnatal heart development in the context of CHDs. Tetralogy of Fallot (TOF) is the most common cyanotic (hypoxemic) CHD. However, how the hypoxic environment contributes to TOF pathogenesis after birth is poorly understood. We performed Genome-wide transcriptomeanalysis on right ventricle outflow tract (RVOT) specimens from cyanotic and noncyanotic TOF. Co-expression network analysis identified gene modules specifically associated with clinical diagnosis and hypoxemia status in the TOF hearts. In particular, hypoxia-dependent induction of myocyte proliferation is associated with E2F1-mediated cell cycle regulation and repression of the WNT11-RB1 axis. Genes enriched in epithelial mesenchymal transition (EMT), fibrosis, and sarcomere were also repressed in cyanotic TOF patients. Importantly, transcription factor analysis of the hypoxia-regulated modules suggested CREB1 as a putative regulator of hypoxia/WNT11-RB1 circuit. The study providesa high-resolution landscape of transcriptome programming associated with TOF phenotypes and unveiled hypoxia-induced regulatory circuit in cyanotic TOF. Hypoxia-induced cardiomyocyte proliferation involves negative modulation of CREB1 activity upstream of the WNT11-RB1 axis. KEY MESSAGES: Genetic and environmental factors contribute to congenital heart defects (CHDs). How hypoxia contributes to Tetralogyof Fallot (TOF) pathogenesis after birth is unclear. Systems biology-based analysis revealed distinct molecular signature in CHDs. Gene expression modules specifically associated with cyanotic TOF were uncovered. Key regulatory circuits induced by hypoxia in TOF pathogenesis after birth were unveiled.

Chamber-specific and temporally regulated perinatal cardiac growth and maturation is critical for functional adaptation of the heart and may be altered significantly in response to perinatal stress, such as systemic hypoxia (hypoxemia), leading to significant pathology, even mortality. Understanding transcriptome regulation of neonatal heart chambers in response to hypoxemia is necessary to develop chamber-specific therapies for infants with cyanotic congenital heart defects (CHDs). We sought to determine chamber-specific transcriptome programming during hypoxemic perinatal circulatory transition. We performed transcriptome-wide analysis on right ventricle (RV) and left ventricle (LV) of postnatal day 3 (P3) mouse hearts exposed to perinatal hypoxemia. Hypoxemia decreased baseline differences between RV and LV leading to significant attenuation of ventricular patterning (AVP), which involved several molecular pathways, including Wnt signaling suppression and cell cycle induction. Notably, robust changes in RV transcriptome in hypoxemic condition contributed significantly to the AVP. Remarkably, suppression of epithelial mesenchymal transition (EMT) and dysregulation of the TP53 signaling were prominent hallmarks of the AVP genes in neonatal mouse heart. Furthermore, members of the TP53-related gene family were dysregulated in the hypoxemic RVs of neonatal mouse and cyanotic Tetralogy of Fallot hearts. Integrated analysis of chamber-specific transcriptome revealed hypoxemia-specific changes that were more robust in RVs compared with LVs, leading to previously uncharacterized AVP induced by perinatal hypoxemia. Remarkably, reprogramming of EMT process and dysregulation of the TP53 network contributed to transcriptome remodeling of neonatal heart during hypoxemic circulatory transition. These insights may enhance our understanding of hypoxemia-induced pathogenesis in newborn infants with cyanotic CHD phenotypes. KEY MESSAGES: During perinatal circulatory transition, transcriptome programming is a major driving force of cardiac chamber-specific maturation and adaptation to hemodynamic load and external environment. During hypoxemic perinatal transition, transcriptome reprogramming may affect chamber-specific growth and development, particularly in newborns with congenital heart defects (CHDs). Chamber-specific transcriptome changes during hypoxemic perinatal transition are yet to be fully elucidated. Systems-based analysis of hypoxemic neonatal hearts at postnatal day 3 reveals chamber-specific transcriptome signatures during hypoxemic perinatal transition, which involve attenuation of ventricular patterning (AVP) and repression of epithelial mesenchymal transition (EMT). Key regulatory circuits involved in hypoxemia response were identified including suppression of Wnt signaling, induction of cellular proliferation and dysregulation of TP53 network.

Transcatheter valve replacement offers a safe and effective alternative to traditional surgical techniques in patients with congenital heart disease, especially those at high surgical risk. The most common causes of morbidity and mortality in patients with D-transposition of the great arteries status post Senning or Mustard repair is severe tricuspid valve (TV) regurgitation. Replacement of the systemic TV may be useful in those without severe systemic ventricular dysfunction. We present a case of a patient with D-loop transposition of the great arteries status post Mustard repair and TV ring placement with subsequent severe systemic TV regurgitation, at high surgical risk, who underwent a transcatheter valve replacement via a trans-apical approach using an Edwards Sapien XT valve.

We aimed to evaluate the outcomes of systemic-to-pulmonary (SP) shunt procedures utilizing heparin-coated (HC) polytetrafluoroethylene (PTFE) vascular grafts compared to uncoated (non-HC) grafts, in order to observe any benefits in pediatric patients. Our institution switched from using non-HC grafts to HC grafts in March 2011. We conducted a retrospective review of consecutive pediatric patients receiving SP shunts from May 2008 to December 2015. Perioperative variables including baseline characteristics, morbidity, mortality, and blood product utilization were evaluated between the HC and non-HC groups. A total of 142 pediatric patients received SP shunts during the study period: 69 patients received HC shunts and 73 patients received non-HC shunts. The HC group had significantly fewer desaturation or arrest events (P

Pulmonary vein obstruction after surgical repair of total anomalous pulmonary venous return is a known complication with particularly poor prognosis. A female infant developed left pulmonary vein atresia after obstructed supracardiac total anomalous pulmonary venous return repair. Over the first decade of life, a large venous collateral vessel draining the left pulmonary veins to the paraspinal venous plexus developed, enabling growth of the left pulmonary vasculature to low normal size and resulting in mild right heart dilatation from left-to-right shunting. Multimodality diagnostic imaging, including echocardiography, cardiac catheterization, cardiac CT, and 3D cardiac modeling aided in diagnosis and planning surgical correction of the left pulmonary venous drainage back to the left atrium. Unexpected right heart enlargement and growth of a branch pulmonary artery in the presence of ipsilateral pulmonary vein atresia following total anomalous pulmonary venous return repair should prompt further diagnostic investigation. In this case, the evaluation ultimately enabled surgical repair of this unique venous connection.

Bleeding and thrombotic events remain a significant cause of morbidity in pediatric patients supported with ventricular assist devices (VADs). The objective of this study is to identify the association between markers of anticoagulation and bleeding and thrombosis events during Berlin Heart ExCor support. A retrospective, single-center analysis of 9 patients supported with the Berlin Heart ExCor was performed. Inflammatory and anticoagulation parameters including C-reactive protein, fibrinogen, partial thromboplastin time (PTT), and platelet count were measured at 48 and 24 h before and after bleeding or thrombosis events. Patients served as their own controls, and the same parameters were measured during a control period where subjects did not experience either event. All patients received the anticoagulation regimen proposed by Berlin Heart. A total of 31 bleeding or thrombotic events were identified and matched to 18 control events. Patient with predominantly thrombotic events tended to weigh less than those with bleeding events (Δ7.7 kg, p

Objectives: To evaluate the impact of regional cerebral perfusion (RCP) during heart operation on outcomes in neonates undergoing Norwood operation. Methods: We performed a retrospective cohort study using data from the Single Ventricle Reconstruction trial data set. The adjusted effect of RCP use on each outcome was studied using a penalized logistic regression model with bootstrap validation. Results: Of 549 patients included in the study, 252 patients (45.9%) received RCP during their heart operation. In univariate comparisons, the majority of the baseline characteristics and preoperative risk factors were similar in the RCP and No RCP group. The total cardiopulmonary bypass (CPB) time and the total cross-clamp (CC) time were longer in the RCP group (RCP vs No RCP, median CPB time: 161 minutes vs 109 minutes; median CC time: 63 minutes vs 43 minutes). In adjusted models, the use of RCP was not associated with decreased mortality and/or need for heart transplant at hospital discharge (odds ratio [OR]: 0.73; 95% confidence interval [CI]: 0.43-1.25) or prolonged mechanical ventilation (OR: 1.20, 95% CI: 0.62-2.28) or prolonged hospital length of stay (OR: 1.30, 95% CI: 0.73-2.30). We demonstrated that use of RCP was associated with longer CPB times, increased use of ultrafiltration, and higher probability of open chest after Norwood operation. Conclusions: This study did not demonstrate any impact of RCP on in-hospital mortality and/or heart transplantation, prolonged mechanical ventilation, and prolonged hospital length of stay among neonates undergoing Norwood operation.

Introduction Transplantation is the definitive treatment of choice for congenital heart disease not amenable to further surgical repair. Many patients present with complex surgical histories, thus implantation of an orthotopic heart is challenging and preoperative planning imperative. We present a novel cardiectomy technique followed by a bi-atrial to bi-ventricular anastomoses Case Report To avoid taking down the calcified venous baffles, we performed a cardiectomy similar to that for a total artificial heart. An incision was made on the ventricular side of the right ventricular AV groove, which was extended anteriorly across the right ventricular outflow tract just proximal to the pulmonary valve. Posteriorly this was extended across the interventricular septum onto the left ventricular side of the AV groove leaving some residual anterior mitral leaflet and aortic valve tissue in situ. The atrial cuff consisted of approximately 1cm of residual muscle. The donor heart was prepared so that the atria would be anastomosed at the level of the corresponding AV groove. CPB, cross-clamp and ischemic time were 194, 99 and 218 minutes respectively. Post-operative ECHO showed excellent biventricular function, no evidence of mitral valve stenosis or insufficiency, and only mild tricuspid valve insufficiency. Summary This complex case demonstrates the critical need to carefully delineate the technical strategy to adequately plan for complex recipient anatomy in congenital heart patients undergoing transplantation. Utilizing advanced imaging modalities in coordination with pre-operative surgical planning is paramount to successful outcomes of novel transplantation techniques.

Purpose To summarize our single-center safety experience with the off-label use of ferumoxytol for magnetic resonance imaging (MRI) and to compare the effects of ferumoxytol on monitored physiologic indices in patients under anesthesia with those of gadofosveset trisodium. Materials and Methods Consecutive patients who underwent ferumoxytol-enhanced (FE) MRI exams were included. Adverse events (AEs) were classified according to the Common Terminology Criteria for Adverse Events v4.0. In a subgroup of patients examined under general anesthesia, recording of blood pressure, heart rate, oxygen saturation, and end-tidal CO2 was performed. A comparable group of 23 patients who underwent gadofosveset-enhanced (GE) MRI under anesthesia with similar monitoring was also analyzed. Results In all, 217 unique patients, ages 3 days to 94 years, underwent FE-MRI. No ferumoxytol-related severe, life-threatening, or fatal AEs occurred acutely or at follow-up. Two patients developed ferumoxytol-related nausea. Between-group (FE- vs. GE-MRI) comparisons showed no statistical difference in heart rate (P = 0.69, 95% confidence interval [CI] 96–113 bpm), mean arterial blood pressure (MAP) (P = 0.74, 95% CI 44–52 mmHg), oxygen saturation (P = 0.76, 95% CI 94–98%), and end-tidal CO2 (P = 0.73, 95% CI 31–37 mmHg). No significant change in MAP (P = 0.12, 95% CI 50–58 mmHg) or heart rate (P = 0.25, 95% CI 91–105 bpm) was noted between slow infusion of ferumoxytol (n = 113) vs. bolus injection (n = 104). Conclusion In our single-center experience, no serious AEs occurred with the diagnostic use of ferumoxytol across a wide spectrum of age, renal function, and indications. Because of the limited sample size, firm conclusions cannot be drawn about the generalizability of our results. Thus, vigilance and monitoring are recommended to mitigate potential rare adverse reactions. Level of Evidence: 2 J. Magn. Reson. Imaging 2017;45:804–812.

Background CorMatrix is a decellularized porcine small intestinal submucosa extracellular matrix that has gained attention as a promising alternative to current materials used in cardiac repair. While animal models demonstrate integration of CorMatrix material with host tissue, the histologic characteristics of CorMatrix used in humans are less well-characterized. In this retrospective study, we report our experience with CorMatrix material used in pediatric congenital heart surgery and describe the histology of CorMatrix material and of surrounding native tissue in explanted specimens. Methods Records were reviewed of all pediatric patients implanted with CorMatrix from a single institution (2011–2014). Histologic examinations were performed on CorMatrix and other tissues removed. Explanted samples of CorMatrix and adherent tissues were evaluated for inflammation (acute and chronic), fibrosis, necrosis, degenerative changes, eosinophil response, foreign-body giant cell reaction, neovascularization, and calcification of tissues on a semiquantitative basis (0, none; 1, mild; 2, moderate; 3, marked). Presence of degeneration within CorMatrix and necrosis of surrounding tissue were noted. Results CorMatrix was utilized in 532 pediatric heart reconstruction procedures since 2011. Twelve explanted CorMatrix specimens from 11 pediatric patients including 4 valves (2 mitral and 2 aortic) and 8 outflow/septal/conduit patches were identified and evaluated. Six cases (5 patients) demonstrated clinical evidence of graft failure prior to surgery ( n = 6, 1%). Chronic inflammation was seen in adjacent native tissue in 11/12 cases and consisted predominantly of a mixed population of lymphocytes, macrophages, and plasma cells. Acute inflammation was seen in three cases (3/12). Fibrosis of the surrounding native tissue was seen in all CorMatrix specimens. Eosinophils were present in 6/12 cases. Calcification in surrounding tissue was present in 3/12 cases. Giant cell reaction in adjacent native tissue was seen in 8/12 cases. Neovascularization was seen in surrounding native tissue in 5/12 cases. Degeneration of CorMatrix material was seen in 9/12 cases. Necrosis of surrounding tissue was also identified in 5/12 cases. CorMatrix was not resorbed and no cases demonstrated any remodeling of CorMatrix material by integration of native mesenchymal cells or myocytes. Conclusion CorMatrix may be associated with a marked inflammatory response, including a foreign-body giant cell reaction and fibrosis of the surrounding native tissue. Degenerative changes of CorMatrix material are also seen in a majority of explanted specimens. No histologic differences were seen between patients with clinical evidence of graft failure versus patients requiring graft removal due to other factors. Additionally, no cases showed evidence of tissue integration or recellularization of patch material. Our overall clinical experience with CorMatrix demonstrates a favorable outcome for pediatric patients undergoing cardiac reconstructive surgery. However, there is no histologic evidence that CorMatrix acts as a scaffold for reconstitution of the native cardiovascular structures.

ObjectiveComparative ventricular arrhythmia (VA) outcomes following transcatheter (TC-PVR) or surgical pulmonary valve replacement (S-PVR) have not been evaluated. We sought to compare differences in VAs among patients with congenital heart disease (CHD) following TC-PVR or S-PVR.MethodsPatients with repaired CHD who underwent TC-PVR or S-PVR at the UCLA Medical Center from 2010 to 2016 were analysed retrospectively. Patients who underwent hybrid TC-PVR or had a diagnosis of congenitally corrected transposition of the great arteries were excluded. Patients were screened for a composite of non-intraoperative VA (the primary outcome variable), defined as symptomatic/recurrent non-sustained ventricular tachycardia (VT) requiring therapy, sustained VT or ventricular fibrillation. VA epochs were classified as 0–1 month (short-term), 1–12 months (mid-term) and ≥1 year (late-term).ResultsThree hundred and two patients (TC-PVR, n=172 and S-PVR, n=130) were included. TC-PVR relative to S-PVR was associated with fewer clinically significant VAs in the first 30 days after valve implant (adjusted HR 0.20, p=0.002), but similar mid-term and late-term risks (adjusted HR 0.72, p=0.62 and adjusted HR 0.47, p=0.26, respectively). In propensity-adjusted models, S-PVR, patient age at PVR and native right ventricular outflow tract (RVOT) (vs bioprosthetic/conduit outflow tract) were independent predictors of early VA after pulmonary valve implantation (pConclusionCompared with S-PVR, TC-PVR was associated with reduced short-term but comparable mid-term and late-term VA burdens. Risk factors for VA after PVR included a surgical approach, valve implantation into a native RVOT and older age at PVR.

Ventricular chamber growth and development during perinatal circulatory transition is critical for functional adaptation of the heart. However, the chamber-specific programs of neonatal heart growth are poorly understood. We used integrated systems genomic and functional biology analyses of the perinatal chamber specific transcriptome and we identified Wnt11 as a prominent regulator of chamber-specific proliferation. Importantly, downregulation of Wnt11 expression was associated with cyanotic congenital heart defect (CHD) phenotypes and correlated with O2 saturation levels in hypoxemic infants with Tetralogy of Fallot (TOF). Perinatal hypoxia treatment in mice suppressed Wnt11 expression and induced myocyte proliferation more robustly in the right ventricle, modulating Rb1 protein activity. Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse hearts and reduced Rb1 protein and phosphorylation in neonatal cardiomyocytes. Finally, downregulated Wnt11 in hypoxemic TOF infantile hearts was associated with Rb1 suppression and induction of proliferation markers. This study revealed a previously uncharacterized function of Wnt11-mediated signaling as an important player in programming the chamber-specific growth of the neonatal heart. This function influences the chamber-specific development and pathogenesis in response to hypoxia and cyanotic CHDs. Defining the underlying regulatory mechanism may yield chamber-specific therapies for infants born with CHDs.

Background: Fetal to neonatal transition of heart involves major changes in cardiomyocytes (CMC) including proliferative capacity. However, the chamber specific CMC proliferation programs of remain poorly understood. Elucidating the mechanisms involved is critical to develop chamber specific therapies for newborn infants with single ventricle physiology and other congenital heart defects (CHDs). Methods: Transcriptomes of mouse left ventricle (LV) and right ventricle (RV) were analyzed by RNA-seq at postnatal days 0 (P0), P3 and P7. R package and Ingenuity suite were used for weighted gene co-expression network analysis (WGCNA) and gene ontology studies. Mechanistic analysis was conducted using gain and loss of function approaches. Results: Mouse neonatal cardiac transcriptome was mostly affected by developmental stage. WGCNA revealed 5 LV and 8 RV modules that were significantly correlated with maturation stage and highly preserved between both ventricles at P0 and P7. In contrast, P3 specific gene modules exhibited the largest chamber specific variations in cell signaling, involving proliferation in LV and Wnt signaling molecules, including Wnt11, in RV. Importantly, Wnt11 expression significantly decreased in cyanotic CHDs phenotypes and correlated with O2 saturation levels in hypoxemic infants with Tetralogy of Fallot (TOF). Notably, Perinatal hypoxia treatment in mice suppressed Wnt11 expression, induced CMC proliferation, downregulated Rb1 expression and enhanced Rb1 phosphorylation more robustly in RV vs. LV. Remarkably, Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse heart and reduced Rb1 expression and phosphorylation in primary neonatal CMC. Importantly, downregulated Wnt11 in hypoxemic TOF infantile heart was also associated with Rb1 suppression and inversely correlated with proliferation marker Plk1 in human. Conclusion: Using integrated systems genomic and functional biology analyses of perinatal cardiac transcriptome, we revealed a previously uncharacterized function for Wnt11 in chamber specific growth and cyanotic CHD. Reduction of Wnt11 expression by hypoxia plays a critical role in neonatal CMC proliferation via modulating Rb1 expression and activity.

Objective: Since April 2010, our institution has repaired complete atrioventricular septal defects (CAVSDs) with a two-patch technique utilizing CorMatrix extracellular material. This material is potentially an attractive patch because of its theorized eventual integration with the host tissue. We sought to analyze initial outcomes of CAVSD repair with CorMatrix. Methods: Data were collected on consecutive pediatric (age Results: Fifteen patients were identified. The average age at operation was 205 days, with mean follow-up time at 1,364 days. Echocardiograms revealed the following: 12 (80%) patients showed either improved or stable left AV valve performance remaining at “mild” or less insufficiency, while two (13%) declined from “none” to mild and one (7%) from mild to “severe,” which required reoperation. There was no residual shunting or LVOT obstruction at follow-up. The single (7%) reoperation was performed after three years due to left AV valve zone of apposition dehiscence. No permanent pacemakers were needed, and no deaths were reported. Conclusion: Our initial experience with CorMatrix in the repair of CAVSD in children has resulted in good initial and midterm outcomes. The CorMatrix patch remained stable through midterm follow-up, thus may be efficacious for use in CAVSD repair.

Extracellular matrices (ECM) are commonly used to repair congenital heart defects; however, there is a lack of literature pertaining to outcomes with ECM use in high-pressure conditions. Between 2011 and 2014, a total of 202 patients underwent congenital heart disease repair using the ECM placed in a systemic pressure condition. The operative sites included: defects in the ventricular septum, mitral valve, aortic valve, ascending aorta, and aortic arch. Patients were followed and evaluated for mortality and reoperations due to loss of ECM integrity. Echocardiograms were evaluated for graft malfunction such as aneurysmal dilation, VSD formation, valve malfunction, or outflow tract obstruction. Patients were followed for an average of 1492 days (Median = 1583). Out of the 202 patients, 7 (3.5%) died due to complications unrelated to ECM, and 10 (5%) underwent reoperations due to complications of ECM integrity. Reoperations were as follows: two of 6 patients receiving aortic leaflet replacement required reoperation for leaflet failure; four of 12 patients receiving mitral valve leaflet repairs required reoperation for leaflet failure; and four of 142 patients with VSD repair required reoperation for residual shunting. The average time to reoperation was 208 days. There were no outflow tract obstructions or aneurysmal dilatations observed. This modern case series suggests that the ECM is efficacious and sustainable under systemic conditions in congenital heart defect repair. However, concerns remain about the use of ECM in aortic valve repair and infant mitral valve repair. Further studies are needed to evaluate long-term ECM integrity.

Objectives To provide a comparison of the outcome of infective endocarditis (IE) in patients undergoing transcatheter pulmonary valve replacement (TPVR) versus surgical pulmonary valve replacement (SPVR). Background Although TPVR is thought to be associated with a higher risk of IE than SPVR, there is paucity of data to support this. Methods Patients who underwent TPVR or SPVR at UCLA between October 2010 and September 2016 were included and retrospectively analyzed. Results Three hundred forty-two patients underwent PVR at UCLA including 134 SPVR and 208 TPVR. Patients undergoing TPVR were more likely to have had a history of endocarditis than those undergoing SPVR (5.3% vs. 0.7%, P = 0.03) and a right ventricle to pulmonary artery (RV to PA) conduit (37% vs. 17%, P = 0.0001). Two SPVR and seven TPVR patients developed IE with a 4-year freedom from endocarditis of 94.0% in the SPVR versus 84% in the TPVR group (P = 0.13). In patients who underwent TPVR and developed endocarditis, the mean gradient across the RVOT prior to intervention was higher (28.1 ± 4.5 vs. 17.4 ± 0.6 mmHg, P = 0.02) and were more likely to have a conduit (71% vs. 36%, P = 0.049). Conclusions In this study, patients undergoing TPVR were not at a higher risk of IE than patients undergoing SPVR. TPVR patients were more likely to have had a prior history of IE and RV-PA conduit. The patients at highest risk were those with stenotic RV to PA conduits who were treated with TPVR.

Absent pulmonary valve is a rare and severe variant seen in only 3% to 6% of patients with tetralogy of Fallot. Fetuses with this combined condition who survive through birth typically need intervention in infancy or early childhood because of respiratory distress, heart failure, or failure to thrive. We describe the unusual case of a mildly symptomatic 16-year-old boy with these conditions who underwent successful primary repair. Our search of the medical literature yielded fewer than 5 cases of tetralogy of Fallot with absent pulmonary valve (or variants with an absent left pulmonary artery) and survival without repair into later adolescence or adulthood.

Bicuspidity of both the semilunar valves is rarely reported. We report the first ever case of bilateral bicuspid semilunar valves in a case of transposition.

Background— Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects. Transcriptome programming during perinatal stages is an important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated. Methods and Results— From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45 167 unique transcripts were identified, including 21 916 known and 2033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene co-expression network analysis of mRNA and lncRNA data sets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while few lncRNAs revealed chamber-specific patterns. Out of 2262 lncRNAs located within 50 kb of protein coding genes, 5% significantly correlate with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. This concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated congenital heart defect phenotypes. Conclusions— The study provides the first high-resolution landscape on neonatal cardiac lncRNAs and reveals their potential interaction with mRNA transcriptome during cardiac maturation. Ppp1r1b-lncRNA was identified as a regulator of Tcap expression, with dynamic interaction in postnatal cardiac development and congenital heart defects.

The effects of obesity on venoarterial extracorporeal membrane oxygenation (VA-ECMO) outcomes in pediatric population are unknown. We performed retrospective analysis of 41 children (age 2–18 years) undergoing VA-ECMO. The percentage difference between actual body weight and lean body weight, referred to as Δmass, was calculated. Ratios of Δmass to ECMO flow were calculated at 4 and 24 hours. In patients with Δmass:flow ≥ 0.1 at 4 hours, higher 24-hour lactates (20.0 vs. 14.5 mg/dL; p = 0.002) and inotrope scores (17.3 vs. 11.2; p = 0.015) were observed. However, elevated Δmass:flow was not associated with mortality, and in-hospital mortality rates between groups were similar (53 vs. 45%; p = 0.647). In obese pediatric patients requiring VA-ECMO, increased flow is necessary to avoid complications of hypoperfusion and related complications.

Objective: Seven public and private California cardiac centers have joined to form the first statewide consortium created to improve the quality and value of congenital cardiac care. The overall goals of the consortium are: 1) to understand variation in modifiable perioperative processes of care among participating hospitals, and 2) to determine whether standardization of those process measures will reduce adverse events and cost. In this pilot study, preoperative management of neonates undergoing arterial switch operation (ASO) within one center was analyzed for variation and these process measures were then associated with increased inpatient costs and length of stay. Methods: Through retrospective analysis of neonates undergoing ASO for Transposition of the Great Arteries with Intact Ventricular Septum (TGA/IVS) (n=34) at one center between 2004-2014, variation within the following preoperative process measures was described: feeding protocols, ventilation management, use of balloon atrial septostomy (BAS) and prostaglandin, and timing of surgery. Independent review by echocardiologists (SS, SP, AMG) confirmed preoperative and discharge diagnoses. Risk factors for increased total hospital length of stay (TLOS), postoperative length of stay (PLOS) and inpatient hospital costs were analyzed by univariable linear regression. Results: The population (N=34) was predominantly male (80%, 27/34) with low overall prenatal diagnosis rate (27%, 9/34). Birth weight was 3295±521 grams and gestational age (GA) was 39.1±1.4 weeks. Variation was found in duration of preoperative hospital stay (7.1±3.7 days), proportion of preoperative stay spent in the Cardiac ICU (0.58±0.35), use of BAS (53%, 18/34), preoperative enteral feeding (50%, 17/34) and preoperative extubation (24%, 8/34). Increased birth weight was negatively associated with costs (p=0.01), TLOS (p=0.14) and PLOS (p=0.02). Delayed timing of surgery was positively associated with TLOS (p=0.0004) and total costs (p=0.01) but not PLOS (p=0.93). Preoperative Cardiac ICU management trended towards negative association with total costs (p=0.20) but not TLOS (p=0.35) or PLOS (p=0.99) when compared with preoperative Neonatal ICU management. Lower GA, preoperative BAS, preoperative enteral feeding and preoperative extubation were not significantly associated with increased costs, TLOS, and PLOS. Conclusions: Variations in preoperative management of neonates undergoing ASO for TGA/IVS are significantly associated with total healthcare costs and hospital LOS. Concatenated data from the remaining consortium members will be critical to validate these findings and to power morbidity and mortality analysis. Integrated findings will allow the consortium to develop and implement consensus based recommendations regarding standardization of those process measures that will reduce major complications and cost.

Background Although transbronchial biopsy (TBB) is the definitive method for diagnosing graft dysfunction after pediatric lung transplantation, concern over procedural complications has limited its use. We reviewed our institutional experience with clinically indicated TBB to determine its safety and efficacy with emphasis on how biopsy findings altered management. Methods A retrospective chart review was done of 61 pediatric lung transplantation patients undergoing 179 TBB procedures. Data were collected on pre-TBB symptoms, pulmonary function testing, and imaging studies. The prebiopsy diagnosis was noted and compared with the findings from TBB to see how frequently treatment changed after biopsy. Results Age at TBB ranged from 2 months to 20 years, with an average of 3 biopsies per patient. There was no procedure-related mortality. The incidence of complications was 9% and included important bleeding with spontaneous resolution in 6% and pneumothorax in 3%. The usual indication for TBB was a change in the chest roentgenogram, frequently accompanied by a decrease in flows on spirometry. The TBB specimens were adequate for pathologic analysis 92% of the time, and a specific pathologic diagnosis could be made in 54% of cases. The findings from TBB altered the clinical management of the patient 64% of the time. Conclusions In pediatric lung transplant recipients presenting with graft dysfunction, TBB is a low-risk diagnostic procedure that yields clinically useful information in a majority of cases. In our experience, the findings from TBB altered medical treatment in 64% of patients. Treatment was most often changed in the group diagnosed with rejection as the probable cause of graft dysfunction.

Objective Phrenic nerve injury resulting in hemidiaphragm paresis leads to morbidity in children undergoing repair of congenital heart defects. Previous studies have documented short-term benefits of diaphragm plication, but little is known about the return of diaphragm function. Methods We reviewed 46 consecutive patients undergoing hemidiaphragm plication after repair of congenital heart defects. The function of plicated diaphragms was measured at follow-up fluoroscopy using excursion of the unplicated side as a control. Results The median age at the procedure resulting in phrenic nerve injury was 6.4 months (0–62 months). Among the 46 patients, 29 (63%) and 17 (37%) had repair for single and 2-ventricle defects, respectively. Hemidiaphragm paresis occurred on the left side in 32 patients (70%). Phrenic nerve injury was documented at a median of 8 days (1–84 days) after operation. The median time from diagnosis to plication was 2 days (0–21 days). Five patients required prolonged ventilation after plication. One patient died 10 weeks later, and 4 patients required tracheostomy. The remaining 41 patients were extubated within 2 days (0–19 days). In 17 patients, fluoroscopy assessing diaphragm motion was performed at a mean interval of 16.4 months after plication. Excursion of the plicated diaphragm was 77% of the contralateral side. There was a trend toward improved function over time. Conclusions Hemidiaphragm paresis results in significant morbidity after repair of congenital heart defects. Early diagnosis and plication result in timely extubation. The plicated diaphragm demonstrates return of function that may improve over time. This is the first study to numerically quantitate the degree of diaphragm recovery.

Ebstein’s anomaly is characterized by malformation of the tricuspid valve, right ventricle, and right atrium. On the whole, Ebstein’s anomaly is rare, occurring in 1:200,000 live births. Manifestation of the spectrum of malformation can be from the asymptomatic patient to the neonate in extremis on maximal support. Severely symptomatic neonates generally present with a “wall-to-wall” heart on chest radiograph due to massive right atrial and atrialized right ventricular dilation. Such neonates generally have variable amounts of right ventricular outflow tract obstruction with a high incidence of anatomic or physiologic pulmonary atresia. They require intensive preoperative support for biventricular failure. Preoperative treatment consists of mechanical ventilation, prostaglandin therapy, and moderate- to highdose inotropic support. Historically, neonatal intervention for this anomaly was unsuccessful, generally resulting in mortality. In 1987, Starnes and coworkers first successfully used a single ventricle approach to palliate the severely symptomatic neonate with Ebstein’s anomaly. 1 This approach involved exclusion of the malformed right ventricle with a glutaraldehyde-fixed autologous pericardial patch sewn at the “anatomic” level of the tricuspid valve annulus. Pulmonary blood flow was provided by a systemic to pulmonary artery shunt. Over time, this procedure evolved to include a fenestration in the pericardial patch. The evolution of the right ventricular exclusion has focused on decompression of the malformed right ventricle. Maneuvers such as keeping the coronary sinus on the atrial side of the patch and interrupting any pulmonary insufficiency are paramount to effective decompression of the excluded right ventricle. It appears that effective decompression of the abnormal right ventricle has a significant effect on the systemic left ventricle as well. Following right ventricular exclusion, we have noted that the septal impingement that occurs in these massively dilated hearts is ameliorated and that the systemic ventricle returns to the globular shape seen in the normal heart. This ventriculo–ventricular interaction is the reason that simply providing pulmonary blood flow alone has no significant effect on the patient survival. The goals of this procedure are as follows: to exclude and decompress the malformed right ventricle; to assure an uninterrupted atrial communication; to perform a reduction atrioplasty; and to provide pulmonary blood flow via a systemic to pulmonary shunt.

Objectives Neonates with Ebstein anomaly can have severe left ventricular dysfunction caused by right ventricular enlargement and ventricular septal displacement. Fenestrated right ventricular exclusion and Blalock–Taussig shunt (Starnes procedure) have been performed to mitigate this problem; however, the fate of the excluded ventricle and its effect on the systemic ventricle have yet to be documented. Methods Intermediate-term data have been retrospectively collected on the 12 survivors of neonatal right ventricular exclusion. Echocardiographic examinations were compared from the time of the original right ventricular exclusion and before second-stage Glenn palliation. Measurement of the Great Ormond Street ratio (area of right atrium plus atrialized right ventricle divided by area of trabeculated right ventricle plus left atrium and left ventricle), ratio of right ventricular to left ventricular area, degree of ventricular septal impingement into the left ventricle, and left ventricular shortening fraction have been documented. Results In the 12 survivors of right ventricular exclusion, a decrease in the mean Great Ormond Street ratio was observed (before fenestrated right ventricular exclusion: 1.04 ± 0.49 vs before Glenn palliation: 0.31 ± 0.10, P = .01). The average pre-Glenn right ventricular/left ventricular ratio was substantially less than 1.0 (mean, 0.63 ± 0.27), demonstrating right ventricular regression. The degree of left ventricular septal impingement decreased by an average of 38% ( P = .008), normalizing left ventricular morphology. At the time of Glenn palliation, the left ventricular shortening fraction was normal in all patients (mean, 42% ± 7%). Conclusions After neonatal right ventricular exclusion (Starnes procedure) for severe Ebstein anomaly, there is a reduction in right ventricular size, as demonstrated by echocardiographic evidence of a significant decrease in Great Ormond Street ratios. This regression correlates with ventricular septal realignment and normalization of left ventricular function.

Purpose of review Advancements in surgical technique and perioperative care have significantly improved the survival of infants born with hypoplastic left heart syndrome. A recent modification to the Norwood procedure is being adopted by many centers to improve postoperative hemodynamic stability and survival to stage II palliation. The late effects of this modification, however, are speculated and have not been investigated. Recent findings Center-specific improved short-term outcomes have been reported in a few small, nonrandomized studies of a new approach to the Norwood procedure, which utilizes a right ventricle to pulmonary artery shunt or Sano modification to provide pulmonary blood flow rather than the standard modified Blalock-Taussig shunt. Summary The classic Norwood procedure and Sano modification each have specific advantages and disadvantages in both the short and long term. Data comparing the two techniques are nonrandomized, contradictory, and utilize historical controls. The optimal shunt to improve survival to the second-stage palliation is unknown. A multicenter randomized clinical trial comparing the Sano with the modified Blalock-Taussig shunt in hypoplastic left heart syndrome or variants is currently in progress and should hopefully provide future guidelines for shunt selection based on clinical presentation.

Background: Fetal to neonatal transition of heart is an elaborate process, during which, neonatal cardiomyocytes undergo functional maturation and terminal exit from the cell cycle. However, transcriptome programming in neonatal cardiac chambers during perinatal stages is understudied. In particular, the changes in long non-coding RNAs (lncRNAs) in neonatal heart have not been explored. Objective: To achieve transcriptome-wide analysis of lncRNAs in neonatal left ventricle (LV) and right ventricle (RV) during maturation stages using deep RNA-Sequencing Methods: Deep RNA-sequencing was performed on male newborn mouse (C57 BL) LV and RV at 3 time points of perinatal circulatory transition: P0, P3 and P7. Reads were mapped to mouse genome (mm10). The lncRNAs annotated in NONCODE database were identified. Differentially expressed lncRNAs were defined as those with coefficient of variation ≥0.2, at a false discovery rate ≤0.05, and expressed at ≥3 RPKM in at least one sample. Correlated lncRNAs/ gene pairs were identified using Pearson’s (r2≥0.8, P≤0.05). A subset of LncRNAs/gene expression was validated using qRT-PCR. Results: Out of the 70, 983 observed unique lncRNAs, approximately 7000 were identified exhibiting significant variation during maturation windows with highly spatial-temporal dependent expression patterns, including approximately 5000 known and 2000 novel lncRNAs. Notably, 20% of these lncRNAs were located within 50 KB of a protein coding gene. Out of a total of 2400 lncRNAs/gene pairs, 10 % exhibited significantly concordant (lncRNA/gene) expression patterns. These correlated genes were significantly enriched in metabolism, cell cycle and contractility functional ontology. Interestingly, some of these lncRNAs exhibited concordance with their neighboring gene in human tissues with congenital heart defects, suggesting conserved, potentially significant, regulatory function. Conclusions: Transcriptome programming during neonatal heart maturation involves global changes in lncRNAs. Their expression concordance with neighboring protein coding genes implicates potential important regulatory role of lncRNAs in neonatal heart chamber specification and congenital diseases.

Background: Chamber-specific and temporally orchestrated perinatal cardiac growth and maturation is critical to functional adaptation of heart to the dramatic changes in hemodynamic load and nutrient environment, and perturbation of this process may have major implications in congenital heart defects (CHDs). However, the responsible molecular regulatory mechanisms are still poorly understood. Objective: To determine the factors that control chamber specificity of neonatal heart growth during perinatal maturation Methods: Total transcriptome was analyzed from deep RNA-seq in male newborn mouse (C57BL) left ventricle (LV) and right ventricle (RV) at postnatal day 0, 3 and 7. Functional validation was performed in Neonatal Rat Ventricular Myocytes (NRVMs) and intact neonatal mice. Results: Chamber specific- regulation of cell cycle genes was correlated with chamber specific- expression of the non-canonical Wnt11. Exogenous expression of Wnt11 induced maturation markers and suppressed cell cycle genes in myocytes. In contrast, targeted Wnt11 inhibition induced myocyte proliferation associated with upregulated cell cycle genes both in cultured NRVMs and in the intact heart. Notably, Wnt inhibition also significantly enhanced β-catenin phosphorylation without impacting JNK, PKCα, or p38- activities. Remarkably, both Wnt mediated signals and cell cycle markers were altered in heart samples from infants cyanotic CHDs. Furthermore, hypoxia exposure suppressed Wnt11 and induced cell cycle genes in cultured cardiomyocytes. Conclusions: Differential expression of Wnt11 and downstream cell cycle genes are novel molecular basis for chamber specific maturation. Wnt11 mediated-signaling has potential impact on cyanotic CHDs. Differential role of Wnt signaling in chamber specific post-natal heart maturation can lead to potential chamber-specific diagnoses and therapies for congenital heart diseases.

Fibroblast growth factor-23 (FGF23) levels are elevated in cardiopulmonary bypass (CPB)-associated acute kidney injury (AKI); however, it is unknown how much of the circulating FGF23 is intact and bioactive. Hypoxia may induce FGF23 production, yet its impact in humans is unknown. Pediatric cardiac surgery patients have both a high incidence of CPB-associated AKI and a high prevalence of chronic hypoxemia. We assessed the effects of hypoxemia and CPB-associated AKI on C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 32 pediatric cardiac surgery patients with normal estimated glomerular filtration rate (eGFR). Plasma cFGF23 and iFGF23 were measured preoperatively and serially postoperatively. Despite normal renal and ventricular function, preoperative cFGF23 levels were high and elevated out of proportion to iFGF23 levels. Preoperative oxygen saturation measurements correlated inversely with FGF23 levels. Preoperative cFGF23 and oxygen saturation both predicted postoperative AKI. Postoperatively, cFGF23 and iFGF23 increased by 2 h postreperfusion; iFGF23 then returned to baseline, but cFGF23 remained elevated through 24 h postreperfusion. Group status (AKI vs. non-AKI) modified the effect of time on changes in iFGF23 levels but not cFGF23 levels. Preoperative cFGF23 may predict CPB-associated kidney dysfunction. Changes over time in cFGF23 and iFGF23 levels post-CPB differ. Chronic hypoxemia may affect FGF23 production in humans.

Heparin-induced thrombocytopenia presents a challenge for anticoagulation techniques during cardiac surgery and ventricular assist device implantation. Bivalirudin is currently recommended for use during cardiopulmonary bypass for patients with heparin-induced thrombocytopenia but requires the use of special techniques to avoid blood stagnation. We report the successful use of bivalirudin during cardiopulmonary bypass for implantation of the Total Artificial Heart with late operative bleeding likely resulting from heavy cell saver use.

Background Neonates with complex congenital heart disease (CCHD) often require transcatheter or surgical intervention in the first month of life. Transthoracic 2D/Doppler echocardiography (2DE) is the diagnostic modality of choice, but occasionally may be inadequate for surgical planning. Unresolved pre-operative questions may require complete delineation of extracardiac vascular anatomy and/or ventricular volumes. In these cases, cardiac magnetic resonance imaging and angiography (CMR/MRA) may be delayed in favor of repeat 2DE studies, which often remain inconclusive. This approach may lead to unnecessary costs and has yet to be formally evaluated.

Background. We have shown that treatment with molecularly engineered, allochimeric [α 1 h l/u ]-RT1.A a class I MHC antigens bearing donor-type Wistar-Furth (WF, RT1.A u ) amino acid substitutions for host-type ACI (RTI.A a ) sequences in the α 1 -helical region induces donor-specific tolerance to cardiac allografts in rat recipients. This study examined the effect of allochimeric molecules on the development of chronic rejection. Methods. Allochimeric [α 1 h l/u ]-RT1.A a class I MHC antigenic extracts (1 mg) were administered via the portal vein into ACI recipients of WF hearts on the day of transplantation in conjunction with subtherapeutic oral cyclosporine (CsA, 10 mg/kg/day, days 0-2). Control groups included recipients of syngeneic grafts and ACI recipients of WF heart allografts treated with high-dose CsA (10 mg/kg/day, days 0-6). Results. WF hearts in ACI rats receiving 7 days of CsA exhibited myocardial fibrosis, perivascular inflammation, and intimal hyperplasia at day 80. At day 120, these grafts displayed severe chronic rejection with global architectural disorganization, ventricular fibrosis, intimal hyperplasia, and progressive luminal narrowing. In contrast, WF hearts in rats treated with [α 1 h l/u ]-RT1.A a molecules revealed only mild perivascular fibrosis, minimal intimal thickening, and preserved myocardial architecture. Alloantibody analysis demonstrated no IgM alloantibodies in all groups. An attenuated, but detectable, anti-WF IgG response was present in recipients receiving allochimeric molecules, with IgG1 and IgG2a subclasses predominating. Immunohistochemical analysis of allografts demonstrated minimal T cell infiltration and IgG binding to vascular endothelium. Conclusion. Treatment with allochimeric molecules prevents the development of chronic rejection. Such effect may be in part caused by deviation of host alloantibody responses.