Cardiac Transcription Factors and Regulatory Networks.

Cardiac development is a fine-tuned process governed by complex transcriptional networks, in which transcription factors (TFs) interact with other regulatory layers. In this chapter, we introduce the core cardiac TFs including Gata, Hand, Nkx2, Mef2, Srf, and Tbx. These factors regulate each other's expression and can also act in a combinatorial manner on their downstream targets. Their disruption leads to various cardiac phenotypes in mice, and mutations in humans have been associated with congenital heart defects. In the second part of the chapter, we discuss different levels of regulation including cis-regulatory elements, chromatin structure, and microRNAs, which can interact with transcription factors, modulate their function, or are downstream targets. Finally, examples of disturbances of the cardiac regulatory network leading to congenital heart diseases in human are provided.

Staged repair of transposition of the great arteries with anomalous coronary anatomy and complete atrioventricular canal.

The association of complete atrioventricular canal with transposition of the great arteries is rare, with a prevalence of less than 3-5%. We present an 18-month-old patient with a complete atrioventricular canal, side-by-side transposition of the great arteries, and anomalous coronary anatomy, managed initially with pulmonary banding and then by arterial switch with complete atrioventricular canal repair at early infancy.

Clinical Syndromic Phenotypes and the Potential Role of Genetics in Pulmonary Vein Stenosis.

Pulmonary vein stenosis (PVS) is a rare, frequently lethal disease with heterogeneous phenotypes and an unclear etiology. Limited studies have reported associations between PVS and congenital heart disease (CHD), chronic lung disease (CLD), and/or prematurity; however, to date, there have been no studies that report detailed clinical syndromic phenotypes and the potential role of genetics in PVS. An existing registry of multivessel PVS patients seen at Boston Children's Hospital (BCH) was queried between August 2006 and January 2017 for all existing genetic testing data on these patients. PVS was defined as an intraluminal pulmonary venous obstruction in ≥2 vessels with mean pressure gradients > 4 mmHg. One-hundred-and-fifty-seven patients (46% female, with a median age at PVS diagnosis of 3 months) formed the cohort. Seventy-one (45%) patients had available genetic testing information. Of the 71 patients, a likely genetic diagnosis was found in 23 (32%) patients: 13 (57%) were diagnosed with Trisomy 21 (T21), five (22%) with Smith-Lemli-Opitz Syndrome, five (22%) had other pathologic genetic disease, and 24 (33%) had variants of unknown significance. The majority of 13 patients with T21 and PVS had common atrioventricular canal (CAVC) (10, 77%) and all had severe pulmonary hypertension (PHTN), which led to their PVS diagnosis. In our study, PVS was associated with T21, the majority of whom also had CAVC and PHTN. Therefore, complete assessment of the pulmonary veins should be considered for all T21 patients, especially those with CAVC presenting with PHTN. Furthermore, prospective standardized genetic testing with detailed clinical phenotyping may prove informative about potential genetic etiologies of PVS.

Long-term trends in the prevalence of congenital heart defects in patients with Down syndrome in southern Poland.

OBJECTIVE: Introduction: Down syndrome is one of the most common chromosomal abnormalities in humans. Patients have typical dysmorphic features and various congenital malformations. Congenital heart defects were reported as the most common of the latter, occurring in approximately 50% of the cases. The aim: We aimed to analyse the long-term trends in the prevalence of Down syndrome and related heart defects in the population of southern Poland (Krakow region). PATIENTS AND METHODS: Material and methods: We analysed 500 consecutive patients with Down syndrome who were born from 2006 through 2017 and were diagnosed at the Department of Medical Genetics, Jagiellonian University. Next, we compared our results with the data obtained in previous regional studies. RESULTS: Results: The prevalence of Down syndrome in the assessed period was 1.65 per 1,000 live births and was similar to the historical prevalence in our region. Cardiac malformations were detected in 57.6% of the patients and the common atrioventricular canal (CAVC) was the most frequent anomaly (35.1%). However, detailed analysis of the frequency of severe heart defects that usually require prompt surgical treatment in the course of infancy revealed that the percentage of CAVC has been significantly lower in recent years (p=0.033). CONCLUSION: Conclusions: The prevalence of Down syndrome and the overall frequency of congenital heart defects have not significantly changed in recent years. However, the frequency of CAVC has decreased, which could be related to the technical progress in prenatal detection of this severe anomaly, and to the subsequent elective terminations of affected pregnancies. Further population studies are required to confirm the presence of this trend and elucidate its background.

The matter of "unbalance" in right dominant atrioventricular septal defect.

Unbalance in atrioventricular septal defect can be found in more than one anatomic level and in different degrees at each level. The definition of "unbalance" has historically been focused in comparing the dimensions of main cardiac structures, such as the atrioventricular valve and the ventricles. However, the hemodynamic aspects of unbalance need to be considered as having, at least, similar relevance. New concepts and already described parameters must be combined and understood as a whole to help the surgical decision-making process.

Complete atrioventricular canal repair with a decellularized porcine small intestinal submucosa patch.

BACKGROUND: Congenital heart defects affect nearly 1% of all children born per year in the United States, and complete atrioventricular canal (CAVC) accounts for 2%-9%. While several patch materials have been used for septal defect closure during CAVC repair, clear superiority of one material over another has yet to be established. METHODS: A retrospective review of clinical outcomes following CAVC repair at Morgan Stanley Children's Hospital/Columbia University was performed on operations conducted from March 2010 to September 2017. Univariate and Kaplan-Meir survival analyses were utilized to evaluate primary outcomes of interest following CAVC repair in the modern surgical era. RESULTS: A total of 73 patients were analyzed, with an average operative age of 22 weeks. The majority (71%) of the patients underwent a 2-patch repair. A CorMatrix patch was used for ventricular septal defect(VSD) closure in 77% of the patients, and/or in 75% of atrial septal defect closures. There was one in-hospital mortality (1.4%) due to respiratory failure. One patient required a pacemaker. At mid-term follow-up (1.6 years), a total of 7 patients required 8 reoperations due to cardiac-related indications, including 5 for left atrioventricular valve (LAVV) repair, 1 for LAVV replacement, and 2 isolated residual VSDs. CONCLUSION: A standardized repair for CAVC results in excellent outcomes in the current era, with low rates of reoperations. CorMatrix for the closure of CAVC has proven to produce good results with equivalent outcomes to other patch materials. Its ease of use and pliability make it an attractive alternative for consideration.

Cardiac Function After Tetralogy of Fallot/Complete Atrioventricular Canal Repair.

BACKGROUND: Repair of complete atrioventricular canal (CAVC) with tetralogy of Fallot (TOF) is a challenging operation increasingly being performed as a complete, primary repair in infancy. Previous studies have focused on perioperative outcomes; however, midterm valve function, ventricular function, and residual obstruction have received little attention. METHODS: We retrospectively reviewed 20 patients who underwent CAVC/TOF repair (January 2005 to December 2014). A two-patch repair was used in all patients to correct the CAVC defect. Tetralogy of Fallot repair included transannular patch in 11 (65%) patients and valve-sparing in 6 (35%) patients. RESULTS: The average age at surgery was 72 ± 122 weeks, 40% were male, and 80% had trisomy 21. Mean echo follow-up was 3.0 ± 3.0 years. There were no in-hospital or late mortalities. The rate of reoperation was 20%. At the latest follow-up, moderate left atrioventricular valve regurgitation was present in three (15%) patients and mild stenosis present in seven (35%) patients. One (5%) patient had moderate right ventricular outflow tract (RVOT) obstruction. The valve-sparing population was smaller at the time of surgery than the non-valve-sparing cohort (body surface area: 0.28 ± 0.04 vs 0.42 ± 0.11, P = .002) and less likely to have had a previous shunt (0% vs 64%, P = .01). Among the valve-sparing patients (six), at the latest follow-up, moderate pulmonary insufficiency was present in two (33%) patients. CONCLUSION: Repair of CAVC concomitant with TOF can be performed with low mortality and acceptable perioperative morbidity. Management of the RVOT remains a challenge for the long term.

Feasibility of Biventricular Repair in Right Dominant Unbalanced Atrioventricular Septal Defect: A New Echocardiographic Metric to Refine Surgical Decision-Making.

BACKGROUND: Unbalanced forms of atrioventricular septal defect continue to be challenging and present poor surgical outcomes. Echocardiographic indicators such as atrioventricular valve index, right ventricle/left ventricle inflow angle, and size of the ventricular septal defect have been identified as relevant discriminators that may guide surgical strategy. Our purpose is to describe another metric to refine surgical decision-making. METHODS: We outline a geometrical description of the anatomic features of atrioventricular septal defect and describe equations that help explain the interplay between the main echocardiographic variables. RESULTS: A new metric called "indexed ventricular septal defect" is defined as the size of the defect in relation to the valve diameter. We derive a final equation relating this index with the atrioventricular valve index and the right ventricle/left ventricle inflow angle. In the light of that equation, we discuss the interdependence of variables and employ data from a Congenital Heart Surgeons' Society study to set the limits of the new index. CONCLUSION: Combined use of indexed ventricular septal defect and atrioventricular valve index might help clarify surgical decision-making in patients with mild and moderate unbalance (modified atrioventricular valve index between 0.2 and 0.39). For indexed ventricular septal defect smaller than 0.2, biventricular repair may be recommended. Between 0.2 and 0.35, this strategy could probably be achieved depending on other factors. However, other strategies should be considered for those patients showing an indexed ventricular septal defect between 0.35 and 0.5. For values above 0.5 to 0.55, univentricular palliation might be a reasonable strategy.

Biventricular repair for common atrioventricular canal defect with parachute left atrioventricular valve.

OBJECTIVES: Parachute left atrioventricular (AV) valve can complicate repair of common atrioventricular canal (CAVC), and single-ventricle palliation is sometimes preferred. The goal of this study is to review our single institutional experience in biventricular repair in this patient group. METHODS: The demographic, procedural and outcome data were obtained for all children who underwent biventricular repair for complete CAVC with parachute [single left ventricular (LV) papillary muscle] or forme fruste parachute left AV valve (closely spaced LV papillary muscles) from 2001 to 2012. Primary outcomes were survival, freedom from left AV valve stenosis (defined as an inflow gradient ≥7 mmHg and post-capillary pulmonary hypertension) and freedom from left AV valve replacement. RESULTS: A total of 24 patients were included (21 parachutes, 3 forme frustes). There was 1 early death (4.2%). At discharge, no patient had more-than-mild regurgitation and 1 had stenosis. During a median follow-up of 3.7 years (IQR 4 months to 5 years), there were 2 late deaths (8.3%), 6 patients (25%) presented significant left AV valve stenosis and 2 patients (8.3%) required valve replacement. Freedom from stenosis was 95 ± 4.9% at 1 year, 83.1 ± 8.9% at 3 years, 64.7 ± 13.5% at 5 years and 51.7 ± 15.8% at 10 years. Complete cleft closure was not associated with a significantly different freedom from left AV valve reoperation (log-rank test, P = 0.89) or significant stenosis (P = 0.47). CONCLUSION: Biventricular repair in parachute left AV valve and CAVC is feasible with acceptable mortality and freedom from stenosis. The burden of reoperation remains significant in this patient group.

Palliation of Truncus Arteriosus Associated With Complete Atrioventricular Canal--Results of Single Ventricle Palliation.

BACKGROUND: Truncus arteriosus associated with complete atrioventricular canal defect is rare and continues to be a surgical challenge with high morbidity and mortality. In the absence of extension of the ventricular septal defect to the outlet septum, biventricular repair is precluded, and single ventricle palliation remains the only option. We present our experience with five patients with truncus arteriosus and complete atrioventricular canal defect who underwent single ventricular palliation. METHODS: Five patients with truncus arteriosus and complete atrioventricular canal defect managed along the single ventricle palliation pathway were retrospectively reviewed. Demographic, echocardiographic, cardiac catheterization, and perioperative data were analyzed. RESULTS: All patients underwent neonatal palliation tailored to their anatomy (excision of pulmonary arteries from the common trunk and systemic to pulmonary artery shunt in two patients, excision of pulmonary artery and right ventricle to pulmonary artery conduit in two patients, and bilateral branch pulmonary artery bands in one patient). There were two early deaths after neonatal palliation. At a median follow-up of 210 days (interquartile range 1,210 days), all three survivors have undergone second-stage palliation. Of these patients, one is interstage II to III, and two patients have completed their Fontan procedure and are doing well. CONCLUSION: Truncus arteriosus with complete atrioventricular canal defect is a rare combination of defects. Single ventricle palliation pathway with a tailored neonatal approach may be employed for patients with uncommitted ventricular septal defects.

A Novel Technique for Repair of Complete Atrioventricular Canal Defect: The Central Patch Technique.

BACKGROUND: Two-patch, single-patch, and modified single-patch repairs are accepted techniques for repair of complete atrioventricular (AV) canal defects. We propose a novel, alternative technique: the central patch technique. METHODS: For the central patch technique, the superior and inferior bridging leaflets are attached with simple sutures to the right and left of their coaptation point. Both bridging leaflets are incised along a line above the ventricular crest, similar to a traditional single-patch technique. An oval pericardial patch is sewn to the central defect created in the AV valve tissue. Interrupted, horizontal mattress sutures are placed along the ventricular crest, through the midline of the central patch and through the edge of the atrial septal defect (ASD) patch. Tying the sutures simultaneously closes the ventricular septal defect (VSD) and secures the ASD patch to the ventricular crest. Repair of the left AV valve and ASD closure are performed in the routine fashion. RESULTS: Five patients underwent the central patch technique repair of complete AV canal defect. Weight was 4.8 to 6.3 kg; age was four to eight months. Cardiopulmonary bypass and myocardial times averaged 137 minutes and 109 minutes, respectively. No patient had more than mild left AV valve regurgitation or trivial residual VSD at completion of repair. No patient developed left ventricular outflow tract obstruction. CONCLUSION: The central patch technique is applicable to all forms of complete AV canal defect. Subjectively, it offers technical advantages compared to standard techniques and may result in a shorter learning curve for junior congenital heart surgeons. Results are preliminary but are consistent with standard techniques.

A case of complete repair of type-B atrioventricular canal defect and cor triatriatum.

The association of atrioventricular canal defect and cor triatriatum sinister is very rare and only a few anecdotal reports of successful surgical repair and outcome have been reported. We report a case of Rastelli type-B atrioventricular canal defect with cor triatriatum which was successfully repaired.

Outcome after two-patch repair of complete common atrioventricular canal defects in patients weighing four kilograms or less.

BACKGROUND: Early repair of a complete common atrioventricular canal defect (CCAVCD) may benefit patients who exhibit congestive heart failure and failure to thrive. However, concern about increased risk and fragility of valve tissue has commonly led to delaying the surgical repair until the patients achieve a predetermined weight. We report our experience with a strategy of early repair independent of age or weight. METHODS: Between 2003 and 2009, 32 patients underwent two-patch repair of CCAVCD at our institution; 22 patients weighed between 2.5 and 4 kg (group #1) and 10 weighed more than 4 kg (group #2). Medical records and echocardiographic studies were reviewed to determine whether there was a difference in the incidence of mortality, rate of reintervention, and complications between the two groups. RESULTS: Operative mortality was 3.1% (1 of 32), with one additional death two years after repair, for an overall mortality of 6.25%. Median duration of mechanical ventilation, median hospital stay, and intropic score was similar between both groups. Freedom from valve reintervention was 91% in group #1 (20 of 22), and 89% in group #2 (8 of 9, p = 1.00). CONCLUSIONS: Complete common atrioventricular canal defect can be repaired safely and effectively in patients under 4 kg. Although mortality was not increased, smaller patients have a tendency for longer intensive care and hospital stay as well as a higher incidence of atrioventricular valve regurgitation. However, valve function improved during the period of follow-up and did not impact the freedom from reintervention.

Management of complete atrioventricular canal defect with aortic arch obstruction: an unresolved debate.

Patients with complete atrioventricular canal defect and aortic arch obstruction represent a particular challenge for management. The incidence is rare, so surgical experience is limited. A reasonable treatment option for newborns and young infants with competent atrioventricular valves is the staged approach, with the arch obstruction repaired first, followed at an appropriate interval by repair of the complete atrioventricular canal defect. If there is a significant degree of atrioventricular valve regurgitation, the primary single-stage correction of both aortic arch obstruction and the intracardiac malformation should be undertaken, irrespective of age. It remains to be seen whether this surgical strategy can be adopted for the entire spectrum of atrioventricular canal defect associated with arch obstruction.

Individualized approach to repair of complete atrioventricular canal: selective use of the traditional single-patch technique versus the Australian technique.

The traditional single-patch technique for repair of complete atrioventricular (AV) canal requires surgical division of the superior and inferior common leaflets. In the neonate and young infant, subsequent resuspension of very delicate AV valve tissue on the pericardial patch can be problematic. Selective application of the modified single-patch technique as described by Nunn (Australian technique) minimizes manipulation of the AV valve leaflet tissue. Previous reports have documented that since the late 1980s, the traditional single-patch approach with leaflet resuspension is possible with a mortality of 3% or less. A review of the initial 33 patients managed with the Australian technique was undertaken. The ventricular septal defect was moderate or large in 29 patients (88%). In the balanced canal subgroup, there was no early mortality; 1 patient underwent reoperative mitral repair for cleft dehiscence 1 year postoperatively, and 1 patient with heterotaxy required pacemaker implantation. In the unbalanced canal subgroup, 2 patients died perioperatively (22%). There have been no late deaths or new left ventricular outflow tract obstruction in either subgroup. Selective application of the single-patch technique currently allows excellent results for surgical repair in the neonatal period or early infancy. Even during the learning phase of the Australian technique, satisfactory results were achieved.