Single-cell reconstruction and mutation enrichment analysis identifies dysregulated cardiomyocyte and endothelial cells in congenital heart disease.

Congenital heart disease (CHD) is one of the most prevalent neonatal congenital anomalies. To catalog the putative candidate CHD risk genes, we collected 16,349 variants [single-nucleotide variants (SNVs) and Indels] impacting 8,308 genes in 3,166 CHD cases for a comprehensive meta-analysis. Using American College of Medical Genetics (ACMG) guidelines, we excluded the 0.1% of benign/likely benign variants and the resulting dataset consisted of 83% predicted loss of function variants and 17% missense variants. Seventeen percent were de novo variants. A stepwise analysis identified 90 variant-enriched CHD genes, of which six (GPATCH1, NYNRIN, TCLD2, CEP95, MAP3K19, and TTC36) were novel candidate CHD genes. Single-cell transcriptome cluster reconstruction analysis on six CHD tissues and four controls revealed upregulation of the top 10 frequently mutated genes primarily in cardiomyocytes. NOTCH1 (highest number of variants) and MYH6 (highest number of recurrent variants) expression was elevated in endocardial cells and cardiomyocytes, respectively, and 60% of these gene variants were associated with tetralogy of Fallot and coarctation of the aorta, respectively. Pseudobulk analysis using the single-cell transcriptome revealed significant (P < 0.05) upregulation of both NOTCH1 (endocardial cells) and MYH6 (cardiomyocytes) in the control heart data. We observed nine different subpopulations of CHD heart cardiomyocytes of which only four were observed in the control heart. This is the first comprehensive meta-analysis combining genomics and CHD single-cell transcriptomics, identifying the most frequently mutated CHD genes, and demonstrating CHD gene heterogeneity, suggesting that multiple genes contribute to the phenotypic heterogeneity of CHD. Cardiomyocytes and endocardial cells are identified as major CHD-related cell types.NEW & NOTEWORTHY Congential heart disease (CHD) is one of the most prevalent neonatal congenital anomalies. We present a comprehensive analysis combining genomics and CHD single-cell transcriptome. Our study identifies 90 potential candidate CHD risk genes of which 6 are novel. The risk genes have heterogenous expression suggestive of multiple genes contributing to the phenotypic heterogeneity of CHD. Cardiomyocytes and endocardial cells are identified as major CHD-related cell types.

Neonatal sutureless pericardial marsupialization for isolated iatrogenic pulmonary vein stenosis.

A 12-day-old girl underwent extended end-to-end aortic arch reconstruction with proximal pulmonary autograft patch augmentation on moderately hypothermic cardiopulmonary bypass. At the end of the procedure, the right superior pulmonary vein developed a severe stenosis at the insertion site of the left atrial vent, as a consequence of multiple hemostatic sutures. We report the successful intraoperative ad hoc application of the sutureless pericardial marsupialization technique for the herewith described severe, isolated, iatrogenic pulmonary vein stenosis in a neonate.

Implementation of On-table Extubation After Pediatric Cardiac Surgery in the Developing World.

In the recent years there has been increasing trend towards the practice of on-table extubation after pediatric cardiac surgery among practitioner in European and non-European countries. In this article we share our experience with on-table extubation among children after cardiac surgery in the developing world supported with the currently available literature.

Managing the posterior coronary loop in the arterial switch operation: the 'inverse flap' technique.

Posterior coronary looping remains a risk factor when performing an arterial switch operation for transposition of the great arteries. In such a situation, to avoid the risk of overstretching, we use an 'inverse' flap technique, resulting in a tension-free relocation.

Surgery for primary cardiac tumors in children: early and late results in a multicenter European Congenital Heart Surgeons Association study.

BACKGROUND: To evaluate indications and results of surgery for primary cardiac tumors in children. METHODS AND RESULTS: Eighty-nine patients aged ≤18 years undergoing surgery for cardiac tumor between 1990 and 2005 from 16 centers were included retrospectively (M/F=41/48; median age 4.3 months, range 1 day to 18 years). Sixty-three patients (68.5%) presented with symptoms. Surgery consisted of complete resection in 62 (69.7%) patients, partial resection in 21 (23.6%), and cardiac transplant in 4 (4.5%). Most frequent histotypes (93.2%) were benign (rhabdomyoma, myxoma, teratoma, fibroma, and hemangioma). Postoperative complications occurred in 29.9%. Early and late mortality were 4.5% each (mean follow-up, 6.3±4.4 years); major adverse events occurred in 28.2% of the patients; 90.7% of patients are in New York Heart Association class I. There were no statistically significant differences in survival, postoperative complications, or adverse events after complete and partial resection in benign tumors other than myxomas. Cardiac transplant was associated significantly with higher mortality rate (P=0.006). Overall mortality was associated to malignancy (P=0.0008), and adverse events during follow-up (P=0.005). CONCLUSIONS: Surgery for primary cardiac tumors in children has good early and long-term outcomes, with low recurrence rate. Rhabdomyomas are the most frequent surgical histotypes. Malignant tumors negatively affect early and late survival. Heart transplant is indicated when conservative surgery is not feasible. Lack of recurrence after partial resection of benign cardiac tumors indicates that a less risky tumor debulking is effective for a subset of histotypes such as rhabdomyomas and fibromas.

Pneumatic pulsatile ventricular assist device as a bridge to heart transplantation in pediatric patients.

Despite the remarkable advances with the use of ventricular assist devices (VAD) in adults, pneumatic pulsatile support in children is still limited. We report on our experience in the pediatric population. A retrospective review of 17 consecutive children offered mechanical support with Berlin Heart as a bridge to heart transplant from February 2002 to April 2010 was conducted. The median patient age was 3.9 years (75 days to 13.3 years). The median patient weight was 14.1 kg (2.9-43kg). Before VAD implantation, all children were managed by multiple intravenous inotropes and mechanical ventilation (14) or extracorporeal membrane oxygenation (3). All patients had right ventricular dysfunction. Nine patients required biventricular mechanical support (BVAD), but in all other cases a single left ventricular assist device proved sufficient (47%). The median duration of VAD support was 47 days (1-168 days). The median pre-VAD pulmonary vascular resistance index (Rpi) was 5.7 WU/m(2) (3.5 to 14.4WU/m(2) ). Eleven patients (65%) were successfully bridged to heart transplantation after a median duration of mechanical support of 68 days (6-168 days). Six deaths occurred (35%), three for neurological complications, one for sepsis, and two others for device malfunctioning. Since 2007, the survival rate of our patients has increased from 43% to 80%, and the need for BVAD has decreased from 86% to 30%. In two patients with Rpi >10WU/m(2) , unresponsive to pulmonary vasodilatator therapy, Rpi dropped to 2.2 and 2WU/m(2) after 40 and 23 days of BVAD support, respectively. Seven patients (41%) required at least one pump change. Of 11 patients undergoing heart transplant, four developed an extremely elevated (>60%) panel reactive antibody by enzyme-linked immunosorbent assay, confirmed by Luminex. All of them experienced at least one acute episode of rejection in the first month after heart transplant, needing plasmapheresis. The survival rate after heart transplantation was 100% with a median follow-up of 25.4 months (6 days to 7.7 years). Mechanical support in children with end-stage heart failure is an effective strategy as a bridge to heart transplantation with a reasonable morbidity and mortality. BVAD support may offer an additional means to reverse extremely elevated pulmonary vascular resistance.

Determinants of outcome after surgical treatment of pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries.

OBJECTIVES: Identification of variables influencing surgical outcome in patients treated for pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries. METHODS: A total of 90 consecutive patients (median age, 12 months; range, 20 days to 35 years), who had primarily undergone either 1-stage unifocalization (n = 69) or palliation to promote native pulmonary arterial development (n = 21), were studied. Chromosome 22q11 deletion had occurred in 37% of the cases. Ventricular septal defect closure was accomplished in 70 patients (78%), with a mean postoperative right/left ventricular pressure ratio of 0.48 ± 0.14. RESULTS: The rate of 14-year survival, freedom from conduit reintervention, and freedom from percutaneous intervention on the pulmonary arteries was 75%, 46%, and 52%, respectively. At a median interval of 95 months (range, 1.5-164 months), the right/left ventricular pressure ratio did not differ significantly from early postoperatively. Univariate analysis showed that an absence of confluent intrapericardial pulmonary arteries favorably affected the postoperative right/left ventricular pressure ratio after ventricular septal defect closure (P = .04). Kaplan-Meier estimates showed age of 30 days or younger (P = .0004) and weight of 3 kg or less (P = .0004) at unifocalization and chromosome 22q11 deletion (P = .001) significantly affected survival. Chromosome 22q11 deletion was significantly associated with mortality, even in the Cox regression model (hazard ratio, 8.26; P = .003). Finally, ventricular septal defect closure during single-stage and single/multiple-stage procedures significantly correlated with both early (P = .0013 and P < .00001, respectively) and overall (P = .013 and P = .0007, respectively) survival. CONCLUSIONS: The results of surgery were satisfactory and durable, despite the need for repeated percutaneous or surgical reinterventions. The outcomes were negatively affected by neonatal age and low body weight and positively affected by simultaneous or staged ventricular septal defect closure. Finally, chromosome 22q11 deletion remained an independent variable affecting survival.

Mechanical assist device as a bridge to heart transplantation in children less than 10 kilograms.

BACKGROUND: Despite the remarkable advances with the use of ventricular assist devices (VAD) in adults, pneumatic pulsatile support in children is still limited. We report a retrospective review of our experience in very small children (<10 kg of body weight). METHODS: Ten consecutive children weighing less than 10 kg were offered mechanical support with Berlin Heart (Berlin Heart AG, Berlin, Germany) as a bridge to heart transplant from March 2002 to March 2010. RESULTS: The median patient age was 10.4 months (38 days to 2.2 years). The median patient weight was 6.4 kg (2.9 to 10 kg). Prior to VAD implantation, all children were managed by multiple intravenous inotropes and mechanical ventilation (8) or extracorporeal membrane oxygenation (2). The median pre-VAD pulmonary vascular resistance index was 5.7 Woods units/m(2). Three patients required biventricular mechanical support, but in all other cases a single left VAD proved sufficient. The median duration of VAD support was 61 days (2 to 168 days). Four deaths occurred; from stroke in three and sepsis in one. Five patients were successfully bridged to heart transplantation after a median duration of mechanical support of 89 days (37 to 168 days) and another is still waiting a suitable organ after 77 days of VAD support. There were no complications related to postoperative bleeding. Five patients required at least one pump change. Of 5 patients undergoing heart transplant, 3 developed an extremely elevated (>60%) panel reactive antibody by enzyme-linked immunosorbent assay, confirmed by Luminex (Luminex Corp, Austin, TX). All 3 experienced at least one acute episode of rejection in the first month after heart transplant, needing plasmapheresis. The survival rate after heart transplantation was 100% with a median follow-up of 7.5 months. CONCLUSIONS: Mechanical support in very small children with end-stage heart failure is an effective strategy of bridge to heart transplantation with a reasonable mortality rate. The high rate of complications suggests to optimize indications and timing of VAD implantation.

Aberrant left innominate artery from the left descending aorta in right aortic arch: echocardiographic diagnosis.

A right aortic arch with a left descending aorta and an aberrant left innominate artery is a rare but recognized vascular anomaly that can result in compression of the trachea and the esophagus. This vascular anomaly has been diagnosed using cardiac catheterization and angiography. Recently, computed tomography and magnetic resonance imaging have been used for noninvasive diagnosis. The aim of this report is to highlight the possibility of echocardiographic diagnosis.

Initial single-center experience with levosimendan infusion for perioperative management of univentricular heart with ductal-dependent systemic circulation.

The aim of this study was to evaluate the safety and the efficacy of levosimendan, a novel calcium sensitizer agent, on postoperative hemodynamic and metabolic parameters of neonates affected by single ventricle anatomy. Twenty consecutive neonates scheduled for the Norwood procedure with Blalock Taussig shunt were prospectively enrolled. All patients received an infusion of levosimendan at 0.1 µg/kg/min commencing 24 hours before surgery, and the infusion was continued for 48 hours after surgery. No side effects (intolerance to the drug, hypotension, arrhythmias) were shown. A median inotropic score (IS) of 37 was necessary to maintain a mean arterial pressure between 45 and 50 mm Hg at intensive care unit (ICU) admission: IS was significantly reduced after 72 hours (P < .05). Brain natriuretic peptide values decreased significantly from 1210 to 459 pg/mL in 72 hours (P < .05). Median SvO2 increased significantly from 38% to 59% during the evaluated period (P < .05). Cerebral near-infrared spectroscopy values were close to 40% at ICU admission with a significant stable increase to 50% after 12 hours (P < .05). Median lactate level was 13 mmol/L at ICU admission but showed a trend to a rapid and significant decrease after 12 hours (P < .05). Median urine output was surprisingly elevated, always remaining between 5.2 and 6.2 mL/kg/h throughout the postoperative period. Survival rate was 85% at 30 days (17/20 patients) and 75% (15/20) at hospital discharge. Levosimendan infusion in a cohort of neonates with univentricular anatomy was safe and potentially beneficial on postoperative hemodynamic and metabolic parameters.

Extracorporeal membrane oxygenation and high-dose continuous veno-venous hemodiafiltration in a young child as a successful bridge to heart transplant for management of combined heart and kidney failure: a case report.

Combined heart and kidney transplant is an established treatment modality in patients with coexisting end-stage heart and kidney failure. However, there is scarce information on the optimal management of children that are listed for cardiac transplantation with mild to severe renal dysfunction. Herein we report the case of a young child who presented with life-threatening dilative cardiomyopathy and severe renal dysfunction, and who required urgent extracorporeal membrane oxygenation associated with continuous veno-venous hemodiafiltration and eventually underwent successful isolated heart transplantation followed by complete recovery of kidney function.