Tolvaptan treatment in an adult Fontan patient with protein-losing enteropathy: a serial 23Na-MRI investigation.

BACKGROUND: Protein-losing enteropathy (PLE) is a severe complication of the univentricular Fontan circulation and associated with disturbances in salt and water homeostasis. Fontan patients with PLE have a poor prognosis, with increased morbidity and mortality. Due to limited therapeutic strategies, patients are often treated only symptomatically. METHODS: We report our first experience of Tolvaptan (TLV) treatment in a Fontan patient with PLE, severe volume retention and hyponatraemia, refractory to conventional diuretic therapy. In addition to clinical parameters, we monitored drug effects including tissue sodium and volume status via serial 23Na-magnetic resonance imaging (23Na-MRI) and bioimpedance spectroscopy compared with age-matched controls. RESULTS: 23Na-MRI identified elevated tissue sodium, which decreased under TLV treatment, as well as volume status, while serum sodium increased and the patient's symptoms improved. During long-term treatment, we were able to differentiate between sodium and volume status in our patient, suggesting that TLV uncoupled body sodium from water. CONCLUSION: TLV in addition to loop diuretics improved clinical symptoms of PLE and lowered tissue sodium overload. Long-term effects should be further evaluated in Fontan patients.

Lymphocyte Immune Response and T Cell Differentiation in Fontan Patients with protein-losing enteropathy.

BACKGROUND: Protein-losing enteropathy (PLE) is a severe complication of the Fontan circulation. There is increasing discussion about whether lymphatic dysregulation is involved as pathomechanism of PLE. This investigation focuses on the interplay between alteration of lymphatic cells and immunologic pathway alterations. METHODS: Micro-ribonucleic acid (miRNA) expression profiling was performed in 49 patients (n = 10 Fontan patients with PLE, n = 30 Fontan patients without PLE, and n = 9 patients with dextro-transposition of the great arteries (dTGA). miRNA pathway analysis was performed to identify significantly enriched pathways. To determine lymphocyte populations and subtypes multiparameter flow cytometry was used. RESULTS: miRNAs pathway analysis of Fontan patients with PLE revealed 20 significantly changed networks of which four of the ten largest were associated with immunologic processes. This finding is supported by significant T cell deficiency with decreased CD4+ count (p = 0.0002), altered CD4 +/CD8+ ratio, and significantly modified CD4+ (p < 0.0001) and CD8+ (p = 0.0002) T cell differentiation toward effector and terminal differentiated T cells in Fontan patients with PLE. Analyses of CD4+ T cell subsets demonstrated significantly increased frequencies of CD4+ CD25+ CD127- regulatory T cells (Treg) in Fontan patients with PLE (p = 0.0011). CONCLUSION: PLE in Fontan patients is associated with severe lymphopenia, T cell deficiency, significant alterations of T cell differentiation, and increased Treg frequency reflecting an immune status of chronic inflammation and shortened protection against pathogens and autoimmunity. These cellular alterations seemed to be dysregulated by several miRNA controlled immunological pathways.

Multisite measurement of regional oxygen saturation in Fontan patients with and without protein-losing enteropathy at rest and during exercise.

BACKGROUND: Protein-losing enteropathy (PLE) is a severe complication of Fontan circulation with increased risk of end-organ dysfunction. We evaluated tissue oxygenation via near-infrared spectroscopy (NIRS) at different exercise levels in Fontan patients. METHODS: Assessment of multisite NIRS during cycle ergometer exercise and daily activities in three groups: Fontan patients with PLE; without PLE; patients with dextro-transposition of the great arteries (d-TGA); comparing univentricular with biventricular circulation and Fontan with/without PLE. Renal threshold analysis (<65%;<55%;<45%) of regional oxygen saturation (rSO2) was performed. RESULTS: Fontan patients showed reduced rSO2 (p < 0.05) in their quadriceps femoris muscle compared with biventricular d-TGA patients at all time points. rSO2 in renal tissue was reduced at baseline (p = 0.002), exercise (p = 0.0062), and daily activities (p = 0.03) in Fontan patients with PLE. Renal threshold analysis identified critically low renal rSO2 (rSO2 < 65%) in Fontan patients with PLE during exercise (95% of monitoring time below threshold) and daily activities (83.7% time below threshold). CONCLUSION: Fontan circulation is associated with decreased rSO2 values in skeletal muscle and hypoxemia of renal tissue solely in patients with PLE. Reduced rSO2 already during activities of daily life, might contribute to comorbidities in patients with Fontan circulation, including PLE and renal failure.

First experience with Tolvaptan for the treatment of neonates and infants with capillary leak syndrome after cardiac surgery.

BACKGROUND: Postoperative fluid management in critically ill neonates and infants with capillary leak syndrome (CLS) and extensive volume overload after cardiac surgery on cardiopulmonary bypass is challenging. CLS is often resistant to conventional diuretic therapy, aggravating the course of weaning from invasive ventilation, increasing length of stay on ICU and morbidity and mortality. METHODS: Tolvaptan (TLV, vasopressin type 2 receptor antagonist) was used as an additive diuretic in neonates and infants with CLS after cardiac surgery. Retrospective analysis of 25 patients with CLS including preoperative and postoperative parameters was performed. Multivariate regression analysis was performed to identify predictors for TLV response. RESULTS: Multivariate analysis identified urinary output during 24 h after TLV administration and mean blood pressure (BP) on day 2 of TLV treatment as predictors for TLV response (AUC = 0.956). Responder showed greater weight reduction (p < 0.0001), earlier weaning from ventilator during TLV (p = 0.0421) and shorter time in the ICU after TLV treatment (p = 0.0155). Serum sodium and serum osmolality increased significantly over time in all patients treated with TLV. CONCLUSION: In neonates and infants with diuretic-refractory CLS after cardiac surgery, additional aquaretic therapy with TLV showed an increase in urinary output and reduction in bodyweight in patients classified as TLV responder. Increase in urinary output and mean BP on day 2 of treatment were strong predictors for TLV response.

Evaluation of ventricular septal defects using high pitch computed tomography angiography of the chest in children with complex congenital heart defects below one year of age.

BACKGROUND: Aim of this study was to assess the accuracy of ventricular septal defects (VSD) using high pitch computed tomography angiography (CTA) of the chest in children below 1 year of age, compared to the intraoperative findings and echocardiography. METHODS: Out of 154 patients that underwent Dual-Source CTA of the chest using a high-pitch protocol at low tube voltages (70-80 kV), 55 underwent surgical repair of a VSD (median age 8 days, range 1-348 days). The margins of the VSDs and their relation to the surrounding structures were reproduced by en-face views using multiplanar reformations (MPR). Absolute diameter, normalized area and relative area compared to the aortic valve annulus were used for discrimination between restrictive and non-restrictive defects. Localization was classified into four subtypes. The results were compared to two-dimensional echocardiography and intraoperative findings. RESULTS: Median absolute size of VSDs did not differ significantly between CTA-measurements (10.8 mm, range 2.8-18.1 mm) and intraoperative findings (12.0 mm, 3.0-25.0 mm, p = 0.09). Echocardiographic values were significantly lower (9.6 mm, 3.0-18.5 mm, both p < 0.01). The classification of the location and orientation matched the intraoperative situs in 96.4% of all cases using CT and in 87.3% using echocardiography. Echocardiography missed the relation to valves in 11% of all cases. Pre-interventional sensitivity and specificity for detection of a VSD were 97.2/98.9% compared to echocardiography. Median radiation dose was 0.32 mSv (range 0.12-2.00 mSv) and differed significantly between second and third generation Dual-Source CT (0.43 vs. 0.22 mSv, p = 0.003). CONCLUSION: Size and subtype of VSDs can be accurately assessed by CTA of the chest in patients with complex congenital heart defects at a very low radiation dose.

Systemic-to-pulmonary artery shunting using heparin-bonded grafts.

OBJECTIVES: Systemic-to-pulmonary artery shunting remains an important palliative procedure in the staged management of complex congenital heart defects. The use of heparin-bonded polytetrafluoroethylene shunts (HBPSs) should enhance graft patency. This study aimed to review the single-centre experience using HBPS in the context of congenital cardiac surgery. METHODS: The records of 51 patients treated using HBPS between 2010 and 2016 were retrospectively reviewed. The median age and weight of the patients were 8 (range 3-83) days and 3.2 (range 1.8-5.7) kg, respectively. Selected shunt size was 3.5 mm in all patients. Fourteen (27.5%) patients were planned for future biventricular repair and 37 (72.5%) patients underwent univentricular pathway. Shunt modifications included central aortopulmonary shunts (n = 35; 68.6%) and modified Blalock-Taussig shunts (n = 16; 31.4%). Shunt patency and survival until estimated 2nd procedure were calculated using the Kaplan-Meier method. RESULTS: Shunt patency was 90 ± 4% after a median duration of 133 (range 0-315) days. Early mortality (30 days) was 3.9% (n = 2). Another 3 patients died during their hospital stay. All the deceased patients had univentricular morphology, and the cause of death was not shunt related in all patients. Five patients developed subtotal HBPS thrombosis intraoperatively (n = 3), early postoperatively after 3 days (n = 1, 1.9%) or late after 41 days (n = 1, 1.9%). Treatment of those patients comprised right ventricular outflow tract opening (n = 2, 3.9%) or new shunting (n = 3, 5.9%). Elective shunt takedown was performed during corrective surgery (n = 10, 19.6%), bidirectional Glenn (n = 25, 49%) or shunt replacement (n = 5, 9.8%). At the end of follow-up, 1 (1.9%) patient had still an HBPS in situ. The survival rate until planned 2nd procedure was 87 ± 6% in univentricular patients and 100% in biventricular patients (P = 0.17). CONCLUSIONS: The use of HBPS in the context of palliative heart surgery is safe and seems to warrant a long-term patency of systemic-to-pulmonary shunts. However, by acting on only 1 site of Virchow's triad, shunt thrombosis, occurring predominantly early, cannot be totally excluded.

A map of human circular RNAs in clinically relevant tissues.

Cellular circular RNAs (circRNAs) are generated by head-to-tail splicing and are present in all multicellular organisms studied so far. Recently, circRNAs have emerged as a large class of RNA which can function as post-transcriptional regulators. It has also been shown that many circRNAs are tissue- and stage-specifically expressed. Moreover, the unusual stability and expression specificity make circRNAs important candidates for clinical biomarker research. Here, we present a circRNA expression resource of 20 human tissues highly relevant to disease-related research: vascular smooth muscle cells (VSMCs), human umbilical vein cells (HUVECs), artery endothelial cells (HUAECs), atrium, vena cava, neutrophils, platelets, cerebral cortex, placenta, and samples from mesenchymal stem cell differentiation. In eight different samples from a single donor, we found highly tissue-specific circRNA expression. Circular-to-linear RNA ratios revealed that many circRNAs were expressed higher than their linear host transcripts. Among the 71 validated circRNAs, we noticed potential biomarkers. In adenosine deaminase-deficient, severe combined immunodeficiency (ADA-SCID) patients and in Wiskott-Aldrich-Syndrome (WAS) patients' samples, we found evidence for differential circRNA expression of genes that are involved in the molecular pathogenesis of both phenotypes. Our findings underscore the need to assess circRNAs in mechanisms of human disease. KEY MESSAGES: circRNA resource catalog of 20 clinically relevant tissues. circRNA expression is highly tissue-specific. circRNA transcripts are often more abundant than their linear host RNAs. circRNAs can be differentially expressed in disease-associated genes.

Comparable Cerebral Blood Flow in Both Hemispheres During Regional Cerebral Perfusion in Infant Aortic Arch Surgery.

BACKGROUND: Cerebral protection during aortic arch repair can be provided by regional cerebral perfusion (RCP) through the innominate artery. This study addresses the question of an adequate bilateral blood flow in both hemispheres during RCP. METHODS: Fourteen infants (median age 11 days [range, 3 to 108]; median weight, 3.6 kg [range, 2.8 to 6.0 kg]) undergoing RCP (flow rate 54 to 60 mL · kg-1 · min-1) were prospectively included. Using combined transfontanellar/transtemporal two- and three-dimensional power/color Doppler sonography, cerebral blood flow intensity in the main cerebral vessels was displayed. Mean time average velocities were measured with combined pulse-wave Doppler in the basilar artery, and both sides of the internal carotid, anterior, and medial cerebral arteries. In addition, bifrontal regional cerebral oximetry (rSO2) was assessed. Comparing both hemispheres, measurements were performed at target temperature (28°C) during full-flow total body perfusion (TBP) and RCP. RESULTS: A regular circle of Willis with near-symmetric blood flow intensity to both hemispheres was visualized in all infants during both RCP and TBP. In the left internal carotid artery, blood flow direction was mixed (retrograde, n = 5; antegrade, n = 8) during TBP and retrograde during RCP. Comparison between sides showed comparable cerebral time average velocities and rSO2, except for higher time average velocities in the right internal carotid artery (TBP p = 0.019, RCP p = 0.09). Unilateral comparison between perfusion methods revealed significantly higher rSO2 in the right hemisphere during TBP (82% ± 9%) compared with RCP (74% ± 11%, p = 0.036). CONCLUSIONS: Bilateral assessment of cerebral rSO2 and time average velocity in the main great cerebral vessels suggests that RCP is associated with near-symmetric blood flow intensity to both hemispheres. Further neurodevelopmental studies are necessary to verify RCP for neuroprotection during aortic arch repair.

The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5.

G protein-coupled receptor kinase 5 (GRK5) is a regulator of cardiac performance and a potential therapeutic target in heart failure in the adult. Additionally, we have previously classified GRK5 as a determinant of left-right asymmetry and proper heart development using zebrafish. We thus aimed to identify GRK5 variants of functional significance by analysing 187 individuals with laterality defects (heterotaxy) that were associated with a congenital heart defect (CHD). Using Sanger sequencing we identified two moderately frequent variants in GRK5 with minor allele frequencies <10%, and seven very rare polymorphisms with minor allele frequencies <1%, two of which are novel variants. Given their evolutionarily conserved position in zebrafish, in-depth functional characterisation of four variants (p.Q41L, p.G298S, p.R304C and p.T425M) was performed. We tested the effects of these variants on normal subcellular localisation and the ability to desensitise receptor signalling as well as their ability to correct the left-right asymmetry defect upon Grk5l knockdown in zebrafish. While p.Q41L, p.R304C and p.T425M responded normally in the first two aspects, neither p.Q41L nor p.R304C were capable of rescuing the lateralisation phenotype. The fourth variant, p.G298S was identified as a complete loss-of-function variant in all assays and provides insight into the functions of GRK5.

Performance of stented biological valves for right ventricular outflow tract reconstruction.

OBJECTIVES: This retrospective single-centre review presents mid- and long-term results of stented biological valves (SBVs) in the pulmonary position. METHODS: Fifty-two SBVs (17 Carpentier-Edwards Supraannular; 13 Carpentier-Edwards Perimount; 12 St. Jude Medical Trifecta; 4 Sorin Mitroflow; 4 Sorin Soprano; 2 Sorin More) were implanted between 2000 and 2015. The median valve size, patient age and weight were 23 mm (range 19-27), 22.8 years (range 5-77) and 62.0 kg (range 14-110), respectively. The main cardiac diagnosis was tetralogy of Fallot in 26 patients (50%). Forty-four patients (85%) had previous cardiac surgery; 12 patients (23%) had previous conduit or biological valve replacement. Valve degeneration was defined as a valvular peak pressure gradient >50 mmHg or pulmonary valve regurgitation more than moderate. RESULTS: The mean follow-up was 7.9 ± 5.5 years. Two patients died after 5.8 and 6.1 years of causes not related to SBVs. Eleven SBVs (21%) had to be replaced surgically (n = 6) or interventionally (n = 5) after 9.0 ± 4.1 years due to valve degeneration (n = 8), endocarditis (n = 2) or right ventricular dysfunction (n = 1). The rates of freedom from valve replacement were 100%, 92% [95% confidence interval (CI) 79-97], 81% (CI 64-91) and 60% (CI 40-78) after 1, 5, 10 and 15 years, respectively. Successful interventional valve-in-valve implantation resulted in 100% freedom from surgical valve replacement in all patients older than 19.1 years. Multivariate analysis identified patient age <19.1 years (P = 0.007) as a risk factor for earlier valve degeneration. CONCLUSIONS: SBVs in the pulmonary position showed encouraging long-term results in mature patients. The design of SBVs enables interventional valve implantation, postponing the need for reoperation.

Pediatric Extracorporeal Life Support Using a Third Generation Diagonal Pump.

This study reports a single-centre experience of the Medos Deltastream diagonal-pump (DP3) for extracorporeal cardiac, pulmonary, or combined support in a single-center pediatric cohort. Twenty-seven consecutive patients with 28 runs of the DP3 between January 2013 and June 2014 were included for analysis. Median patient age, weight, and duration of support were 278 days (range: 0 days-14.2 years), 7.2 kg (range: 2.5-39 kg), and 8 days (range: 2-69 days). Midline sternotomy (n = 20, 71.4%) or cervical approaches (n = 8, 28.6%) were used for cannulation. The DP3 was employed for either veno-arterial extracorporeal life support (ECLS, n = 16), veno-venous extracorporeal membrane oxygenation (ECMO, n = 5), or ventricular assist devices (right ventricular assist device [RVAD], n = 1; left ventricular assist device [LVAD], n = 1; and univentricular assist device [UNIVAD], n = 5). Three patients initially supported with ECLS were switched to UNIVAD and one patient with UNIVAD was changed to ECLS. Required flow for neonates (n = 8) ranged between 0.2 and 0.75 L/min. Irreversible pump damage occurred in one patient during deairing after air block. Successful weaning, 30 day and hospital survival were 89.3% (n = 25), 85.7% (n = 24), and 71.4% (n = 20). All patients on UNIVAD, who did not require further extracorporeal respiratory assist, survived. In conclusion, the DP3 can be used for individual patient demands and adapted to their most suitable method of support. Meticulous flow adjustments render this pump highly effective for extracorporeal support particularly in pediatric patients.

Transmural Placement of Endocardial Pacing Leads in Patients With Congenital Heart Disease.

BACKGROUND: This study evaluates the feasibility and outcomes of transmural placement of endocardial leads (TML) in patients with congenital heart disease. METHODS: Between October 2009 and May 2015, 29 TML procedures were performed in 27 patients. Leads are grouped according to their pacing site: atrial (TML-A, n = 24) or ventricular (TML-V, n = 12). The TML-V includes transatrial and transventricular approaches. Clinical outcome, functional properties of TML, and Kaplan-Meier freedom from lead dysfunction were evaluated. RESULTS: Median age was 4 years (range, 29 days to 43 years). Median follow-up duration was 2 years (range, 1 day to 5.7 years). There was no early mortality. Three late deaths were observed (2 unrelated, 1 related to pacing). In group TML-A, no lead dysfunction was noted. In group TML-V, there were 3 lead dislodgements and 1 lead fracture. Kaplan-Meier freedom from lead dysfunction after 0.5, 1, and 5 years, respectively, was 100% in group TML-A and 82% ± 11%, 73% ± 13%, and 59% ± 17% in group TML-V (log rank p < 0.01). Mean acute (at implantation) and chronic (at last follow-up) sensing thresholds were 3.1 ± 2.3 mV and 3.5 ± 2.5 mV in group TML-A and 11.6 ± 4.9 mV and 7.5 ± 4.6 mV in group TML-V, respectively. Mean acute and chronic pacing thresholds at 0.5 ms were 1.1 ± 0.6 V and 0.6 ± 0.3 V in group TML-A and 1.0 ± 0.6 V and 0.9 ± 0.5 V in group TML-V, respectively. CONCLUSIONS: The transmural approach provides an alternative method in patients with congenital cardiac defects who cannot receive transvenous leads and who have extensive epicardial scarring. Subanalysis shows superior midterm performance for TML-A compared with TML-V.

Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly.

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.

Novel loci for non-syndromic coarctation of the aorta in sporadic and familial cases.

BACKGROUND: Coarctation of the aorta (CoA) accounts for 5-8% of all congenital heart defects. CoA can be detected in up to 20% of patients with Ullrich-Turner syndrome (UTS), in which a part or all of one of the X chromosomes is absent. The etiology of non-syndromic CoA is poorly understood. In the present work, we test the hypothesis that rare copy number variation (CNV) especially on the gonosomes, contribute to the etiology of non-syndromic CoA. METHODS: We performed high-resolution genome-wide CNV analysis using the Affymetrix SNP 6.0 microarray platform for 70 individuals with sporadic CoA, 3 families with inherited CoA (n=13) and 605 controls. Our analysis comprised genome wide association, CNV burden and linkage. CNV was validated by multiplex ligation-dependent probe amplification. RESULTS: We identified a significant abundance of large (>100 kb) CNVs on the X chromosome in males with CoA (p=0.005). 11 out of 51 (~ 22%) male cases had these large CNVs. Association analysis in the sporadic cohort revealed 14 novel loci for CoA. The locus on 21q22.3 in the sporadic CoA cohort overlapped with a gene locus identified in all familial cases of CoA (candidate gene TRPM2). We identified one CNV locus within a locus with high multipoint LOD score from a linkage analysis of the familial cases (SEPT9); another locus overlapped with a region implicated in Kabuki syndrome. In the familial cases, we identified a total of 7 CNV loci that were exclusively present in cases but not in unaffected family members. CONCLUSION: Of all candidate loci identified, the TRPM2 locus was the most frequently implicated autosomal locus in sporadic and familial cases. However, the abundance of large CNVs on the X chromosome of affected males suggests that gonosomal aberrations are not only responsible for syndromic CoA but also involved in the development of sporadic and non-syndromic CoA and their male dominance.

PDE3A mutations cause autosomal dominant hypertension with brachydactyly.

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.

Aortic arch obstruction neonates with biventricular physiology: left-open compared to closed inter-atrial communication during primary repair--a retrospective study.

BACKGROUND: Leaving an inter-atrial communication (IAC) open for left atrial decompression is often recommended in neonates with aortic arch obstruction undergoing primary repair. In this study, outcomes in these patients were compared to those with intact atrial septum after repair. METHODS: Between 2000 and 2013, 53 consecutive neonates with severe aortic arch obstruction (hypoplasia: n = 45, interruption: n = 8) underwent primary repair from an anterior approach. Median age and weight were 8 days (range: 2-30) and 3.2 kg (range: 2.4-4.4), respectively. Cardiac morphology included a ventricular septal defect (VSD, large: n = 28, small: n = 7), malposition of great arteries (n = 10), and severe left ventricular outflow tract obstruction (LVOTO, n = 10). During corrective surgery IAC was closed (group-I, n = 37) or partially left-open (group-II, n = 16). Primary endpoints were hospital death, and re-intervention (surgery and/or balloon) due to aortic arch re-coarctation or recurrent LVOTO. Statistically significant variables by univariate analysis were incorporated in the corresponding multivariable regression model. RESULTS: Regarding morphological discrepancies more patients in group-II presented with LVOTO (p = 0.05), or the combination of arch hypoplasia, intact ventricular septum and normal ventriculo-arterial connection (p = 0.017). Hospital mortality was 8.1% in group-I and 37.5% in group-II (p = 0.016). Re-intervention was performed in 13 patients (group-I: n = 6 vs. group-II: n = 7) due to aortic arch re-coarctation (n = 12) and/or recurrent LVOTO (n = 3), and resulted in a Kaplan-Meier freedom from re-intervention of 87 ± 6% and 79 ± 8% in group-I, and 64 ± 14% and 64 ± 14% in group-II after 1 and 5 years, respectively (p = 0.016). Multivariate analysis revealed LVOTO as an independent risk factor for hospital death (p = 0.042), whereas both LVOTO and left-open IAC (p = 0.001 and 0.01) were independent risk factors for re-intervention. CONCLUSIONS: A left-open IAC increases risk of re-intervention at the left heart aorta complex. Sustained left-to-right shunting on atrial level seems to induce preload reduction of the often restrictive left ventricle leading to decreased aortic blood flow.

Aortic Arch Reconstruction in Neonates with Biventricular Morphology: Increased Risk for Development of Recoarctation by Use of Autologous Pericardium.

BACKGROUND: The aim of this study was to analyze risk factors promoting development of recoarctation (Re-CoA) in neonates who survived aortic arch repair from an anterior approach. METHODS: Fifty consecutive neonates with biventricular morphology and ductal-dependent lower body perfusion who were discharged home following aortic arch repair with cardiopulmonary bypass between 2000 and 2012 were retrospectively reviewed. Arch anatomy was either interruption (n = 10) or hypoplasia with coarctation (n = 40). Aortic arch reconstruction was performed by using patch material (bovine pericardium, n = 30, homograft, n = 10, or glutaraldehyde-treated autologous pericardium, n = 7), and three patients underwent direct end-to-side anastomosis. Antegrade cerebral and continuous myocardial perfusion was performed in 39 and 21 patients, respectively. Kaplan-Meier freedom from Re-CoA was calculated. Morphologic and perioperative data indicating increased risk of Re-CoA by univariate analysis were included in multivariate Cox regression analysis. RESULTS: Mean follow-up was 5.3 ± 4.1 years. Re-CoA occurred in 13 patients and was treated successfully by balloon dilatation (n = 6) or surgery (n = 7). Freedom from Re-CoA after 1 and 5 years was 83 ± 5 and 79 ± 6%, respectively. Two patients died early after surgical repair of Re-CoA. The use of autologous pericardium for aortic arch augmentation was the only independent risk factor for development of Re-CoA (hazard ratio: 4.3 [95% confidence interval: 1.2-16.1]; p = 0.028). CONCLUSION: Re-CoA following neonatal aortic arch surgery can be treated by balloon dilatation or surgery, if adequate. In this study, the risk for development of Re-CoA was independently increased by the use of autologous pericardium during initial arch repair.

Feasibility and related outcome of intraluminal pulmonary artery banding.

OBJECTIVES: This retrospective study evaluated the feasibility and related outcome of intraluminal pulmonary artery banding (I-PAB). METHODS: Thirty-two children underwent I-PAB between July 2006 and April 2014. The median age and weight were 60 days (range: 5 days to 4.2 years) and 3.7 kg (range: 2.6-13.0 kg), respectively. Cardiac diagnoses included single ventricle morphology (n = 11), complex ventricular septal defects (n = 11), balanced atrioventricular septal defects (n = 3), congenitally corrected transposition of the great arteries (n = 2) and aortic arch hypoplasia with ventricular septal defects (n = 5). On cardiopulmonary bypass (CPB), 2 I-PAB modifications with either 1 (n = 24) or 2 ('hour-glass-technique', n = 8) fenestrated pericardial patches were performed. RESULTS: The median fenestration size was 5 mm (range: 4-6.5 mm). In 18 patients I-PAB was a solitary procedure; in 3 of them the decision was made intraoperatively. There was no hospital mortality. The median interval to debanding was 189 days (range: 112 days to 2.6 years). During this period, we observed a significant increase in the pressure gradient over I-PAB (P < 0.01), whereas arterial saturations remained stable. Four patients received balloon dilatation of I-PAB to prolong the palliation period. No patient experienced band occlusion, pulmonary hypertension related to I-PAB, coronary or pulmonary valve impairment. Debanding was performed in 27 patients and one of them required pulmonary patch arterioplasty due to I-PAB-associated pulmonary trunk distortion. Three patients are still awaiting further surgery. There were 2 late deaths prior to, and 3 after debanding, all not related to I-PAB. CONCLUSIONS: I-PAB with an exactly defined internal orifice is feasible and effective. Although arterial saturations seem to remain stable, balloon dilatation of I-PAB can be performed safely and efficiently in order to prolong the palliation period. The rate of I-PAB-related complications is low, which might improve the long-term patient outcome. Therefore, despite requiring CPB, I-PAB is our institutional preference for children who require pulmonary artery banding.

Rare variants in NR2F2 cause congenital heart defects in humans.

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10(-7)) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters.