Atrial Isomerism Research Articles

Pitx2 confers left morphological, molecular, and functional identity to the sinus venosus myocardium

AimsThe sinus venous myocardium, comprising the sinoatrial node (SAN) and sinus horns (SH), is a region subject to congenital malformations and cardiac arrhythmias. It differentiates from symmetric bilateral mesenchymal precursors, but morphological, molecular, and functional left/right differences are progressively established through development. The role of the laterality gene Pitx2 in this process is unknown. We aimed to elucidate the molecular events driving left/right patterning in the sinus venosus (SV) myocardium by using a myocardial Pitx2 knockout mouse.Methods and resultsWe generated a myocardial specific Pitx2 knockout model (cTP mice). cTP embryos present several features of Pitx2 null, including right atrial isomerism with bilateral SANs and symmetric atrial entrance of the systemic veins. By in situ hybridization and optical mapping analysis, we compared throughout development the molecular and functional properties of the SV myocardium in wt and mutant embryos. We observed that Pitx2 prevents the expansion of the left-SAN primordium at the onset of its differentiation into myocardium; Pitx2 promotes expansion of the left SH through development; Pitx2 dose-dependently represses the autorhythmic properties of the left SV myocardium at mid-gestation (E14.5); Pitx2 modulates late foetal gene expression at the left SH-derived superior caval vein.ConclusionPitx2 drives left/right patterning of the SV myocardium through multiple developmental steps. Overall, Pitx2 plays a crucial functional role by negatively modulating a nodal-type programme in the left SV myocardium.

The incidence and characteristics of supraventricular tachycardia in left atrial isomerism: A high incidence of atrial fibrillation in young patients

BackgroundIn left atrial isomerism (LAI), both atria show left atrial morphology. Although bradyarrhythmias are frequent and highly complex in LAI patients, previous studies have reported a low incidence of supraventricular tachycardia (SVT). MethodsTo evaluate the incidence and characteristics of SVT in LAI, we retrospectively evaluated the clinical characteristics of SVTs in 83 patients with LAI (age at last follow-up, 15.3±10.5years). ResultsThere were 27 SVTs in 19 patients (23%), including nine episodes of atrial fibrillation (AF) and eight non-reentrant SVTs. Sixteen of the 19 patients with SVT had histories of atriotomy, but the three patients with AF or non-reentrant tachycardia had no history of atriotomy. The rates of freedom from SVT were 66% and 59% at ages of 20 and 30years, respectively; the corresponding rates for freedom from AF were 89% and 74%. In multivariate analysis, the predictors of SVT were age (OR, 1.14; 95% CI, 1.06–1.26; p=0.003) and sinus node dysfunction (SND) (OR, 3.88; 95% CI, 1.57–13.34; p=0.01). ConclusionsIn patients with LAI, SVTs are common, and AF and non-reentrant SVTs are the major type of SVTs. The incidence of AF was high in young patients with LAI. The lack of anatomical barriers in the atria that allow the formation of macro-reentrant circuits may account for the higher incidence of AF and non-reentrant SVT than macro-reentrant tachycardia. Moreover, the increasing prevalence of SND with age should contribute to a higher incidence of SVT.

Systemic venous anatomy in congenital heart disease: implications for electrophysiologic testing and catheter ablation

Cardiac arrhythmias are a significant problem in patients with congenital heart disease. Many patients with congenital heart disease have abnormal systemic venous anatomy which can complicate electrophysiologic testing, catheter ablation and pacemaker and defibrillator implantation. We reviewed the systemic venous anatomy in a cohort of patients undergoing electrophysiologic testing and catheter ablation. We reviewed all electrophysiologic studies performed in patients with adult congenital heart disease (n = 80) at our institution between January 1998 and October 2009. Ten patients (13%) had a congenital systemic venous anomaly. Of these, seven (9%) had a left superior vena cava and four (5%) had infrahepatic interruption of the inferior vena cava (two had both anomalies). One patient's inferior vena cava was connected to a left-sided atrium; she had right atrial isomerism. In four patients (40%), systemic venous abnormalities were discovered at the time of electrophysiologic testing. Systemic venous anomalies occur frequently in the congenital heart disease population and may complicate electrophysiologic testing and catheter ablation. Pre-procedural imaging may assist in facilitating a successful procedure.

Outcomes following the Kawashima procedure for single-ventricle palliation in left atrial isomerism

Patients with left atrial isomerism and interrupted inferior vena cava palliated with a superior cavopulmonary connection or Kawashima procedure (KP) have a high incidence of developing pulmonary arteriovenous malformations. The necessity for hepatic vein redirection (HVR) and its timing remains a controversy. We aimed to assess the clinical outcome of patients with left atrial isomerism following a KP. The main end points were death, requirement for HVR and the impact of HVR on oxygen saturation. Retrospective review of 21 patients with a diagnosis of left atrial isomerism, interruption of the inferior vena cava and single-ventricle physiology managed with a KP at a single centre between January 1990 and March 2010. Twenty-one patients had a KP, with 12 subsequently undergoing HVR. There was relatively a constant monthly decrement in the proportion of patients who were free from death or HVR up until 60 months following the KP, with a dramatic increase in the hazard after this time. The Cox proportional hazards regression model demonstrated a reduced early risk for HVR or death in patients who underwent pulmonary artery banding versus arterial shunt as the primary procedure (hazard ratio: 0.10; P = 0.01), and an increased risk with bilateral superior vena cavas (SVCs) (hazard ratio: 3.4; P = 0.04) and age at KP (hazard ratio: 1.02 per month increase in age at KP; P = 0.02). HVR mortality was relatively high with 3 of 12 patients dying in the early postoperative period with profound cyanosis. The timing of HVR after the KP did not influence the postoperative rate of increase in oxygen saturation. These findings confirm that the majority of patients who undergo a KP will require HVR. Patients who are older at the time of the KP or having an initial arterial shunt or bilateral SVCs are at higher risk of HVR or death. The relatively high mortality at HVR was characterized by severe postoperative cyanosis.

Hypoplastic left heart syndrome with restrictive atrial septum and advanced heart block documented with a novel fetal electrocardiographic monitor

Hypoplastic left ventricle with congenital heart block has been reported previously in a fetus with concurrent left atrial isomerism and levo-transposition of the great arteries. We present the unusual case of an infant diagnosed in utero with hypoplastic left heart syndrome, a restrictive atrial septum and advanced heart block but with D-looping of the ventricles and no atrial isomerism. In addition, fetal heart rhythm was documented with the assistance of a new fetal electrocardiographic monitor.

Role of four‐dimensional ultrasound (spatiotemporal image correlation and Sonography‐based Automated Volume Count) in prenatal assessment of atrial morphology in cardiosplenic syndromes

To assess the diagnostic role of four-dimensional ultrasound using spatiotemporal image correlation and Sonography-based Automated Volume Count (STIC-SonoAVC) in the identification of the morphology of the atrial appendages in cases with cardiosplenic syndrome. This was a retrospective investigation of 22 fetuses with cardiosplenic syndromes seen at our institution over a 5-year period from January 2004. As control groups, 10 normal fetuses, five cases with a non-isomeric atrioventricular septal defect and five cases with other congenital heart diseases were also analyzed. For all fetuses, one or more cardiac volume datasets were available for offline analysis. Two-dimensional and four-dimensional echocardiography was carried out in all cases at the time of diagnosis using high quality three-dimensional equipment. Dedicated software was used to assess chamber morphology using the SonoAVC technique, which allows the creation of casts of hollow structures. Two different operators used the software. The first performed all steps up to positioning of the region of interest box. The second operator, who was blinded to clinical information, then rendered the cardiac chambers using the SonoAVC technique. This operator then used the rendered image to subjectively assess atrial morphology. Suitable rendered images of the cardiac chambers could be produced in 40/42 fetuses. In two cases of left atrial isomerism, advanced (34 weeks) and early (13 weeks) gestational age made it impossible to obtain adequate rendered images. In the remaining 40 cases (13 cases of left atrial isomerism, seven cases of right atrial isomerism, five cases of non-isomeric atrioventricular septal defect, five cases of other congenital heart diseases and 10 normal fetuses), atrial morphology was correctly identified by evaluation of the rendered images. Four-dimensional ultrasound with SonoAVC rendering allows correct identification of the morphology of atrial appendages in all cases of cardiosplenic syndromes in which an adequate cardiac volume dataset can be obtained for analysis.

Sequence variations of NKX2-5 and HAND1 genes in patients with atrial isomerism

Atrial isomerism is a congenital disorder, which is characterized by lateralization defects in normally asymmetrical developing organs like the heart. Atrial isomerism is supposed to be caused by molecular defects during early development. The NKX2-5 is a cardiac specific transcription factor, which initiates and regulates downstream transcriptional cascades of cardiogenesis. The HAND1 is another transcription factor expressed in the heart, and it is characterized by an asymmetrical pattern of expression. In this study, we aimed to test whether mutations in NKX2-5 and HAND1 genes play a role in the etiology of atrial isomerism. This case-control study consisted of 70 patients who underwent surgical treatment for congenital heart defects including atrial isomerism, 80 healthy subjects (HAND1 gene) and 40 healthy subjects (NKX2-5 gene). All exons and exon-intron boundaries of NKX2-5 and HAND1 genes were analyzed by SSCP, and suspected samples were sequenced for mutation analysis. Digestion with appropriate restriction enzymes was performed for analysis of known mutations and polymorphisms. The frequencies of the alleles and the genotypes were compared among patient and control groups using the Chi-square and the Fisher tests when appropriate. In intronic region of HAND1 gene, we identified a C>G substitution both in patients and controls. Frequency of mutant allele (11, 42%) was found higher (p=0.046) in patient group than that of the control group (2.5%). Association between atrial isomerism and genotypes with mutant allele was found borderline significant (p=0.054). In NKX2-5 gene, we identified heterozygous Q170X (Gln170ter) mutation in one patient. We did not found any correlation between defined sequence variations and clinical properties of the patients. Our results suggest that mutations or sequence variations in HAND1 or NKX2-5 genes may play role in etiology or pathogenesis of atrial isomerism.

Is Pitx2 Growing Up?

In this issue of Circulation: Cardiovascular Genetics , Kirchhof et al1 present an interesting study on the expression of the developmental transcription factor Pitx2c in adult heart and its potential role in atrial fibrillation (AF). AF is the most common sustained cardiac arrhythmia, with a prevalence that increases with age and affects 1% to 2% of the general population.2 Despite recent advances in AF research, underlying pathophysiologic mechanisms are not fully understood. In general, initiation and perpetuation of AF needs a trigger for its onset and a vulnerable substrate for its maintenance.3 Focal ectopic activity can act as a trigger to initiate AF on the basis of a single- or multiple-circuit reentry.4 Especially, cardiomyocyte sleeves around the pulmonary veins have been shown as an origin of focal activity.5 Underlying mechanisms are early and delayed after depolarizations as a result of disturbances in depolarizing inward (Na+ or Ca2+) or repolarizing outward (K+) currents.6 Article see p 123 Once initiated, AF itself induces structural and electric remodeling, which stabilizes reentry and AF maintenance.6 Structural remodeling due to signaling through angiotensin, profibrotic cytokines like transforming growth factor-β, or microRNAs leads to upregulation of extracellular matrix proteins (eg, collagen) and downregulation of matrix-degrading enzymes (eg, matrix metalloproteinase), resulting in progressive atrial fibrosis. Electric remodeling is caused by expressional changes in ion channel subunits. AF induces calcium overload and increases activity of protein phosphatases, leading to downregulation of depolarizing L-type calcium channels and upregulation of repolarizing potassium channels. Measurable substrate of these changes in atrial electric properties is the shortening of action potential duration (APD), leading to shortening of refractory period and enabling reentry mechanisms. In most cases, therefore, AF is self-terminating (paroxysmal) in the beginning, developing to more sustained forms (persistent and permanent) over …

Echocardiography in Heterotaxy Syndrome

The important anatomic aspects of heterotaxy syndrome can be diagnosed by Doppler echocardiography in the newborn and infant. An organized approach and an understanding of asplenia (right atrial isomerism) and polysplenia (left atrial isomerism) are integral to the echocardiographic study. Detailed and precise depiction of the anatomy is the mainstay for staging subsequent medical and surgical management.

Complex cardiac anatomy and catheter access: the role of imaging in patients referred for catheter ablation

A 66-year-old man with Kartagener's syndrome, situs inversus totalis, and recurrent supraventricular tachycardia and a 49-year-old man with atrial fibrillation and drug-refractory rapid ventricular rate response were referred for catheter ablation. In the first case, the mirrored anatomy of the right atrium was reconstructed using three-dimensional electroanatomical mapping, which guided successful ablation of a typical atrioventricular nodal reentrant tachycardia. In the second case, computerized tomography showed the presence of left atrial isomerism with interruption of the inferior vena cava and azygous continuation into the superior vena cava, guiding advancement of the ablation catheter for access into the positionally right atrial ablation site. These cases illustrate the role of imaging in patients with unusual anatomy of the cardiac chambers and major blood vessels guiding optimal catheter access for catheter ablation.

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q

Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21-33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-cM critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.

Síndrome de heterotaxia

The arrangement of the heart is basically symmetrical along the right-left longitudinal axis. The heterotaxy syndromes are a group of diseases characterised by an incorrect alignment of the cardiac structures themselves, or in relation to other organs. This leads to a plethora of congenital heart diseases, which include changes in visceral situs. This left atrial isomerism is a form of situs ambiguous which is often associated with the polysplenia syndrome. This is characterised by the presence of two morphologically left atria, with their respective atrial appendices. Other cardiac or extra-cardiac anomalies may appear, which show a wide variability in their anatomy, clinical presentation and prognosis. Approximately 14% of cases have minor cardiac lesions, and they enter adult life asymptomatic. We present an example of left atrial isomerism which was diagnosed late, amongst other extra-cardiac anomalies which come within the polysplenia syndrome.

Heterotaxy and isomerism of the atrial appendages☆

Several of the assertions made by Serraf and colleagues [1], when describing heterotaxy syndrome, should be questioned. The syndrome is, indeed, a disorder that involves ‘abnormal lateralization of the abdominal viscera, thoracic organs and cardiac atria’; but this definition would include patients having so-called ‘situs inversus’. In support of their statement that ‘HS tends to fall into two readily recognized subtypes, namely right and left atrial isomerism’, they cite a publication that sought to deny the existence of ‘atrial isomerism’ [2]. There is justification for this argument, as the essence of the subsets of patients having morphologic isomerism within the heart is the presence of bilaterally symmetrical atrial appendages [3]. If the morphology of the appendages is assessed on the basis of the extent of the pectinate muscles, there are no intermediate categories [3]. Thus, it is incorrect for the authors to state that ‘several exceptions to this rule were found’. To the best of my knowledge, only Uemura and colleagues [3] have specifically used the morphology of the appendages to stratify a large cohort of patients with socalled heterotaxy. Their definitions create further problems when attention is directed to Table 1 in their article. They suggest that a majority of their patients had either ‘situs solitus’ or ‘situs inversus’, but give no information as to the criteria used to reach these diagnoses. If based on patterns of venous return, such an approach breaks the rules of the ‘morphologic method’, the principle established by Van Praagh and colleagues [4] stating that one cardiac anatomic feature should not be defined on the basis of another variable feature. When using this rule, it is only the morphology of the atrial appendages that serves accurately to discriminate between the subsets of heterotaxy. Serraf then argues, in his response to the excellent question posed by Stellin in

Interventricular dyssynchrony due to unilateral atrioventricular conduction block in a patient with right atrial isomerism and twin atrioventricular nodes

We often experience heterotaxy syndrome and twin atrioventricular (AV) nodes. Their ventricular morphologies are complicated and heterogeneous. Moreover, the associated conduction system anatomy has not yet been fully elucidated. On the other hand, experimental AV node modification has been conducted for AV reciprocating tachycardia involving 2 distinct AV nodes 1 Wu M.H. Lin J.L. Wang J.K. Chiu I.S. Young M.L. Electrophysiological properties of dual atrioventricular nodes in patients with right atrial isomerism. Br Heart J. 1995; 74: 553-555 Crossref PubMed Scopus (21) Google Scholar , 2 Wu M.H. Wang J.K. Lin J.L. et al. Supraventricular tachycardia in patients with right atrial isomerism. J Am Coll Cardiol. 1998; 32: 773-779 Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar , 3 Bae E.J. Noh C.I. Choi J.Y. et al. Twin AV node and indued supraventricular tachycardia in Fontan patients. Pacing Clin Electrophysiol. 2005; 28: 126-134 Crossref PubMed Scopus (48) Google Scholar , 4 Epstein M.R. Saul J.P. Weindling S.N. Triedman J.K. Walsh E.P. Atrioventricular reciprocating tachycardia involving twin atrioventricular nodes in patients with complex congenital heart disease. J Cardiovasc Electrophysiol. 2001; 12: 671-679 Crossref PubMed Scopus (106) Google Scholar or junctional tachycardia in patients with heterotaxy syndrome. 5 Wu M.H. Wang J.K. Lin J.L. Lin M.T. Chiu S.N. Chen C.A. Long-term outcome of twin atrioventricular node and supraventricular tachycardia in patients with right isomerism of atrial appendage. Heart Rhythm. 2008; 5: 224-229 Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar , 6 Toyohara K. Yoshimoto J. Ozaki N. Nakamura Y. Successful catheter ablation of reentrant junctional tachycardia in a patient with asplenia syndrome before total cavo-pulmonary connection. Pacing Clin Electrophysiol. 2010; 33: e43-e45 Crossref PubMed Scopus (5) Google Scholar Herein we describe a patient with right atrial isomerism who required cardiac resynchronization therapy (CRT) because of severe interventricular dyssynchrony due to unilateral AV block.

Total Anomalous Pulmonary Venous Connection

Background— Late mortality after repair of total anomalous pulmonary venous connection is frequently associated with pulmonary venous obstruction (PVO). We aimed to describe the morphological spectrum of total anomalous pulmonary venous connection and identify risk factors for death and postoperative PVO. Methods and Results— We conducted a retrospective, international, collaborative, population-based study involving all 19 pediatric cardiac centers in the United Kingdom, Ireland, and Sweden. All infants with total anomalous pulmonary venous connection born between 1998 and 2004 were identified. Cases with functionally univentricular circulations or atrial isomerism were excluded. All available data and imaging were reviewed. Of 422 live-born cases, 205 (48.6%) had supracardiac, 110 (26.1%) had infracardiac, 67 (15.9%) had cardiac, and 37 (8.8%) had mixed connections. There were 2 cases (0.5%) of common pulmonary vein atresia. Some patients had extremely hypoplastic veins or, rarely, discrete stenosis of the individual veins. Sixty (14.2%) had associated cardiac anomalies. Sixteen died before intervention. Three-year survival for surgically treated patients was 85.2% (95% confidence interval 81.3% to 88.4%). Risk factors for death in multivariable analysis comprised earlier age at surgery, hypoplastic/stenotic pulmonary veins, associated complex cardiac lesions, postoperative pulmonary hypertension, and postoperative PVO. Sixty (14.8%) of the 406 patients undergoing total anomalous pulmonary venous connection repair had postoperative PVO that required reintervention. Three-year survival after initial surgery for patients with postoperative PVO was 58.7% (95% confidence interval 46.2% to 69.2%). Risk factors for postoperative PVO comprised preoperative hypoplastic/stenotic pulmonary veins and absence of a common confluence. Conclusions— Preoperative clinical and morphological features are important risk factors for postoperative PVO and survival.

The Clinical Course and Incidence of Supraventricular Tachyarrhythmias After Extra-Cardiac Conduit Fontan Procedures in Relation to an Atrial Situs

The extra-cardiac conduit Fontan (EC) has a lower incidence of tachyarrhythmias than other types of Fontan. However, some intrinsic arrhythmogenic conditions, such as atrial isomerism, have been associated with a high incidence of arrhythmias. We retrospectively reviewed the clinical course of the supraventricular tachyarrhythmias (SVTs) in 212 patients after an EC, compared the results according to the atrial situs and investigated the substrate of the SVTs. The atrial situs was a solitus or inversus (SS/SI) in 152 patients, right isomerism (RI) in 45 and left isomerism (LI) in 15. Twenty-four SVTs occurred in 22 (11%) patients ≥3 months after the EC. The freedom from SVT after the EC was 95%, 76% and 77% in the SS/SI, RI and LI patients at 5 years, respectively (P<0.0001). Among the 16 SVTs associated with atrial isomerism, 10 were not related to the atrioventricular (AV) node. For the atrial isomerism, the predictors of SVT ≥3 months after the EC were a history of an AV valve repair (risk ratio (RR) 1.9; P=0.02) and complications associated with sinus node dysfunction (RR 1.9; P=0.03). Death related to SVT occurred in 3 patients. Postoperative SVTs after the EC with an atrial isomerism were not uncommon, mostly did not involve the AV node and possibly were caused by atrial tissue damage. A comprehensive therapeutic strategy should be considered.

Successful Ablation for Atrioventricular Nodal Reentrant Tachycardia in a Patient with Left Atrial Isomerism

Left atrial isomerism (LAI) is characterized by the presence of two morphologically identical atria. It is commonly associated with conduction defects. We report a case of LAI presenting with highly symptomatic atrioventricular nodal reentrant tachycardia, which was cured by ablation.

Atrioventricular valve repair in patients with functional single ventricle

We aimed to evaluate surgical repair of atrioventricular valve regurgitation in patients with functional single ventricle. The medical records of 65 consecutive patients with functional single ventricle who underwent atrioventricular valve repair between January 1999 and October 2008 were reviewed retrospectively. Their characteristics were as follows: median age, 9.5 months; median weight, 6.0 kg; atrial isomerism, 31 patients; and hypoplastic left heart syndrome, 12 patients. Regurgitation was repaired at the palliative, Glenn, and Fontan stage in 21, 29, and 15 patients, respectively. The overall survival was 79% and 70% at 1 and 5 years, respectively. The risk factors for mortality were age less than 3 months (P < .001), body weight less than 4 kg (P < .001), hypoplastic left heart syndrome (P = .001), concomitant Norwood (P < .001), and the palliative stage (P = .004) on the univariate analysis, and body weight less than 4 kg (P = .010, hazard ratio, 9.8; 95% confidence interval, 1.7-55.6) on the multivariate analysis. Twenty patients underwent reoperation (repairs in 15; replacements in 5), and freedom from reoperation at 1 and 5 years was 69% and 57%, respectively. Concomitant systemic-to-pulmonary shunt (P = .040) was a risk factor for reoperation on the univariate analysis. Of the 48 survivors, 38 underwent Fontan completion, 7 underwent the Glenn procedure, and 3 are awaiting the Glenn procedure. The midterm results of atrioventricular valve repair in patients with functional single ventricle were favorable; however, young and small patients, especially those with hypoplastic left heart syndrome, still had poor outcomes.

Sutureless pericardial repair of total anomalous pulmonary venous connection in patients with right atrial isomerism☆

Surgical repair of total anomalous pulmonary venous connection (TAPVC) in patients with right atrial isomerism is associated with a significant risk of recurrent pulmonary venous obstruction (PVO). We evaluate the effect of sutureless repair to reduce the risk of recurrent PVO. Since November 2007, five patients, including three neonates, with right atrial isomerism underwent sutureless repair of TAPVC. The sutureless repair was used in three neonates as an initial procedure and in two infants as a procedure for postrepair PVO. Under deep hypothermic circulatory arrest or low flow cardiopulmonary bypass, pulmonary vein (PV) was incised as long as possible. The atrial wall was partially resected and anastomosed to the pericardial wall around the incised PV. There were no early deaths. No patients showed recurrence of PVO. There was one late death. Two patients underwent a bidirectional Glenn shunt after the sutureless repair. The pulmonary venous confluence was confirmed to be left open at the time of the Glenn surgery. The sutureless technique may be useful not only for postrepair PVO but also for non-operated TAPVC in neonates with right atrial isomerism.

Recessively inherited right atrial isomerism caused by mutations in growth/differentiation factor 1 (GDF1)

Right atrial isomerism (RAI) is a heterotaxy syndrome with disturbances in the left-right axis development, resulting in complex heart malformations and abnormal lateralization of other thoracic and abdominal organs. Although autosomal-recessive inheritance of heterotaxy syndrome is seen in multiple families, underlying gene defects have remained unknown. Here we identify the molecular genetic basis of a kindred with five siblings with RAI. Linkage analysis and positional candidate gene approach showed that the affected children were compound heterozygotes for truncating mutations in the growth/differentiation factor 1 (GDF1) gene. Individuals heterozygous for the mutations were clinically healthy. This finding, supported by the similar phenotype in Gdf1 knockout mouse, provides firm evidence that RAI can occur as a recessively inherited condition, with GDF1 as the culprit gene. The results will shed light on the biological basis of human laterality defects and facilitate molecular diagnosis of RAI.