Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5

Heterozygous mutations in the cardiac homeobox gene, NKX2-5, underlie familial cases of atrial septal defect (ASD) with severe atrioventricular conduction block. In this study, mice heterozygous for Nkx2-5-null alleles were assessed for analogous defects. Although ASD occurred only rarely, atrial septal dysmorphogenesis was evident as increased frequencies of patent foramen ovale and septal aneurysm, and decreased length of the septum primum flap valve. These parameters were compounded by genetic background effects, and in the 129/Sv strain, septal dysmorphogenesis bordered on ASD in 17% of Nkx2-5 heterozygotes. In a proportion of neonatal heterozygotes, as well as in adults with ASD, we found that the size of the foramen ovale was significantly enlarged and altered in shape, potentially exposing the normally thin septum primum to excessive hemodynamic forces. Therefore, defective morphogenesis of the septum secundum may be one contributing factor in the generation of patent foramen ovale, septal aneurysm, and certain ASDs. Mild prolongation of P-R interval in females and an increased frequency of stenotic bicuspid aortic valves were also features of the Nkx2-5 heterozygous phenotype. Our data demonstrate that the complex effects of Nkx2-5 haploinsufficiency in mice are weaker but convergent with those in humans. As in the mouse, the phenotype of human NKX2-5 mutations may be modulated by interacting alleles.     

Webbed left atrial septal pouch—A new anatomical variant

Atrial septal pouch is a recently described anatomical entity. We describe webbed left atrial septal pouch (LSP), a new variant in the spectrum of fusion of septum primum and septum secundum. In the continuum of the natural history of atrial septal closure from patent foramen ovale (PFO) to complete fusion of the septum, we propose the septal anatomy in our patient to be secondary to partially developed adhesions or septa. Potential association of LSP with stroke due to in situ thrombosis and atrial fibrillation has been described. Recognition of septal anatomy is vital to avoid complications related to transseptal puncture.     

Platypnea-orthodeoxia in a patient with ostium primum atrial septal defect with normal right heart pressures

We describe an adult patient with an ostium primum atrial septal defect (ASD) and a patent foramen ovale (PFO) with normal right heart pressures who presented with platypnea and orthodeoxia. A dilated aortic root encroaching into the region of the ASD and PFO, along with a tricuspid regurgitant jet moving into the left atrium through the ASD found on the transesophageal echocardiogram may have been responsible for orthodeoxia. Surgical closure of these defects resulted in the disappearance of both platypnea and orthodeoxia.     

Patent foramen ovale with right atrial septal pouch

A patent foramen ovale (PFO) is a communication across the inter‐atrial septum and a right atrial septal pouch (RASP) is an indentation of the atrial septum caused by an incomplete fusion of the septum primum and septum secundum with its base opening into the right atrium. A 63‐year‐old male who had a history of two strokes and episodes of transient neurological deficit was diagnosed to have a small right‐to‐left shunt. At the time of PFO closure, an angiogram of the atrial septum revealed a small PFO associated with a RASP. The small PFO was crossed with a straight‐tipped guide wire and was closed using a 25‐mm GORE CARDIOFORM Septal Occluder (W.L. Gore and Associates, AZ). It is hypothesized that stagnant blood in the RASP may generate a clot that can cross the PFO and cause an infarct. © 2015 Wiley Periodicals, Inc.     

Iatrogenic erosion of the septum primum resulting in an atrial septal defect with left‐to‐right shunt: A rare pitfall of patent foramen ovale percutaneous closure

Iatrogenic erosion of the septum primum after foramen ovale closure is an anecdotal event. We report the case of a 39‐year‐old woman admitted to our institution for multifocal cryptogenic cerebral ischemia and a patent foramen ovale (PFO) associated with an aneurysm of the septum primum. The patient underwent percutaneous closure of the PFO with an Amplatzer PFO Occluder device. At the 6‐months follow up, the device was in the right position, but a jagged defect of the septum primum and evidence of significant left‐to‐right shunting was detected. The atrial septal defect was then repaired by a surgical approach. Although this event is not life‐threatening, it should be considered as a therapeutic pitfall, resulting in a risk of paradoxical embolism recurrences and long‐term hemodynamic impairment. © 2013 Wiley Periodicals, Inc.     

Detection of atrial septal defect by right sternal border echocardiography

The atrial septum can be visualized by right sternal border 2-dimensional echocardiography (2-D echo). To evaluate the usefulness of this approach in the evaluation of atrial septal defect (ASD), 50 patients who underwent cardiac catheterization were studied by 2-D echo. Twenty-one patients (Group A) had ASD (3 ostium primum, 18 ostium secundum) and 29 (Group B) had mitral valve disease and an intact atrial septum. Subcostal and right sternal border approaches were used to visualize the atrial septum. Both approaches identified the 3 cases of ostium primum ASD; secundum ASD was identified using the subcostal approach in 11 patients and using the right sternal border approach in 13. In 15 patients the ASD was imaged at least by 1 of the 2 approaches. Two-dimensional contrast echocardiography showed a positive or negative contrast effect in 13 of 18 cases (12 with standard approaches, 11 with right sternal border approach). In all patients in Group B, the right sternal border approach showed an intact atrial septum. Thus, the right sternal border approach is a useful approach that increases the sensitivity of 2-D echo in the diagnosis of ASD.     

Structural and compliant anatomy of the patent foramen ovale in patients undergoing transcatheter closure

BACKGROUND: Most current intracardiac closure devices target the atrial septal defect. However, defects such as the patent foramen ovale (PFO) have unique structural features that may influence rational device design. With mounting interest in transcatheter techniques for closure of PFO in patients with cryptogenic stroke, a clearer understanding of these features is warranted. METHODS: Retrospectively, we reviewed angiograms obtained at the time of transcatheter closure of PFOs with a non-self-centering device in a group of 21 patients with a history of stroke. RESULTS: The PFO appeared as a tunnel of varying length (2.4 to 19.5 mm, mean 9.1 +/- 4.7 mm) bounded by septum secundum and septum primum. The potential area of the defect was as small as 12.2 mm(2) and as large as 121.1 mm(2). With device placement, the tunnel length shortened or disappeared (0.5 +/- 1.6 mm) by inferior displacement of the more compliant septum primum. CONCLUSIONS: In patients with PFO referred for transcatheter closure, the defect most commonly appeared as a tunnel-like defect between a thicker, less compliant septum secundum and a thinner, more compliant septum primum. Although the length of the undisturbed tunnel varied widely, the tunnel was shortened or eliminated by placement of a non-self-centering device. The observation that PFO anatomy can be predictably altered by some devices may have an impact on device design or implantation technique.     

Atrial and ventricular septal defects can safely be closed by percutaneous intervention

Various transcatheter devices and methods to close congenital heart defects are currently available. Devices have been designed specifically for atrial septal defect (ASD), patent foramen ovale (PFO), and ventricular septal defect (VSD) closure. The trend in interventional treatment of intracardiac shunts shows toward defect-specific systems. The PFO is a tunnel defect requiring occluders that adapt to its length while common ASD strongly vary in their diameter, making a large scale of device sizes indispensable. VSDs are predominantly sealed by coils or tissue-adapted devices like muscular or perimembranous occluders. Since VSDs may occur with an aneurysm (VSA), a multi-perforated septum, an instable myocardial situation (postinfarction) or a high interventricular pressure gradient, closure of these defects is regarded sometimes as complicated. But during the last 30 years (since King and Mills implanted the first double-umbrella occluding system) several studies have proven procedure efficacy and safety of both ASD and VSD closure. This article reviews a large scale of studies and includes our single center data on 1,609 PFO, ASD, and VSD patients.     

The matricellular protein CCN1 is essential for cardiac development

The matricellular protein CCN1 (formerly named CYR61) regulates cell adhesion, migration, proliferation, survival, and differentiation through binding to integrin receptors and heparan sulfate proteoglycans. Here we show that Ccn1-null mice are impaired in cardiac valvuloseptal morphogenesis, resulting in severe atrioventricular septal defects (AVSD). Remarkably, haploinsufficiency for Ccn1 also results in delayed formation of the ventricular septum in the embryo and persistent ostium primum atrial septal defects (ASD) in approximately 20% of adults. Mechanistically, Ccn1 is not required for epithelial-to-mesenchymal transformation or cell proliferation and differentiation in the endocardial cushion tissue. However, Ccn1 deficiency leads to precocious apoptosis in the atrial junction of the cushion tissue and impaired gelatinase activities in the muscular component of the interventricular septum at embryonic day 12.5, when fusion between the endocardial cushion tissue and the atrial and ventricular septa occurs, indicating that these defects may underlie the observed AVSD. Moreover, human CCN1 maps to 1p21-p31, the chromosomal location of an AVSD susceptibility gene. Together, these results provide evidence that deficiency in matrix signaling can lead to autosomal dominant AVSD, identify Ccn1(+/-) mice as a genetic model for ostium primum ASD, and implicate CCN1 as a candidate gene for AVSD in humans.     

Percutaneous treatment of atrial septal aneurysm

Among a total number of 203 patients with atrial septal defects (ASD) or patent foramen ovale (PFO) who were treated by percutaneous closure, we selected 29 (19 with ASD and 10 with PFO) who fulfilled the criteria for atrial septal aneurysm. Eight patients had functional class II or III dyspnea, and 12 had a history of previous cerebrovascular accident (38%). Seven of the patients with ASD, had a single defect and 12 had multiple defects; 14 received a single occluder and 5 patients needed 2 or 3 devices. Follow-up transthoracic ultrasound study at 6 months showed the defect to be successfully closed in all 29 patients. After a mean follow-up time of 31 +/- 19 months, all patients were alive and symptom-free. Patients with atrial septal aneurysm and associated ASD or PFO can be successfully treated with Amplatzer septal occluders.     

Beware of the LASP! A structure with thrombogenic potential

The left atrial septal pouch (LASP) is a recently identified anatomical variant of the interatrial septum. It is the result of the incomplete fusion of septum primum and septum secundum and defined as a recessus communicating with the left atrium without interatrial shunt. Such anatomical feature has been suspected representing a potential thrombogenic source, but its actual role as risk factor for cryptogenic stroke still remains unclear. In this case report, we show two distinct thrombotic masses emerging from the LASP and its related areas.     

Partial atrioventricular septal defect assessed by real-time three-dimensional echocardiography: a case report

A 48-year-old woman was admitted with a heart murmur and increased difficulty in breathing. Two-dimensional echocardiography revealed a defect in the lower part of the atrial septum [(primum atrial septal defect (ASD)] and a pouch at the interventricular septum. Color Doppler echocardiography detected grade 3/4 mitral regurgitation. Real-time three-dimensional echocardiography (RT-3DE) revealed a cleft in the anterior leaflet of the mitral valve toward the tricuspid valve, and the ASD located near the atrioventricular valves with 14mm in minor axis. Color Doppler three-dimensional echocardiography disclosed left-to-right ASD shunt toward the atrial posterior wall. No shunt through the pouch at the membranous part, left ventricular outflow obstruction, or partial anomalous pulmonary venous connection was observed. RT-3DE is quite useful to describe complicated congenital heart disease.     

Patency of the interatrial septum in children undergoing cardiac catheterization

Catheter passage into the left atrium from the right atrium greatly facilitates invasive cardiovascular evaluation and reduces the risks attendant on cardiac catheterization studies. We reviewed 371 consecutive cardiac catheterizations to establish the presence of natural interatrial communications. Catheter course, pressure equalization, and left-to-right atrial shunt on recirculation angiography were considered to determine intact interatrial septum (IIS), patent foramen ovale (PFO) or atrial septal defect (ASD). During the first year of life, 88% of infants had PFO or ASD; in 12%, the interatrial septum was intact. In children 1–10 years old, 49% had IIS, 27% had PFO, and 24% had ASD. In children 10–21 years old, 24% had PFO, or ASD. Though there seems to be a greater likelihood of ISS in those with left heart obstruction, hemodynamic factors did not completely explain the timing of closure of the foramen ovale. Presence of an interatrial communication allows catheter entrance into all left heart structures including the aorta; therefore, in patients with PFO or ASD, retrograde arterial procedure or transseptal puncture technique can be avoided when performing left heart catheterization. This appears possible in 88% of those under 1 year of age, in 51% of those 1–10 years old, and in 24% of children 10–21 years old.     

Transcatheter patent foramen ovale closure is effective in reducing migraine independently from specific interatrial septum anatomy and closure devices design

BackgroundRelationships between migraine improvement after transcatheter patent foramen ovale (PFO) closure and both specific interatrial septum anatomy and different devices design have not been investigated yet. We sought to assess effectiveness of transcatheter PFO closure in reducing or curing migraine with aura in patients with previous paradoxical embolism in relation with specific interatrial septum anatomy and different closure devices.Methods and ResultsWe prospectively enrolled 34 patients (22 female and 12 male, mean age 40±3.7 years) who were referred to our centre over a 12-month period for PFO transcatheter closure and migraine with aura and previous paradoxical embolism. All procedures were performed using mechanical intracardiac echocardiographic guidance. Patients were assigned to Amplatzer PFO or ASD Multifenestrated Occluder and Premere Occlusion System implantation dependently from intracardiac echocardiography anatomical findings, which included short-channel with moderate atrial septal aneurysm (ASA) in 6 patients (17.6 %), long-channel with moderate ASA in 3 patients (8.8%), short-channel with huge ASA in 5 patients (14.7%), multifenestrated ASA in 4 patients (11.7%), long-channel PFO without ASA in 10 patients (29.4%), and long-channel PFO with mild ASA in 6 patients (17.6%). Accordingly, 18 patients received an Amplatzer Occluder (9 PFO Occluder and 7 ASD Multifenestrated Occluder), and 16 received a Premere Occlusion System. After a mean follow-up of 9.0±2.8 months, all patients improved their migraine symptoms (mean Migraine Disability Assessment Score 30±1.5 at baseline versus 6.0±2.9 in the follow up, P<.03) independently from specific interatrial septum anatomy and different closure devices.ConclusionAlthough our study had several limitations, it suggests that independently from interatrial septum anatomy and device type, PFO closure in patients with migraine with aura resulted in a high rate of migraine improvement.     

Catheter closure of atrial septal defects and patent foramen ovale in patients with an atrial septal aneurysm using different devices

BACKGROUND: Atrial septal aneurysm is frequently associated with patent foramen ovale (PFO) and atrial septal defects (ASD). Moreover, a relationship between atrial septal aneurysm and embolic cerebrovascular events has been suggested. The aims of this study were to analyze morphological and functional characteristics of atrial septal aneurysm in PFO and ASD patients and to assess the feasibility and efficacy of different devices for transcatheter closure and the influence of atrial septal aneurysm. METHODS: Between March 1997 and May 2000 transcatheter ASD or PFO closure was attempted in 63 patients (mean age 47 +/- 13 years) with an atrial septal aneurysm using one of the following devices: Angelwings (n = 3), Cardioseal (n = 5), Cardioseal-Starflex (n = 7), Amplatzer (n = 11), Amplatzer-PFO (n = 5), PFO-Star (n = 25), or Helex (n = 7). RESULTS: Implantation was primarily successful (after the first or second attempt) in all patients. One PFO-Star device embolized 12 hours after the procedure. During follow-up (0.6-37 months, mean 10.4 +/- 9.2) a residual shunt could be detected by transesophageal echocardiography after 2 weeks in four patients and after 6 months in one patient. Three PFO patients had cerebrovascular events after implantation. Two patients had a transient ischemic attack (TIA) and one patient a stroke. A thrombus formation on the device detected in three patients disappeared after antithrombotic therapy. CONCLUSION: We conclude that ASDs and PFOs with an associated atrial septal aneurysm can be closed with different available devices. There seem to be no additional risks compared with patients without atrial septal aneurysm.     

Accidental sizing of patent foramen ovale during atrial septal defect sizing for device

A 21 year old lady with a 22 mm secundum atrial septal defect with adequate rims, and thin septum at the region of the fossa ovalis, but no additional atrial septal defect by transthoracic and transoesophageal echocardiogram was taken up for ASD sizing with a view to device closure. Initially, the ASD was sized to only 8 mm. However, the distal balloon was not fully opened out, and seemed to be conical with restricted opening. Inadvertent passage of sizing balloon through a patent foramen ovale (PFO) was immediately confirmed by transthoracic echocardiogram. The ASD was then recrossed and sized to 24 mm with normal opening out of the distal balloon. This was confirmed by transthoracic echocardiogram. A 28 mm ASD device was deployed across the ASD under transthoracic echocardiographic guidance with no residual flow.     

Subcostal two-dimensional echocardiographic identification of anomalous attachment of septum primum in patients with left atrioventricular valve underdevelopment

Five variations of atrial septal morphology occur in hypoplastic left heart syndrome. One variety, termed anomalous attachment of septum primum, has been described only in necropsy series. Two-dimensional echocardiography was utilized to determine the incidence of this anomaly in patients with left atrioventricular (AV) valve underdevelopment, including those with other ventriculoarterial alignments, such as transposition of the great arteries. Forty-eight (37%) of 129 patients with normally aligned great arteries (and two ventricles) had anomalous attachment of septum primum. Ten (34%) of 29 patients with double outlet right ventricle and left AV valve underdevelopment had this anomaly. Four (50%) of eight patients with single ventricle exhibited this atrial septal variant. The most reliable view to identify anomalous attachment was the subcostal left oblique-equivalent cut. Recognition of atrial septal morphology has implications for preoperative and intraoperative management of patients with left AV valve underdevelopment. The similar prevalence of this atrial septal variant in patients with normally aligned great arteries, double outlet right ventricle and transposed great arteries suggests that there may be a common mechanism for left AV valve underdevelopment that is independent of the development of the arterial portion of the heart.     

Echocardiographic characteristics of successful deployment of the Das AngelWings atrial septal defect closure device: initial multicenter experience in the United States

The AngelWings device is a newer transcatheter device used for closure of secundum atrial septal defects (ASD) and patent foramen ovale (PFO), which consists of a self-centering, 2-disk system. Transesophageal echocardiography (TEE) plays a pivotal role in the deployment of the 2 disks of this device, on the appropriate sides of the atrial septum. The objective of this study is to describe the echocardiographic findings associated with successful deployment of the AngelWings device for closure of ASD and PFO. We evaluated the TEE studies of 70 patients enrolled in 4 United States centers, for closure of ASD and PFO with the AngelWings device. The TEE characteristics of successful and unsuccessful deployments were analyzed. Residual shunts across the atrial septum were assessed by TEE at the end of the procedure, 24 hours later by transthoracic echocardiography, and at 6 months by TEE. The deployment of the device was successful in 65 patients (93%). In the unsuccessful group, ASD size by TEE was larger (13.4 +/- 3.1 vs 8.9 +/- 4.7 mm, p <0.05). TEE was successful in identifying snagging of the device by intracardiac structures and prolapse of corners of the left or right atrial disk through the ASD, features that were difficult to identify by fluoroscopy. The echocardiographic characteristics outlined here are important guidelines for successful deployment of the AngelWings device.     

Transcranial Doppler quantification of residual shunt after percutaneous patent foramen ovale closure: correlation of device efficacy with intracardiac anatomic measures

Background: Percutaneous, mechanical closure of defects of the atrial septum fails to completely resolve shunting in up to 20% of cases. Little is known about the factors associated with device failure. Methods: We measured the left atrial opening (X), right atrial opening (Z), tunnel length (Y), septum secundum, device‐septum primum separation, and tunnel compressibility of the patent foramen ovale (PFO) in 301 patients with cryptogenic neurological events, PFO anatomy, and severe Valsalva shunting (Spencer Grade 5–5+). All patients then underwent percutaneous closure with the GORE®HELEX Septal Occluder device and were evaluated at 3 months for residual shunt by transcranial Doppler (TCD). Results: Severe residual Valsalva shunt (TCD Grade 5–5+) was found at 3 months in 21 of 301 (7%) patients. X, Y, and Z were associated with failure with a high degree of statistical significance, whereas the width of the septum secundum, device‐septum primum separation, and tunnel compressibility were not. An unanticipated finding was that 14 of 35 (40%) patients sized with a large balloon failed compared with 9 of 280 (3%) sized with a small balloon (P < 0.0001). In the multivariate logistic regression model, X (P = < 0.0001) and balloon size (P < 0.0001) were both strong predictors of failure. Conclusions: In an intracardiac echocardiography‐defined PFO population, characterized by severe baseline Valsalva shunt and a high incidence of persistent (rest) shunting, association of six intracardiac measurements to closure device failure by multivariate logistic regression showed that the width of the left atrial opening was a strong predictor of residual shunting. An unanticipated finding was that use of a large sizing balloon was also strongly associated with failure. (J Interven Cardiol 2012;25:304–312)     

Role of intracardiac echocardiography in atrial septal abnormalities

The purpose of this review is to outline the feasibility of performing a comprehensive atrial septal examination from the internal confine of the right atrium and to evaluate the advantages resulting by intracardiac echocardiography (ICE) evaluation of atrial septal morphology as well as pathophysiology. In this setting, ICE indications have not yet been established because ICE is a relatively new technique that is still evolving. Notwithstanding, during catheter-based secundum atrial septal defect and patent foramen ovale closure, ICE seems useful for diagnosing cardiac abnormalities instantly, guiding and monitoring all stages of the procedures, and assessing proper selection and optimal device placement. Moreover, ICE provides solid anatomical criteria to diagnose fenestrated atrial septal aneurysm, interatrial communications such as ostium primum and sinus venosus defects, partial anomalous pulmonary venous connection, and lipomatous hypertrophy of atrial septum.