Molecular Pathways and Animal Models of Atrial Septal Defect.

The relative simplicity of the clinical presentation and management of an atrial septal defect belies the complexity of the developmental pathogenesis. Here, we describe the anatomic development of the atrial septum and the venous return to the atrial chambers. Experimental models suggest how mutations and naturally occurring genetic variation could affect developmental steps to cause a defect within the oval fossa, the so-called secundum defect, or other interatrial communications, such as the sinus venosus defect or ostium primum defect.

Unexpected diagnosis: large hemangioma in the interatrial septum.

BACKGROUND: Cardiac hemangiomas are very uncommon benign primary tumors. They are usually located preferentially in the right atrium and their location in the interatrial septum is extremely rare. CASE PRESENTATION: We report the case of a 41-year-old patient who was admitted due to a stroke. The transthoracic echocardiogram revealed a large mass in the right atrium adhered to the interatrial septum. Suspecting an atrial myxoma, surgical intervention was performed confirming that the mass extended within the thickness of the interatrial septum, protruding into the right atrial cavity. The histologic report confirmed a hemangioma. CONCLUSIONS: Cardiac hemangiomas are rare primary tumors and are usually misdiagnosed as other cardiac tumors. Histopathological examination is essential for a definitive diagnosis.

Extinction of Lipomatous Hypertrophy of the Interatrial Septum FDG Uptake With Propranolol Premedication.

ABSTRACT: Lipomatous hypertrophy of the interatrial septum is a rare lesion of the heart. CT and cardiac MR are often sufficient to determine the benign lipomatous nature of the tumor and can avoid the need for histological confirmation. Lipomatous hypertrophy of the interatrial septum contains variable amounts of brown adipose tissue, resulting in different degrees of 18 F-FDG uptake in PET. We report the case of a patient with an interatrial lesion suspected of malignancy, discovered on CT and failing cardiac MR, with initial 18 F-FDG uptake. Final characterization was made thanks to 18 F-FDG PET with ß-blocker premedication, avoiding an invasive procedure.

Increased 18F-PSMA and 18F-FDG Uptake in Lipomatous Hypertrophy of the Interatrial Septum.

ABSTRACT: Lipomatous hypertrophy of the interatrial septum (LHIS) is a benign anomaly with low prevalence. Lipomatous hypertrophy of the interatrial septum is asymptomatic in most of the cases and rarely leads to atrial arrhythmias, obstructive flow symptoms, or sudden death. It is mostly diagnosed as an incidental finding in cross-sectional imaging and echocardiography, and increased 18F-FDG uptake on LHIS has been described. We present a case of repeated increased 18F-PSMA uptake in LHIS. Although very rare, familiarity with the typical features and prevalence of LHIS in PET/CT can avoid misinterpretation for metastatic disease.

Lipomatous Hypertrophy of the Interatrial Septum in a Patient with Chronic Dyspnea and Episodes of Paroxysmal Atrial Fibrillation: A Case Report.

Lipomatous Hypertrophy of the Interatrial Septum (LHIS) is an unusual condition usually found as an incidental finding on echocardiography. It can create a mass-like bulge typically sparing the fossa ovalis. We describe a 73-year-old overweight Cypriot woman, who visited our clinic in November 2018 and was complaining of dyspnea on exertion, chest tightness, and two episodes of paroxysmal atrial fibrillation for the last eight months. A big sessile mass was detected in the interatrial septum measuring 3.7×4.7 cm during transoesophageal echocardiography. The patient underwent resection of the mass and pericardial patch reconstruction of the defect with significant improvement of her clinical status during the follow-up period. The histopathological analysis suggested LHIS. In patients with persistent cardiac symptoms, a prompt resection is a useful option, although surgery is generally considered unnecessary in this clinical setting. Preprint of this article is available on: https://www.authorea.com/users/380290/articles/496351-a-patient-with-chronic-dyspnea-and-episodes-of-paroxysmal-atrial-fibrillation-in-the-presence-of-a-right-atrial-mass.

Vascular tangle in the inter-atrial septum - Is it the source of cardiac myxoma?

BACKGROUND: Cardiac myxomas (CMs) are the most common primary tumors of the heart, said to be derived from pluripotent cardiac stem cells. They are most often attached to the left side of the inter-atrial septum (IAS) and a feature noted at the site of attachment is a conglomeration of thick-walled vessels that has been noted to precede the development of myxomas. AIMS: The present study was conducted to compare histology of the normal inter-atrial septa to the septal flap excised with the myxomas and to evaluate the significance of this 'vascular tangle' in the histogenesis of these tumors. MATERIALS AND METHODS: In a 10-year retrospective analysis of all surgically excised CMs, tumors with attached septal sleeves were selected. This histology was compared to the serial sections of 25 normal age-matched septa obtained from normal hearts at autopsy. RESULTS: Of the 56 myxomas seen in 10 years, 38 tumors (all left atrial in location) were received with a flap of the IAS. All of these cases, irrespective of the sizes of the tumor, showed the presence of conglomeration of thick-walled blood vessels, many of which showed abrupt myxoid change in their walls. Another noteworthy feature in many vessels in all flaps was migration of the myxoid tissue through the vascular walls and the endocardium to mushroom out into the atrial lumen. Such vascular channels were not seen in any of the normal IAS. CONCLUSIONS: Based on these findings, we propose a two-step hypothesis: an initial step that stimulates the pluripotent cells toward vasculogenesis with endothelial and smooth muscle differentiation, and a subsequent step leads to production of abundant mucopolysaccharides that splay apart the smooth muscle cells, which would explain rings, cords or nests of myxoma cells around endothelial lined spaces.

Patent foramen ovale closure for secondary prevention of cryptogenic stroke.

Introduction: A patent foramen ovale (PFO) is highly prevalent among the adult population. It allows shunting of blood through the inter-atrial septum and has been associated with cryptogenic stroke, transient ischemic attack, platypnea-orthodeoxia syndrome, decompression sickness (e.g. deep-water divers), and migraines.Areas Covered: In this manuscript, we will review the anatomy of PFO with particular emphasis on the factors associated with increased risk of paradoxical embolization, as well as the different modalities for the diagnosis of PFO. We will discuss medical, surgical, and transcatheter therapy for secondary prevention in patients with PFO and cryptogenic stroke, and summarize the data from observational studies, randomized controlled trials (RCTs), and meta-analysis of RCTs that have established the beneficial effect of transcatheter PFO closure in this patient population. Finally, we will provide a brief overview of the role of transcatheter PFO closure in patients with migraine.Expert Opinion: Transcatheter closure is the preferred treatment option in young (<60 years) patients with PFO and cryptogenic stroke. A multi-disciplinary approach with input from clinical cardiologist, neurologist, hematologist, cardiac surgeon, and interventional cardiologist provides the best therapeutic plan for each patient taking into account the available data, but also medical, social, and occupational considerations.

Endothelial Dysfunction May Link Interatrial Septal Abnormalities and MTHFR-Inherited Defects to Cryptogenic Stroke Predisposition.

We explored the significance of the L-Arginine/asymmetric dimethylarginine (L-Arg/ADMA) ratio as a biomarker of endothelial dysfunction in stroke patients. To this aim, we evaluated the correlation, in terms of severity, between the degree of endothelial dysfunction (by L-Arg/ADMA ratio), the methylene tetrahydrofolate reductase (MTHFR) genotype, and the interatrial septum (IAS) phenotype in subject with a history of stroke. Methods and Results: L-Arg, ADMA, and MTHFR genotypes were evaluated; the IAS phenotype was assessed by transesophageal echocardiography. Patients were grouped according to the severity of IAS defects and the residual enzymatic activity of MTHFR-mutated variants, and values of L-Arg/ADMA ratio were measured in each subgroup. Of 57 patients, 10 had a septum integrum (SI), 38 a patent foramen ovale (PFO), and 9 an ostium secundum (OS). The L-Arg/ADMA ratio differed across septum phenotypes (p ≤ 0.01), and was higher in SI than in PFO or OS patients (p ≤ 0.05, p ≤ 0.01, respectively). In the PFO subgroup a negative correlation was found between the L-Arg/ADMA ratio and PFO tunnel length/height ratio (p ≤ 0.05; r = - 0.37; R2 = 0.14). Interestingly, the L-Arg/ADMA ratio varied across MTHFR genotypes (p ≤ 0.0001) and was lower in subgroups carrying the most impaired enzyme with respect to patients carrying the conservative MTHFR (p ≤ 0.0001, p ≤ 0.05, respectively). Consistently, OS patients carried the most dysfunctional MTHFR genotypes, whereas SI patients the least ones. Conclusions: A low L-Arg/ADMA ratio correlates with impaired activity of MTHFR and with the jeopardized IAS phenotype along a severity spectrum encompassing OS, PFO with long/tight tunnel, PFO with short/large tunnel, and SI. This infers that genetic MTHFR defects may underlie endothelial dysfunction-related IAS abnormalities, and predispose to a cryptogenic stroke. Our findings emphasize the role of the L-Arg/ADMA ratio as a reliable marker of stroke susceptibility in carriers of IAS abnormalities, and suggest its potential use both as a diagnostic tool and as a decision aid for therapy.

Hipertrofia lipomatosa del septum interatrial: reporte de un caso / Lipomatous hypertrophy of the interatrial septum. A case report

Resumen La hipertrofia lipomatosa del septum interauricular (HLSI) es una entidad cardiaca rara y benigna, que se caracteriza por la acumulación de tejido adiposo dentro de algunos segmentos del septum interatrial. Generalmente, los pacientes son asintomáticos y estas lesiones se descubren de manera incidental mediante estudios de imagen realizados por otras razones, o en el contexto de una autopsia. Se han descrito casos de muerte súbita por alteración del ritmo cardiaco en estos pacientes. El diagnóstico diferencial de la HLSI incluye principalmente tumores cardiacos. Se expone el caso de un paciente de 61 años que, después de un estudio de resonancia magnética cardiaca, realizado por una alteración del ritmo cardiaco, presenta una masa en el septum auricular. El paciente es llevado a cirugía y el estudio histopatológico de la lesión confirma el diagnóstico. Se realiza una revisión de las características clínicas y patológicas de la HLSI.

Abstract Lipomatous Hypertrophy of the Interatrial Septum (LHIS) is a rare and benign cardiac entity that is characterized by the accumulation of adipose tissue within some segments of the interatrial septum. Patients are generally asymptomatic, and these lesions are discovered incidentally by imaging studies performed for other reasons, or in the context of an autopsy. In these patients, there have been described cases of sudden death due to disturbance of the heart rhythm. The differential diagnosis of LHIS mainly includes cardiac tumors. Here we present a case of a 61-year-old patient in whom, after a cardiac magnetic resonance study performed for an abnormal heart rhythm, it was documented a mass in the atrial septum. The patient was taken to surgery, and the histopathological study of the lesion confirmed the diagnosis. We conduct a review of the clinical and pathological characteristics of LHIS.

Lipomatous hypertrophy of the interatrial septum is a pathologic, not an anatomic diagnosis.

BACKGROUND AND AIM: Lipomatous hypertrophy of the interatrial septum (LHIS), a fatty tumor, is usually diagnosed on both echo and CT/MRI imaging. Cases of LHIS located outside of the interatrial septum are extremely rare and rarer still are these cases large enough to cause symptoms. The clinical literature demonstrates a misunderstanding that fatty tumors outside the intra-atrial area represent lipomas. However, pathologic understanding of these fatty tumors is clear and is based on microscopic findings. METHODS: The tumor was removed by diving the base of attachment at the left ventricular apex via a median sternotomy on cardiopulmonary bypass. RESULTS: The patient made an uneventful recovery and remains well at 6 months postoperatively. CONCLUSIONS: On rare occasions, LHIS can arise from outside the interatrial septum. An LHIS can be differentiated from a lipoma by the presence of entrapped cardiac myocytes in LHIS, making it a pathological, rather than an anatomic, diagnosis.

Pulmonary venous Doppler patterns and midterm outcomes in fetuses with left-sided obstructive lesions and restrictive atrial septum.

OBJECTIVE: To compare length of stay of the initial neonatal hospitalization and mortality across multiple stages of surgical palliation for infants with left-sided obstructive lesions and severely restrictive or intact atrial septum (I/RAS). METHODS: Retrospective cohort study of patients prenatally diagnosed with left-sided obstructive lesions and I/RAS, defined by fetal pulmonary venous Dopplers. RESULTS: We identified 76 fetal patients with 59 live born intending to pursue intervention. Those with I/RAS had longer durations of mechanical ventilation (P = .031) but no difference in intensive care unit or total length of stay. Survival to discharge from neonatal hospitalization was 41.7% in the I/RAS group and 80.7% in the unrestrictive group (P = .001). There was a higher proportion of deaths between stage 1 and stage 2 in the I/RAS group - 5/9 (55.6%) vs 9/50 (18%) in the unrestrictive group (P = .027). Beyond stage 2 palliation there was trend toward a difference in overall mortality (66.7% in I/RAS vs 35.7% in unrestrictive, P = .05) but no statistically significant difference in transplant-free survival (33.3% in I/RAS vs 53.5% in unrestrictive, P = .11). CONCLUSION: The survival disadvantage conferred by prenatally diagnosed severe atrial septal restriction is most pronounced in the neonatal and early infancy period, with no detectable difference in late midterm transplant-free survival in our cohort.

Bronchogenic cyst of the interatrial septum.

Although bronchogenic cysts are the most common primary mediastinal cysts, intracardiac bronchogenic cysts are extremely rare. We report a case of a bronchogenic cyst of the interatrial septum in a 42-year-old woman who presented with recent onset of dyspnea on exertion. Cardiac investigations including transthoracic echocardiography and computed tomography revealed a cystic homogeneous mass in the interatrial septum. The patient underwent surgical resection, and the resultant atrial septal defect was repaired using an autologous pericardial patch. Histopathological examination of the resected specimen revealed findings consistent with a benign bronchogenic cyst. Although bronchogenic cysts are extremely rare, they should be considered in the differential diagnoses of intracardiac tumors. Complete resection of bronchogenic cysts is recommended primarily for diagnostic and potentially therapeutic purposes.

Atrial septum biopsy for direct substrate characterization in atrial fibrillation.

INTRODUCTION: The aim of this study was to describe and illustrate the technique of performing interatrial septum biopsy and to demonstrate its use for direct histological substrate characterization in atrial fibrillation (AF). METHODS AND RESULTS: Biopsies were performed in four patients who underwent AF catheter ablation. Bipal 7 bioptome was directed through a steerable sheath directly onto the septum. Fluoroscopic views as well as echocardiography-guided techniques were utilized to confirm that the tip was oriented towards the interatrial septum. The bioptome was then placed on the right atrial (RA) septum and maneuvered to obtain the specimens (at least 1 mm in size) from the posterior septal region of the RA, adjacent to the fossa ovalis. Bioptome placement and sample acquisition were successful in all patients at the first attempt. No patient developed any minor or major complications during the procedure and hospital stay. All the biopsy specimens had proper qualities for histological assessments and revealed a variety of pathologies including fibrosis, inflammation, and fatty infiltration. CONCLUSION: Atrial septum biopsies could be safely performed guided by fluoroscopy and transesophageal echocardiography. The obtained specimens allowed for a detailed localized substrate characterization which is of great interest in AF.

Low incidence of atrial septal defects in nonmammalian vertebrates.

The atrial septum enables efficient oxygen transport by separating the systemic and pulmonary venous blood returning to the heart. Only in placental mammals will the atrial septum form by the coming-together of the septum primum and the septum secundum. In up to one of four placental mammals, this complex morphogenesis is incomplete and yields patent foramen ovale. The incidence of incomplete atrial septum is unknown for groups with the septum primum only, such as birds and reptiles. We found a low incidence of incomplete atrial septum in 11 species of bird (0% of specimens) and 13 species of reptiles (3% of specimens). In reptiles, there was a trabecular interface between the atrial septum and the atrial epicardium which was without a clear boundary between left and right atrial cavities. In developing reptiles (four squamates and one crocodylian), the septum primum initiated as a sheet that acquired perforations and the trabecular interface developed late. We conclude that atrial septation from the septum primum only results in a low incidence of incompleteness. In reptiles, the atrial septum and atrial wall develop a trabecular interface, but previous studies on atrial hemodynamics suggest this interface has a very limited capacity for shunting.

Interatrial septum: A pictorial review of congenital and acquired pathologies and their management.

There are many different congenital abnormalities and acquired pathologies involving the interatrial septum. Differentiation of these pathologies significantly affects patient management. We have reviewed the various interatrial septal pathologies and discussed their congenital associates, clinical significance, and management. After reading this article, the reader should be able to better characterize the interatrial septal pathologies using the optimal imaging tools, and have a better understanding of their clinical significance and management.

Interatrial septal fat thickness and left atrial stiffness are mechanistic links between nonalcoholic fatty liver disease and incident atrial fibrillation.

BACKGROUND AND AIM: Recently, a clear evidence suggests that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of incident atrial fibrillation (AF). Yet, the underlying pathogenesis is speculative. Thereby, we aimed to investigate the hypothesis that, interatrial thickness (IAST) and left atrial stiffness (LASt) might have mechanistic links between NAFLD and AF. METHODS: Echocardiography and speckle-tracking assessment of left atrial function, transient elastography (TE) of the liver, basal ECG, and Holter monitoring were performed in 180 patients with (NAFLD) and 80 subjects without NAFLD. RESULTS: Patients with NAFLD had higher values of IAST (P < 0.001), LASt (<0.001), and E/e' ratio (<0.003) compared with controls. IAST was correlated with LASt (r = 0.413; P < 0.001). 15.6% of patients with NAFLD had AF. More so, patients with increased IAST/LASt had a higher incidence of AF (25%) vs 3.8% in those with normal IAST/LASt. The LASt and IAST increased significantly in those with AF compared with those without (P < 0.001). Patients who experienced AF had higher values (P < 0.01) of TE (kPa). The degree of liver stiffness TE (kPa) was correlated with both IAST and LASt (r = 461, r = 0.535; P < 0.001). Furthermore, multivariate regression analysis showed that LASt and IAST were independent predictors of incident AF in subjects with NAFLD. CONCLUSIONS: Our data suggest that increased IAST and LASt index are independently associated with incident atrial fibrillation in patients with NAFLD. Increased IAST and LASt index might provide mechanistic links between NAFLD and incident atrial fibrillation.

Morphological variations of the interatrial septum in ovine heart.

Smooth septum interatrial septum, patent foramen ovale (PFO) channel and atrial septal pouches (SPs) are commonly described variants in humans. Recent discoveries on the clinical significance of left-sided SP may encourage the creation of new strategies and devices for the management of SPs. However, these strategies may first be tested in the ovine model before implementation in humans. Unfortunately, little is known about the presence of SPs in ovine. In this study a total of 60 ovine (Ovis aries) hearts were examined. The interatrial septum morphology was assessed and the PFO channel and SPs were measured. The most commonly occurring variant were PFO channels (25.0%) with channel lengths of 5.4±2.3 mm. Smooth septums were observed in 18.3% of hearts. In the remaining cases, septums had a left septal ridge (15.0%), left SP (11.7%), left septal bridge (10.0%), right SP (10.0%), or had both a right SP and left septal ridge (10.0%). No double SPs were observed. The mean right SP depth was 3.4 ± 1.2 mm, and its mean ostium width and height were 7.9±1.8 mm and 2.8±1.0, respectively. For the left SP, the mean depth was 6.0±1.7mm, the ostium width was 7.9±2.4mm, and the ostium height was 4.1±1.6mm (range: 2.3-6.4mm). In conclusion the interatrial septum of ovine hearts exhibit morphologies that are more similar to humans than they are to swine, which should be taken into account during experimental studies. The presence of a left SP in sheep hearts make ovine models a promising alternative to the human heart for developing left-sided SP management devices and techniques.