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.

Human Cardiac Development.

Many aspects of heart development are topographically complex and require three-dimensional (3D) reconstruction to understand the pertinent morphology. We have recently completed a comprehensive primer of human cardiac development that is based on firsthand segmentation of structures of interest in histological sections. We visualized the hearts of 12 human embryos between their first appearance at 3.5 weeks and the end of the embryonic period at 8 weeks. The models were presented as calibrated, interactive, 3D portable document format (PDF) files. We used them to describe the appearance and the subsequent remodeling of around 70 different structures incrementally for each of the reconstructed stages. In this chapter, we begin our account by describing the formation of the single heart tube, which occurs at the end of the fourth week subsequent to conception. We describe its looping in the fifth week, the formation of the cardiac compartments in the sixth week, and, finally, the septation of these compartments into the physically separated left- and right-sided circulations in the seventh and eighth weeks. The phases are successive, albeit partially overlapping. Thus, the basic cardiac layout is established between 26 and 32 days after fertilization and is described as Carnegie stages (CSs) 9 through 14, with development in the outlet component trailing that in the inlet parts. Septation at the venous pole is completed at CS17, equivalent to almost 6 weeks of development. During Carnegie stages 17 and 18, in the seventh week, the outflow tract and arterial pole undergo major remodeling, including incorporation of the proximal portion of the outflow tract into the ventricles and transfer of the spiraling course of the subaortic and subpulmonary channels to the intrapericardial arterial trunks. Remodeling of the interventricular foramen, with its eventual closure, is complete at CS20, which occurs at the end of the seventh week. We provide quantitative correlations between the age of human and mouse embryos as well as the Carnegie stages of development. We have also set our descriptions in the context of variations in the timing of developmental features.

Surgical Repair of Common Arterial Trunk With Ventriculoarterial Septal Defect and Dual Orifice Truncal Valve.

We present a case of a rare example of a ventriculo-arterial septal defect found in a patient with a common arterial trunk, with balanced aortic and pulmonary components, but with separate valvar orifices within the common truncal valve. We managed the lesion using a two-patch approach. Performing a palliative procedure to relieve the elevated right ventricular pressure aided in the preservation of the pulmonary component of the common valve. We validated the success of the technique using postoperative computerized tomography and four-dimensional flow magnetic resonance imaging.

Complex Atrial Baffling Procedures in Left Isomerism With Right- and Left-Hand Topology.

We describe complex atrial baffling procedures in the setting of left isomerism with right-hand as opposed to left-handed ventricular topology. An appropriate understanding of the connections of the systemic and pulmonary veins, along with the internal atrial anatomy, as revealed using 3D printing, allowed for successful biventricular repair.

Cardiac development demystified by use of the HDBR atlas.

Much has been learned over the last half century regarding the molecular and genetic changes that take place during cardiac development. As yet, however, these advances have not been translated into knowledge regarding the marked changes that take place in the anatomical arrangements of the different cardiac components. As such, therefore, many aspects of cardiac development are still described on the basis of speculation rather than evidence. In this review, we show how controversial aspects of development can readily be arbitrated by the interested spectator by taking advantage of the material now gathered together in the Human Developmental Biology Resource; HDBR. We use the material to demonstrate the changes taking place during the formation of the ventricular loop, the expansion of the atrioventricular canal, the incorporation of the systemic venous sinus, the formation of the pulmonary vein, the process of atrial septation, the remodelling of the pharyngeal arches, the major changes occurring during formation of the outflow tract, the closure of the embryonic interventricular communication, and the formation of the ventricular walls. We suggest that access to the resource makes it possible for the interested observer to arbitrate, for themselves, the ongoing controversies that continue to plague the understanding of cardiac development.

An unusual form of "haemodynamic vise" in supra cardiac totally anomalous pulmonary venous drainage.

We report an unusual variant of obstructed supra cardiac anomalous pulmonary venous drainage where the vertical vein is obstructed by a vice formed between the persistent arterial duct and the left pulmonary artery.

Revisiting the anatomy of the left ventricle in the light of knowledge of its development.

Despite centuries of investigation, certain aspects of left ventricular anatomy remain either controversial or uncertain. We make no claims to have resolved these issues, but our review, based on our current knowledge of development, hopefully identifies the issues requiring further investigation. When first formed, the left ventricle had only inlet and apical components. With the expansion of the atrioventricular canal, the developing ventricle cedes part of its inlet to the right ventricle whilst retaining the larger parts of the cushions dividing the atrioventricular canal. Further remodelling of the interventricular communication provides the ventricle with its outlet, with the aortic root being transferred to the left ventricle along with the newly formed myocardium supporting its leaflets. The definitive ventricle possesses inlet, apical and outlet parts. The inlet component is guarded by the mitral valve, with its leaflets, in the normal heart, supported by papillary muscles located infero-septally and supero-laterally. There is but a solitary zone of apposition between the leaflets, which we suggest are best described as being aortic and mural. The trabeculated component extends beyond the inlet to the apex and is confluent with the outlet part, which supports the aortic root. The leaflets of the aortic valve are supported in semilunar fashion within the root, with the ventricular cavity extending to the sinutubular junction. The myocardial-arterial junction, however, stops well short of the sinutubular junction, with myocardium found only at the bases of the sinuses, giving rise to the coronary arteries. We argue that the relationships between the various components should now be described using attitudinally appropriate terms rather than describing them as if the heart is removed from the body and positioned on its apex.

Clarifying the Anatomy of Tetralogy of Fallot with S-shaped Ascending Aorta.

We recently encountered several cases of tetralogy of Fallot with an abnormally oriented S-shaped ascending aorta. In this retrospective study, we sought to clarify morphology of this unusual under-recognized variant. Databases were reviewed to identify all patients with tetralogy of Fallot having an S-shaped ascending aorta. Computed tomographic angiography was used for the assessment of cardiac morphology. Out of the 21 patients, 18 (86%) had a right aortic arch, 2 (9%) had a left aortic arch, and the remaining patient (5%) had a double aortic arch. Patients with a right aortic arch, compared to age and sex-matched patients with a right aortic arch but normally oriented ascending aorta, had lesser aortic override (29.3 ± 14% vs 54.8 ± 13.2%; p = 0.0001) and a wider ascending aorta (25.2 ± 6.9 vs 18.0 ± 3.2 mm; p = 0.0003). The S-shaped ascending aorta was located posteriorly, with a higher sterno-aortic distance (25.5 ± 7.7 vs 9.9 ± 4.5 mm; p = 0.0001). The ascending aorta among patients with tortuosity was longer (4.12 ± 1.7 vs 3.07 ± 0.82, p = 0.03) but with similar tortuosity index (1.22 ± 0.19 vs 1.15 ± 0.17, p = 0.23). Of the cases with right aortic arch and S-shaped ascending aorta, 16 (89%) had extrinsic compression of the right pulmonary artery (p = 0.0001), while 7 (39%) had crossed pulmonary arteries (p = 0.008), with no such findings among those with normally oriented ascending aorta. Tetralogy of Fallot with an S-shaped ascending aorta is a variant with lesser aortic override and a more posteriorly located ascending aorta. Compression of the right pulmonary artery and crossed pulmonary arteries is frequent in the presence of a right-sided aortic arch. These findings have important implications for optimal diagnosis and surgical repair.

The clinical anatomy of the atrioventricular conduction axis.

It is axiomatic that the chances of achieving accurate capture of the conduction axis and its fascicles will be optimized by equally accurate knowledge of the relationship of the components to the recognizable cardiac landmarks, and we find it surprising that acknowledged experts should continue to use drawings that fall short in terms of anatomical accuracy. The accuracy achieved by Sunao Tawara (1906) in showing the location of the atrioventricular conduction axis is little short of astounding. Our purpose in bringing this to current attention is to question the need of the experts to have produced such inaccurate representations, since the findings of Tawara have been extensively endorsed in very recent years. The recent studies do no more than point to the amazing accuracy of the initial account of Tawara. At the same time, we draw attention to the findings described in the middle of the 20th century by Ivan Mahaim (1947). These observations have tended to be ignored in recent accounts. They are, perhaps, of equal significance to those seeking specifically to pace the left fascicles of the branching atrioventricular bundle.

The changing morphology of the ventricular walls of mouse and human with increasing gestation.

That the highly trabeculated ventricular walls of the developing embryos transform to the arrangement during the fetal stages, when the mural architecture is dominated by the thickness of the compact myocardium, has been explained by the coalescence of trabeculations, often erroneously described as 'compaction'. Recent data, however, support differential rates of growth of the trabecular and compact layers as the major driver of change. Here, these processes were assessed quantitatively and visualized in standardized views. We used a larger dataset than has previously been available of mouse hearts, covering the period from embryonic day 10.5 to postnatal day 3, supported by images from human hearts. The volume of the trabecular layer increased throughout development, in contrast to what would be expected had there been 'compaction'. During the transition from embryonic to fetal life, the rapid growth of the compact layer diminished the proportion of trabeculations. Similarly, great expansion of the central cavity reduced the proportion of the total cavity made up of intertrabecular recesses. Illustrations of the hearts with the median value of left ventricular trabeculation confirm a pronounced growth of the compact wall, with prominence of the central cavity. This corresponds, in morphological terms, to a reduction in the extent of the trabecular layer. Similar observations were made in the human hearts. We conclude that it is a period of comparatively slow growth of the trabecular layer, rather than so-called compaction, that is the major determinant of the changing morphology of the ventricular walls of both mouse and human hearts.

Myocardial Blood Flow Determination From Contrast-Free Magnetic Resonance Imaging Quantification of Coronary Sinus Flow.

BACKGROUND: Determination of myocardial blood flow (MBF) with MRI is usually performed with dynamic contrast enhanced imaging (MBFDCE ). MBF can also be determined from coronary sinus blood flow (MBFCS ), which has the advantage of being a noncontrast technique. However, comparative studies of MBFDCE and MBFCS in large cohorts are lacking. PURPOSE: To compare MBFCS and MBFDCE in a large cohort. STUDY TYPE: Prospective, sequence-comparison study. POPULATION: 147 patients with type 2 diabetes mellitus (age: 56+/-12 years; 106 male; diabetes duration: 12.9+/-8.1 years), and 25 age-matched controls. FIELD STRENGTH/SEQUENCES: 1.5 Tesla scanner. Saturation recovery sequence for MBFDCE vs. phase-contrast gradient-echo pulse sequence (free-breathing) for MBFCS . ASSESSMENT: MBFDCE and MBFCS were determined at rest and during coronary dilatation achieved by administration of adenosine at 140 µg/kg/min. Myocardial perfusion reserve (MPR) was calculated as the stress/rest ratio of MBF values. Coronary sinus flow was determined twice in the same imaging session for repeatability assessment. STATISTICAL TESTS: Agreement between MBFDCE and MBFCS was assessed with Bland and Altman's technique. Repeatability was determined from single-rater random intraclass and repeatability coefficients. RESULTS: Rest and stress flows, including both MBFDCE and MBFCS values, ranged from 33 to 146 mL/min/100 g and 92 to 501 mL/min/100 g, respectively. Intraclass and repeatability coefficients for MBFCS were 0.95 (CI 0.90; 0.95) and 5 mL/min/100 g. In Bland-Altman analysis, mean bias at rest was -1.1 mL/min/100 g (CI -3.1; 0.9) with limits of agreement of -27 and 24.8 mL/min/100 g. Mean bias at stress was 6.3 mL/min/100 g (CI -1.1; 14.1) with limits of agreement of -86.9 and 99.9. Mean bias of MPR was 0.11 (CI: -0.02; 0.23) with limits of agreement of -1.43 and 1.64. CONCLUSION: MBF may be determined from coronary sinus blood flow, with acceptable bias, but relatively large limits of agreement, against the reference of MBFDCE . LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Development of the arterial roots and ventricular outflow tracts.

The separation of the outflow tract of the developing heart into the systemic and pulmonary arterial channels remains controversial and poorly understood. The definitive outflow tracts have three components. The developing outflow tract, in contrast, has usually been described in two parts. When the tract has exclusively myocardial walls, such bipartite description is justified, with an obvious dogleg bend separating proximal and distal components. With the addition of non-myocardial walls distally, it becomes possible to recognise three parts. The middle part, which initially still has myocardial walls, contains within its lumen a pair of intercalated valvar swellings. The swellings interdigitate with the distal ends of major outflow cushions, formed by the remodelling of cardiac jelly, to form the primordiums of the arterial roots. The proximal parts of the major cushions, occupying the proximal part of the outflow tract, which also has myocardial walls, themselves fuse and muscularise. The myocardial shelf thus formed remodels to become the free-standing subpulmonary infundibulum. Details of all these processes are currently lacking. In this account, we describe the anatomical changes seen during the overall remodelling. Our interpretations are based on the interrogation of serially sectioned histological and high-resolution episcopic microscopy datasets prepared from developing human and mouse embryos, with some of the datasets processed and reconstructed to reveal the specific nature of the tissues contributing to the separation of the outflow channels. Our findings confirm that the tripartite postnatal arrangement can be correlated with the changes occurring during development.

Revisiting the anatomy of the right ventricle in the light of knowledge of its development.

Controversies continue regarding several aspects of the anatomy of the morphologically right ventricle. There is disagreement as to whether the ventricle should be assessed in bipartite or tripartite fashion, and the number of leaflets to be found in the tricuspid valve. In particular, there is no agreement as to whether a muscular outlet septum is present in the normally constructed heart, nor how many septal components are to be found during normal development. Resolving these issues is of potential significance to those investigating and treating children with congenitally malformed hearts. With all these issues in mind, we have revisited our own experience in investigating the development and morphology of the normal right ventricle. To assess development, we have examined a large number of datasets, prepared by both standard and episcopic microscopy, from human and murine embryos. In terms of gross anatomy, we have compared dissections of normal autopsied hearts with virtual dissections of datasets prepared using computed tomography. Our developmental and postnatal studies, taken together, confirm that the ventricle is best assessed in tripartite fashion, with the three parts representing its inlet, apical trabecular, and outlet components. The ventricular septum, however, has only muscular and membranous components. The muscular part incorporates a small component derived from the muscularised fused proximal outflow cushions, but this part cannot be distinguished from the much larger part that is incorporated within the free-standing muscular infundibular sleeve. We confirm that the tricuspid valve itself has three components, which are located inferiorly, septally, and antero-superiorly.