Organ Dynamics and Hemodynamic of the Whole HH25 Avian Embryonic Heart, Revealed by Ultrasound Biomicroscopy, Boundary Tracking, and Flow Simulations.

Congenital heart malformations occur to substantial number of pregnancies. Studies showed that abnormal flow biomechanical environments could lead to malformations, making it important to understand the biomechanical environment of the developing heart. We performed 4D high-frequency ultrasound scans of chick embryonic hearts at HH25 to study the biomechanics of the whole heart (atria and ventricle). A novel and high-fidelity motion estimation technique, based on temporal motion model and non-rigid image registration algorithm, allowed automatic tracking of fluid-structure boundaries from scan images, and supported flow simulations. Results demonstrated that atrial appendages were the most contractile portion of the atria, having disproportionately high contribution to atrial blood pumping for its volume in the atria. However, the atria played a small role in blood pumping compared to the ventricle, as it had much lower ejection energy expenditure, and as the ventricle appeared to be able to draw inflow from the veins directly during late diastole. Spatially and temporally averaged wall shear stresses (WSS) for various cardiac structures were 0.062-0.068 Pa, but spatial-averaged WSS could be as high as 0.54 Pa in the RV. WSS was especially elevated at the atrial inlet, atrioventricular junction, regions near to the outflow tract, and at dividing lines between the left and right atrium and left and right side of the ventricle, where septation had begun and the lumen had narrowed. Elevated WSS could serve as biomechanics stimulation for proper growth and development.

Anatomy and Physiologic Roles of the Left Atrial Appendage: Implications for Endocardial and Epicardial Device Closure.

The left atrial appendage has been implicated as a major nidus for thrombus formation, particularly in atrial fibrillation. This discovery has prompted substantial interest in the development of left atrial appendage exclusion devices aimed at decreasing systemic thromboembolism risk. Its deceptively simple appearance belies the remarkable complexity that characterizes its anatomy and physiology. We highlight the key anatomic features and variations of the left atrial appendage as well as its relationships with surrounding structures. We also summarize crucial anatomic factors that should be taken into account by the interventional cardiologist when planning for or performing left atrial appendage exclusion procedures.

The left atrial appendage: from embryology to prevention of thromboembolism.

The left atrial appendage (LAA) is the main source of thromboembolism in patients with non-valvular atrial fibrillation (AF). As such, the LAA can be the target of specific occluding device therapies. Optimal management of patients with AF includes a comprehensive knowledge of the many aspects related to LAA structure and thrombosis. Here we provide baseline notions on the anatomy and function of the LAA, and then focus on current imaging tools for the identification of anatomical varieties. We also describe pathogenetic mechanisms of LAA thrombosis in AF patients, and examine the available evidence on treatment strategies for LAA thrombosis, including the use of non-vitamin K antagonist oral anticoagulants and interventional approaches.

Left atrial appendage isolation using percutaneous (endocardial/epicardial) devices: Pre-clinical and clinical experience.

Atrial fibrillation (AF) is the most common arrhythmia in the elderly population and it is associated with a four-fold to five-fold increased risk of thromboembolic events. It was not until the mid-1950s that the left atrial appendage (LAA) was identified as the main location of thrombus formation, particularly in patients with non-valvular AF. In this review, we explain at some extent its embryology, anatomy and physiology, and as well as the clinical and pre-clinical trials published to date testing the safety and efficacy of most LAA closure devices. Among those devices, the most studied include the PLAATO system (ev3 Endovascular, Plymouth, MN), the Amplatzer cardiac plug (St Jude, Golden Valley, MN; St. Jude Medical, Minneapolis, MN), the WATCHMAN device (Boston Scientific, Plymouth, MN; Atritech Inc., Plymouth, MN), and the LARIAT device (SentreHEART, Palo Alto, CA). Similarly, newer LAA closure devices currently under investigation such as the Transcatheter Patch (Custom Medical Devices, Athens, Greece), AEGIS, and the Coherex WaveCrest (Salt Lake City, UT) will also be discussed. Future perspectives and the need for well-designed prospective studies between devices and new oral anticoagulant drugs are also proposed.

Cor triatriatum or divided atriums: which approach provides the better understanding?

It is frequent, in the current era, to encounter congenital cardiac malformations described in terms of "cor triatriatum". But can hearts be truly found with three atrial chambers? The morphological method, emphasised by Van Praagh et al, states that structures within the heart should be defined on the basis of their most constant components. In the atrial chambers, it is the appendages that are the most constant components, and to the best of our knowledge, hearts can only possess two appendages, which can be of either right or left morphology. The hearts described on the basis of "cor triatriatum", nonetheless, can also be analysed on the basis of division of either the morphologically right or the morphologically left atriums. In this review, we provide a description of cardiac embryology, showing how each of the atrial chambers possesses part of the embryological body, along with an appendage, a vestibule, a venous component, and a septum that separates them. We then show how it is, indeed, the case that the hearts described in terms of "cor triatriatum" can be readily understood on the basis of division of these atrial components. In the right atrium, it is the venous valves that divide the chamber. In the left atrium, it is harder to provide an explanation for the shelf that produces atrial division. We also contrast the classic examples of the divided atrial chambers with the vestibular shelf that produces supravalvar stenosis in the morphologically left atrium, showing that this form of obstruction needs to be distinguished from the fibrous shelves producing intravalvar obstruction.

A detailed comparison of mouse and human cardiac development.

BACKGROUND: Mouse mutants are used to model human congenital cardiovascular disease. Few studies exist comparing normal cardiovascular development in mice vs. humans. We carried out a systematic comparative analysis of mouse and human fetal cardiovascular development. METHODS: Episcopic fluorescence image capture (EFIC) was performed on 66 wild-type mouse embryos from embryonic day (E) 9.5 to birth; 2-dimensional and 3-dimensional datasets were compared with EFIC and magnetic resonance images from a study of 52 human fetuses (Carnegie stage 13-23). RESULTS: Time course of atrial, ventricular, and outflow septation were outlined and followed a similar sequence in both species. Bilateral venae cavae and prominent atrial appendages were seen in the mouse fetus; in human fetuses, atrial appendages were small, and a single right superior vena cava was present. In contrast to humans with separate pulmonary vein orifices, a pulmonary venous confluence with one orifice enters the left atrium in mice. CONCLUSION: The cardiac developmental sequences observed in mouse and human fetuses are comparable, with minor differences in atrial and venous morphology. These comparisons of mouse and human cardiac development strongly support that mouse morphogenesis is a good model for human development.

The role of connexin40 in developing atrial conduction.

Connexin40 (Cx40) is the main connexin expressed in the murine atria and ventricular conduction system. We assess here the developmental role of Cx40 in atrial conduction of the mouse. Cx40 deficiency significantly prolonged activation times in embryonic day 10.5, 12.5 and 14.5 atria during spontaneous activation; the severity decreased with increasing age. In a majority of Cx40 deficient mice the impulse originated from an ectopic focus in the right atrial appendage; in such a case the activation time was even longer due to prolonged activation. Cx40 has thus an important physiological role in the developing atria.

Left cardiac isomerism in the Sonic hedgehog null mouse.

Sonic hedgehog (Shh) is a secreted morphogen necessary for the production of sidedness in the developing embryo. In this study, we describe the morphology of the atrial chambers and atrioventricular junctions of the Shh null mouse heart. We demonstrate that the essential phenotypic feature is isomerism of the left atrial appendages, in combination with an atrioventricular septal defect and a common atrioventricular junction. These malformations are known to be frequent in humans with left isomerism. To confirm the presence of left isomerism, we show that Pitx2c, a recognized determinant of morphological leftness, is expressed in the Shh null mutants on both the right and left sides of the inflow region, and on both sides of the solitary arterial trunk exiting from the heart. It has been established that derivatives of the second heart field expressing Isl1 are asymmetrically distributed in the developing normal heart. We now show that this population is reduced in the hearts from the Shh null mutants, likely contributing to the defects. To distinguish the consequences of reduced contributions from the second heart field from those of left-right patterning disturbance, we disrupted the movement of second heart field cells into the heart by expressing dominant-negative Rho kinase in the population of cells expressing Isl1. This resulted in absence of the vestibular spine, and presence of atrioventricular septal defects closely resembling those seen in the hearts from the Shh null mutants. The primary atrial septum, however, was well formed, and there was no evidence of isomerism of the atrial appendages, suggesting that these features do not relate to disruption of the contributions made by the second heart field. We demonstrate, therefore, that the Shh null mouse is a model of isomerism of the left atrial appendages, and show that the recognized associated malformations found at the venous pole of the heart in the setting of left isomerism are likely to arise from the loss of the effects of Shh in the establishment of laterality, combined with a reduced contribution made by cells derived from the second heart field.

Early morphogenesis of the sinuatrial region of the chick heart: a contribution to the understanding of the pathogenesis of direct pulmonary venous connections to the right atrium and atrial septal defects in hearts with right isomerism of the atrial appendages.

The morphogenesis of the sinuatrial region of embryonic hearts is still not well understood. Current matters of dispute are the topogenesis of the future pulmonary vein orifice and the topogenesis of the primary atrial septum. We analyzed the development of the sinuatrial region in chick embryos ranging from Hamburger and Hamilton (HH) stage 14 to 25. Our study disclosed three features of sinuatrial development. First, the primitive atrium of the HH stage 16 chick embryo heart has a separate inflow component. This inflow component takes up the mouth of the confluence of the systemic veins (sinus venosus) as well as the future mouth of the common pulmonary vein (pulmonary pit). The left portion of the atrial inflow component becomes incorporated into the left atrium and its right portion becomes incorporated into the right atrium. Rightward growth of the sinuatrial fold separates the sinus venosus from the left atrium. Second, the pulmonary pit originally forms as a bilaterally paired structure. Its left and right portions are connected to the left and right portions of the atrial inflow component, respectively. Normally, only the left portion of the pulmonary pit deepens to form the common pulmonary vein orifice, whereas the right portion disappears. Third, the primary atrial septum of the chick heart is not formed at the original midline of the embryonic heart, but is formed to the left of the original midline. This finding is in accord with molecular data suggesting that the primary atrial septum derives from the left heart-forming field. Our findings shed new light on the pathogenesis of direct pulmonary venous connections to the right atrium and atrial septal defects in hearts with right isomerism of the atrial appendages.

Reconstruction of the patterns of gene expression in the developing mouse heart reveals an architectural arrangement that facilitates the understanding of atrial malformations and arrhythmias.

Firm knowledge about the formation of the atrial components and of the variations seen in congenital cardiac malformations and abnormal atrial rhythms is fundamental to our understanding of the normal structure of the definitive atrial chambers. The atrial region is relatively inaccessible and has continued to be the source of disagreement. Seeking to resolve these controversies, we made three-dimensional reconstructions of the myocardial components of the developing atrium, identifying domains on the basis of differential expression of myocardial markers, connexin40, and natriuretic precursor peptide A. These reconstructions, made from serial sections of mouse embryos, show that from the outset of atrial development, the systemic and pulmonary veins are directly connected to the atrium. Relative to the systemic junctions, however, the pulmonary venous junction appears later. Our experience shows that three-dimensional reconstructions have three advantages. First, they provide clear access to the combined morphological and molecular data, allowing clarification and verification of morphogenetic concepts for nonmorphological experts and setting the scene for further discussion. Second, they demonstrate that, from the outset, the myocardium surrounding the pulmonary veins is distinct from that clothing the systemic venoatrial junctions. Third, they reveal an anatomical and molecular continuity between the entrance of the systemic venous tributaries, the internodal atrial myocardium, and the atrioventricular region. All these regions are derived from primary myocardium, providing a molecular basis for the observed nonrandom distribution of focal right atrial tachycardias.