Cardiac Embryology and Molecular Mechanisms of Congenital Heart Disease: A Primer for Anesthesiologists

Abstract

Congenital heart disease is diagnosed in 0.4% to 5% of live births and presents unique challenges to the pediatric anesthesiologist. Furthermore, advances in surgical management have led to improved survival of those patients, and many adult anesthesiologists now frequently take care of adolescents and adults who have previously undergone surgery to correct or palliate congenital heart lesions. Knowledge of abnormal heart development on the molecular and genetic level extends and improves the anesthesiologist's understanding of congenital heart disease. In this article, we aim to review current knowledge pertaining to genetic alterations and their cellular effects that are involved in the formation of congenital heart defects. Given that congenital heart disease can currently only occasionally be traced to a single genetic mutation, we highlight some of the difficulties that researchers face when trying to identify specific steps in the pathogenetic development of heart lesions.

Figure 1

Overview of human embryogenesis. A) Step-wise progression from fertilization (fusion of sperm and oocyte to create a zygote) to morula and blastocyst with blastocyst implantation into uterus. B) Formation of the germ disc with three germ cell layers.

Figure 2

Schematic representation of cardiac embryology. A) Cardiac crescent at day 15. The first heart field is specified to form particular segments of the linear heart tube. The second heart field is located medial and caudal of the first heart field and will later contribute cells to the arterial and venous pole. B) By day 21, cephalocaudal and lateral folding of the embryo establishes the linear heart tube with its arterial (truncus arteriosus) and venous (primitive atrium) poles. C) By day 28, the linear heart tube loops to the right (D-loop) to establish the future position of the cardiac regions (atria, ventricles, outflow tract). D) By day 50, the mature heart has formed. The chambers and outflow tract of the heart are divided by the atrial septum, the interventricular septum, two atrioventricular valves (tricuspid valve, mitral valve) and two semilunar valves (aortic valve, pulmonary valve). Adapted in modified form from Lindsey SE, Butcher JT, Yalcin HC: Mechanical regulation of cardiac development. Front Physiol 5:318, 2014.

Figure 3

A simplified depiction of formation of protein structures. A) A gene is transcribed and translated to form a protein. Proteins are then assembled to larger structures or functional enzymes. B) A more detailed depiction of the process in A) which includes influencing factors such as modulation and modification at different levels.

Figure 4

Human laterality disorders and current models for establishing left-right asymmetry. By their vigorous circular movements, motile monocilia at the embryonic node generate a leftward flow of extra-embryonic fluid (nodal flow). A) The nodal vesicular parcel (NVP) model predicts that vesicles filled with morphogens (such as sonic hedgehog and retinoic acid) are secreted from the right side of the embryonic node and transported to the left side by nodal flow, where they are smashed open by force. The released contents probably bind to specific transmembrane receptors in the axonemal membrane of cilia on the left side. The consequent initiation of left-sided intracellular Ca²⁺-release induces downstream signaling events that break bilaterality. In this model, the flow of extra-embryonic fluid is not detected by cilia-based mechanosensation. B) In the two-cilia model, non-sensing motile cilia in the centre of the node create a leftward nodal flow that is mechanically sensed through passive bending of non-motile sensory cilia at the periphery of the node. Bending of the cilia on the left side leads to a left-sided release of Ca²⁺ that initiates establishment of body asymmetry. C) Schematic illustration of normal left-right body asymmetry (situs solitus) and five laterality defects that affect the lungs, heart, liver, stomach and spleen. Reprinted with permission from Fliegauf M, Benzing T, Omran H: When cilia go bad: Cilia defects and ciliopathies. Nat Rev Mol Cell Biol 8:880-893, 2007.

Figure 5

Overview of the step-wise formation of cardiac progenitor cells: origination from epiblast cells and subsequent differentiation to mesodermal cells and first/ second heart field cells. A) Presomite embryo at day 16 with primitive streak and primitive node. B) Cross-section through the cranial part of the embryo showing the epi- and hypoblast cells. The primitive streak is shown as an invagination through which epiblast cells migrate. During this process, the epiblast cells differentiate into mesodermal cells characterized by expression of the T-box transcription factor Brachyury/T (Bry⁺). C) Mesodermal cells migrate to the lateral splanchnic mesoderm and undergo further differentiation to cardiogenic mesoderm with expression of mesoderm posterior 1 (MesP1), a core factor involved in committing cells to their cardiogenic fate. D) Cardiogenic mesoderm further differentiates into the first and second heart field, characterized by the expression of NK2 Homeobox 5 (NKX2.5), T-Box protein 5 (TBX5) and insulin gene enhancer protein (Isl1), NK2 Homeobox 5 (NKX2.5) and vascular endothelial growth factor receptor 2 (Flk-1), respectively.

Figure 6

Three cardiac progenitor cell populations are listed with their final contributions to the mature human heart. The lower diagram depicts the spatial locations of the cardiac progenitor cell populations.

Figure 7

Overview of processes leading to atrial septation. A) Atrial septation begins with formation of the primary atrial septum (septum primum) that extends from the atrial roof downwards towards the major atrioventricular cushions. The leading edge of the primary atrial septum carries a mesenchymal cap. The venous pole of the heart is attached to dorsal mesocardium. B) As the primary atrial septum continues its migration downwards and approaches the major atrioventricular cushions, it closes a gap known as ostium primum. Mesenchmal cells from the dorsal mesocardium have invaded the common atrium and join the downward growing primary atrial septum as the dorsal mesenchymal protrusion. C) After fusion of the primary atrial septum, mesenchymal cap and dorsal mesenchymal protrusion with the major atrioventricular cushions, the ostium primum is closed. At the same time, part of the cranial septum primum breaks down and forms the ostium secundum. D) Inward folding of the myocardium from the atrial roof produces the secondary atrial septum (septum secundum) which grows downwards to occlude the ostium primum by mechanism of a flap-valve (at birth, pulmonary vasculature dilates leading to a drop in right atrial pressure; the higher left atrial pressure pushes the primary atrial septum against the secondary atrial septum).

Figure 8

Condensed overview of the function and interaction between three major transcription factors that are viewed as key regulators of cardiac differentiation: T-Box protein 5 (TBX5), GATA-binding protein 4 (GATA4) and NK2 Homeobox 5 (NKX2.5).

Figure 9

A) Configuration of the outflow tract in a normally developed heart; B) Persistent truncus arteriosus in which aorta (Ao) and pulmonary artery (PA) share a common outflow tract with a single “truncal” valve; C) Double-outlet right ventricle in which both the aorta and pulmonary artery arise from the right ventricle; D) d-Transposition of the great arteries in which the aorta arises from the right ventricle and the pulmonary artery arises from the left ventricle; E) Tetralogy of Fallot in which the pulmonary artery arises from the right ventricle but includes a right ventricular outflow tract obstruction at the infundibular, valvar or supravalvar level. The aorta is overriding the ventricular septum that includes a septal defect (VSD). Adapted in modified form from Neeb Z, Lajiness JD, Bolanis E, Conway SJ: Cardiac outflow tract anomalies. WIREs Dev Biol 2:499-530, 2013.