Figure 5 summarizes the required steps for the formation of cardiac progenitor cells. In Figure 5A, a presomite embryo at day 16 with the primitive streak and primitive node is shown. In a cross section of the cranial part of the embryo, as shown in Figure 5B, epiblast cells invaginate through the primitive streak. During this transition, signaling pathways including BMP, NODAL, Wnt/β-catenin, and fibroblast growth factor (FGF) trigger mesodermal induction, causing the epiblast cells to differentiate into mesodermal cells. Those mesodermal cells, characterized by expression of the T-box transcription factor Brachyury/T (Bry),29 migrate to the lateral splanchnic mesoderm where they undergo differentiation into cardiogenic mesoderm (Figure 5C). The first differentiation step includes downregulation of Wnt/β-catenin signaling and upregulation of noncanonical Wnt signaling, resulting in the expression of vascular endothelial growth factor receptor 2 (VEGFR2, Flk-1) that serves as a marker for cells committed to cardiogenic fate. For the second step, eomesodermin (T-box transcription factor) signaling induces the expression of the mesoderm posterior 1 (MESP1) gene yielding the basic helix-loop-helix transcription factor MESP1, a core factor involved in programing cells toward cardiogenic fate.30 Cardiogenic mesoderm then further differentiates into first and second heart field cells (Figure 5D). Differentiation into first heart field cells is induced via upregulation of BMP and FGF signaling and downregulation of Wnt/β-catenin signaling, resulting in the expression of NKX2.5 and TBX5. Upregulation of BMP, NOTCH, and noncanonical Wnt signaling causes differentiation into second heart field cells with the expression of insulin gene enhancer protein (Isl1), NKX2.5, and Flk1.31
CARDIAC PROGENITOR CELLS
The fertilized ovum is an uncommitted cell (ie, cell fate not determined) that differentiates into numerous committed cell lines with limited opportunity to be reprogrammed. How does a specific cell know its fate? At least 1 component is the chemical signals provided by other nearby cells. No 1 signal is deterministic; rather, it seems that combination of signals determines cell fate. Similarly, migration of cells in a particular direction seems to be controlled by multiple factors. Part of this process appears to be determined by chemical signals (chemotaxis) from nearby or distant cells while mechanical signals (mechanotaxis) from neighboring cells also play a role.32 Our knowledge of both these processes is incomplete.
The developing and adult heart is composed of several cell populations, including myocytes, fibroblasts, epicardium, specialized cells of the conduction system, endocardial cells, vascular smooth muscle cells, and endothelial cells (Figure 6). Cells that form the heart are derived from 3 distinct precursor populations31: cardiac neural crest cells, cardiogenic mesoderm cells, and proepicardial cells. Cardiac neural crest cells originate from the neuroectoderm, whereas the latter 2 precursor populations are of mesodermal origin.
Cardiogenic Mesodermal Cells
Cardiac progenitor cells are derived from the intraembryonic mesoderm and arise from the cranial third of the primitive streak during early gastrulation. The cellular fate of these cardiac mesodermal cells is uncommitted, but after migration they become specified to differentiate into hemangioblasts (erythroid and vascular precursors) and cardiogenic mesoderm of the first and second heart fields. These mesodermal cells leave the primitive streak and migrate in a cranial-lateral direction to become localized on either side of the primitive streak forming the cardiac crescent, which consists of first heart field cells laterally and second heart field cells medially.31 The cells of the first heart field and second heart field proliferate and migrate as cohorts to form different structures of the heart. The heart tube is formed from cells from the first heart field through fusion in the midline after lateral folding of the embryonic disk. This leads to the formation of the early left ventricle and parts of the atria and right ventricle.
Proliferation and migration of cardiac precursor cells from the second heart field to the cranial and caudal pole contribute to the growth of the heart tube.7,10 The second heart field is composed of progenitor cells from the medial splanchnic mesoderm adjacent to the pharyngeal endoderm and is the source of the outflow tract (conus cordis and truncus arteriosus), as well as the majority of the right ventricle and atria/venous pole of the heart.9,10 The second heart field forms the endothelium, the inner sheath of the cardiac tube, and compartments of the heart as they develop. It plays a critical role in trabeculation of chamber myocardium and in valve formation, initiated by delamination of endocardial cells to form the cushions.33
A subset of cardiogenic caudal dorsal mesoderm of the second heart field differentiates into proepicardial cells.31 These precursor cells predominantly migrate toward the heart tube and envelop it to become epicardium. Another subset undergoes epithelial-to-mesenchymal transformation and form interstitial fibroblasts and coronary blood vessels including vascular smooth muscle cells and endothelium.7 A few of the proepicardial cell precursors differentiate into myocytes located in the muscular ventricular septum and atria.5,31
Cardiac Neural Crest Cells
Cardiac neural crest cells arise from the dorsal neural tube and migrate through the posterior pharyngeal arches into anterior domain of the second heart field before entering the anterior part of the heart tube. They are involved in the formation of the outflow tracts of the heart, including their valves, the myocardium from the aorta and pulmonary artery, aortic arch arteries, septation, cardiac autonomic nervous system, and venous pole. While cardiac neural crest cells differentiate into aortic smooth muscle and autonomic nervous system cells, their only active structural contribution includes cells of the aorticopulmonary septum, endocardial cushions, and parasympathetic nervous system of the heart.34,35 In contrast, their role in formation of the other aforementioned structures lies mainly in the provision of cell signals.31
Etiology of Errors in Cardiac Development
Tracing congenital heart disease to its precise etiology is difficult. Although genetics provide a sound rationale for linking a specific mutation within a gene responsible for cardiac development to an expressed malformation, <20% of congenital heart disease can be explained by either chromosomal defects or single-gene disorders.36,37 Genetic predisposition for congenital heart disease presents on a continuous spectrum from syndromic congenital heart disease (large genetic disruptions leading to alterations in many genes with resultant cardiac defects and extracardiac manifestations) to isolated congenital heart disease (small genetic disruption affecting a single gene responsible for cardiac development, resulting in an isolated cardiac defect).38
In simple terms, there are 3 ways of disrupting normal heart development. Two of them are genetic in nature. That is, congenital heart disease can occur by either inheriting a gene mutation from a parent or by acquiring a de novo somatic gene mutation during embryogenesis. The third reason for disruption of normal heart development is primarily nongenetic and includes a variety of precipitating events, such as infections, maternal exposure to alcohol, some prescription drugs, environmental teratogens, and metabolic disturbances.39 The latter can be influenced by genetic and nongenetic mechanisms.
Genetic alterations also come in different varieties. Conditions defined by chromosomal aneuploidy such as Down syndrome (Trisomy 21), Edwards syndrome (Trisomy 18), Turner syndrome (Monosomy X), and Patau syndrome (Trisomy 13) result in an increase or decrease in the number of copies of a gene. Copy number variants are caused by deletions and duplications and usually involve >1000 base pairs. Finally, mutations can cause defects in single genes as seen in Noonan syndrome or Alagille syndrome.
Recent studies increasingly recognize another factor that can contribute to congenital heart disease: epigenetics. Epigenetics describe changes in the transcriptional potential of cells that are not directly caused by alterations in the DNA itself. For example, proteins that modify histones (alkaline proteins that bind to DNA and organize the DNA-histone complex into nucleosomes) alter the transcriptional propensities of certain DNA sequences and thereby increase or decrease the expression of genes.40 Along those lines, genomic imprinting, an epigenetic phenomenon that describes the variability in the expression of a gene dependent of the parent of origin (eg, an imprinted allele inherited from the father is silenced and only the allele inherited from the mother is expressed), is presumed to be another etiologic contributor to congenital heart disease.41,42
Description of Specific Congenital Heart Defects
In this section, we will try to link the cellular and molecular mechanisms to the final macroscopic expression of specific congenital heart defects. Recall that the majority of congenital heart defects have heterogeneous pathophysiologic mechanisms, and as our knowledge of molecular biology and genetics expands, new pieces of the puzzle are constantly added.
In the first part of this section, we chose 2 conditions (atrial septal defects, heterotaxy) and a group of congenital heart defects that share a similar pathogenesis (cardiac outflow tract anomalies including persistent truncus arteriosus, double-outlet right ventricle, transposition of the great arteries, and tetralogy of Fallot) to provide a conceptual framework. In the second part, we describe additional congenital heart defects, although in a more succinct manner.
The basic tenet of molecular cell biology is the stepwise progression from a gene (located on the DNA) to RNA (transcribed from the gene) to a protein (Figure 2A). A layer of complexity is added by various modifications that can occur along this process as detailed in Figure 2B.
Atrial Septal Defects
An atrial septal defect is the third most common congenital heart defect. On the basis of the location of the defect in the atrial septum, atrial septal defects can be divided into patent foramen ovale, ostium primum defect, ostium secundum defect, sinus venosus defect, coronary sinus defect, and common atrium.43 Atrial septal defects can be observed in aneuploidy syndromes (Patau, Edwards), abnormal chromosomal structure syndromes (del22q11), single-gene mutations syndromes (Noonan), nonsyndromic congenital heart disease with copy number variations, and single-gene mutations causing isolated congenital heart disease (GATA4, GATA6, and ACTC1).
Four main structures form the atrial septum: the superior and inferior atrioventricular cushions, the primary atrial septum with its mesenchymal cap, and the dorsal mesenchymal protrusion (Figure 7).12,44 Both atrioventricular cushions and the mesenchymal cap are derived from endocardium that undergoes epithelial-to-mesenchymal transformation, while the dorsal mesenchymal protrusion arises from the second heart field. The process begins with fusion of the superior and inferior atrioventricular cushions at the level of the atrioventricular canal. A primary atrial septum arises from the atrial roof and grows toward the atrioventricular cushions, partitioning the common atrium into a left and right chamber. The leading part of the primary atrial septum carries a mesenchymal cap. The dorsal mesenchymal protrusion is associated with the mesenchymal cap and accompanies its growth downward toward the atrioventricular cushions. The dorsal mesenchymal protrusion is derived from the dorsal mesocardium that suspends the heart in the pericardial cavity. After breakdown of its central portion, the part suspending the atrial pole proliferates and penetrates through the atrial wall to give rise to the dorsal mesenchymal protrusion.45 After the primary atrial septum reaches close proximity to the atrioventricular cushion, the small opening between the primary atrial septum and the atrioventricular cushions is called ostium primum. It is closed by fusion of the mesenchymal cap with the atrioventricular cushions (anteriorly) and the dorsal mesenchymal protrusion (posteriorly). During the closure of the ostium primum, part of the primary atrial septum at the atrial roof dissolves to create a small opening, the ostium secundum. Inward folding of the atrial roof that gives rise to the secondary atrial septum later closes the ostium secundum.12,46,47
Atrial septation defects arise from a different pathway than the above. The endocardial cushion rests on myocardial cells. Those myocardial cells differ from regular chamber myocardium in their gene expression patterns. Their programing is dependent on TBX2, BMP2, and nuclear factor of activated T-cells, cytoplasmic 2/3/4 (NFATC2/3/4) proteins, which act to suppress chamber-specific genes and induce secretion of endothelial-to-mesenchymal transformation-regulating molecules. Those molecules are secreted into the neighboring endocardial cushion, where they meet endocardial cells with another specific set of gene expression including the following receptors: ALK2/3/5, VEGFR, NOTCH1, and β-catenin. Induced by the secreted molecules from the myocardium, the endocardial cells undergo endothelial-to-mesenchymal transformation and form the superior and inferior atrioventricular cushion, as well as the mesenchymal cap on the primary atrial septum.12 The dorsal mesenchymal protrusion is formed by the secondary heart field. Recently, defects in its formation have been implicated in atrioventricular canal defects and ostium primum atrial septal defects.48,49 Briggs et al50 showed that deletion of the BMP receptor (ALK3) in the secondary heart field resulted in hypoplasia of the dorsal mesenchymal protrusion, leading to impaired secondary heart field cell expansion and subsequent development of an ostium primum defect. Besides impaired cell expansion, aberrant apoptosis of secondary heart field cells in the dorsal mesenchymal protrusion and impaired cell migration can contribute to septation defects.51
Certain genes encode proteins that function as transcription factors, for example, TBX5, TBX20 (both T-box transcription factors), GATA4 (a zinc finger transcription factor), and NKX2.5. Transcription factors bind to specific DNA sequences and influence the transcription rate of the associated gene. In some instances, a transcription factor can perform this role alone, but, more frequently, it forms a complex with other proteins. For example, the interaction between GATA4 and TBX5 leads to activation of cyclin-dependent kinase 4 (CDK4), a member of the cyclin-dependent kinase family that is involved in cell-cycle regulation.52 TBX5 alone is able to activate CDK252 and CDK6.49 TBX5 expression has been demonstrated in the posterior second heart field and is critical for the development of the dorsal mesenchymal protrusion, a second heart field-derived tissue. Both structures are involved in cardiac septation. Mutations in TBX5, TBX20, GATA4, and NKX2.5 have been associated with atrial septal defects.53 Another set of genes encodes structural proteins. In the heart, cardiomyocytes express sarcomeric filaments that allow generation of tension, resulting in a heartbeat that propels blood. Mutations in α-actin gene (ACTC1) or myosin heavy chain genes (MYH6, MYH7) can lead to atrial septal defects.
The involvement of TBX5, GATA4, and NKX2.5 in a variety of processes has established their function as key regulators of cardiac differentiation. Figure 8 gives a condensed overview of their interaction, function, and cross talk. However, a clear relationship between a mutation in TBX5 leading to an atrial septal defect in every case cannot be established. Along this line, the question arises why certain individuals with a set of mutations including TBX5 develop an atrial septal defect, whereas others with similar mutations develop a ventricular septal defect. Two concepts may provide an explanation for this observation: complex inheritance and transcriptional/translational network interaction. From a genetic standpoint, complex inheritance includes the terms heterogeneity, variable expressivity, and reduced penetrance. Heterogeneity is based on the observation that a certain phenotype can be determined not only by one gene but by the interaction of multiple genes. Variable expressivity describes the state in which 2 individuals inherit the same disease allele but may express different phenotypes (eg, one individual develops an atrial septal defect, whereas the second individual develops a ventricular septal defect). Last, reduced penetrance describes the observation that 2 individuals may have inherited the disease allele, but only 1 individual develops the disease, that is, expresses the phenotype.54
Complex transcriptional/translational network interactions are in a way similar to heterogeneity. They describe the phenomenon that cardiac morphogenesis is controlled by a complex network of genes and transcription factors that are subject to constant modification, cross talk, and redundancies, as well as environmental influences.36,55
Heterotaxy describes disorders of defective left-right axis determination resulting in atypical positioning of internal organs. It is important to understand that heterotaxy is part of a spectrum of laterality defects.
The literal translation of the Greek word heterotaxy (composed of “hetero,” meaning “different,” and “taxy,” meaning “arrangement”) is “abnormal arrangement of bodily parts.” Along those lines, the Nomenclature working group of the International Society for Nomenclature of Pediatric and Congenital Heart Disease,56 defined heterotaxy as “[…] an abnormality where the internal thoracoabdominal organs demonstrate abnormal arrangement across the left-right axis of the body.” The expected normal arrangement of internal organs along the left-right axis is known as situs solitus. Unfortunately, the working group’s exclusion of situs inversus (complete mirror-imaged arrangement of internal organs along the left-right axis) from the heterotaxy spectrum may add some confusion. Situs ambiguus describes a state in which organ arrangements as described in situs solitus and situs inversus are found in the same individual, that is, thoracic and abdominal organ positioning does not show a clear lateralization. Impairment of left-right axis formation occurs early in embryonic development (starting at the third week) and is dependent on the establishment of an organizer region, a function provided by the primitive node (see Cell Signaling in Embryogenesis). On the basis of the unique arrangement of thoracic and visceral organs in the adult organism, it is conceivable that defects in left-right axis formation will impact not only the heart but also other internal organs.
Multiple descriptions and characterizations of patients with heterotaxy have been proposed over the years that can become a source of confusion for the clinician not intimately familiar with this condition. A commonly cited description uses splenic anatomy, which yields the designations “right isomerism, bilateral right-sidedness and asplenia syndrome” and “left isomerism, bilateral left-sidedness and polysplenia syndrome.” Right isomerism includes absence of a spleen (asplenia), bilateral trilobed lungs, and cardiovascular abnormalities. Left isomerism is characterized by the presence of multiple spleens (polysplenia), bilateral bilobed lungs, and cardiovascular abnormalities (Figure 4C).18,57 A more contemporary approach advocates segregation of heterotaxy patients by morphology of the atrial appendages, as isomerism in the heart is predominantly restricted to the atria.58,59 Determination of atrial isomerism primes the evaluator to seek specific intracardiac abnormalities, such as univentricular atrioventricular connections, absence of the coronary sinus, pulmonary atresia/stenosis, and totally anomalous pulmonary connection, which are frequently associated with isomeric right atrial appendages, whereas interruption of the inferior caval vein and aortic coarctation are more frequently encountered in individuals with isomeric left atrial appendages.58 Determination of atrial isomerism can be determined clinically with computed tomography angiography60 or echocardiography.61 Loomba et al62 recently reported on the impact of isomerism on survival in heterotaxy and found that right isomerism was associated with decreased survival from birth to age 16 years compared with left isomerism; biventricular repair was associated with superior survival in comparison with univentricular repair.62 The latter finding is important insofar as right isomerism often presents with complex cardiac malformations requiring univentricular repair while left isomerism is associated with less complex cardiac malformations that often can be addressed with biventricular repair.
Individuals diagnosed with heterotaxy can have a variety of organ abnormalities that may involve the gastrointestinal tract (intestinal malrotation, biliary atresia, annular pancreas, anal atresia, tracheoesophageal fistula), respiratory tract (bronchiectasis, ciliary dysfunction, bilateral right- or left-sided lungs), genitourinary tract (horseshoe kidney, hypoplastic/dysplastic/absent kidney, ureteral abnormalities, cryptorchidism), central nervous system (hydrocephalus, absent corpus callosum, holoprosencephaly, meningomyelocele), immunologic system (splenic hypofunction despite polysplenia, increased susceptibility to infections), and vascular system (extrahepatic portocaval communications, interrupted inferior vena cava with azygous or hemiazygous continuation).63,64
The heart, being one of the most important asymmetric organs, can be significantly affected, resulting in complex congenital heart disease presentations, including single ventricle, pulmonary stenosis, left ventricular outflow tract obstruction, transposition of great arteries, tetralogy of Fallot, double-outlet right ventricle, double inlet left ventricle, atrioventricular septal defects, total/partial anomalous pulmonary venous connection, aortic coarctation, atrial isomerism, bilateral/ hypoplastic/absent sinus node(s), single coronary artery, interrupted inferior vena cava, and bilateral superior vena cava.18,65,66 Patients with heterotaxy are prone to arrhythmias. The presence of 2 atrioventricular conducting pathways when there are duplicated atrioventricular nodes increases susceptibility for supraventricular reentrant tachycardias, whereas the lack of a normally situated sinus node can predispose patients to development of atrioventricular conduction blocks. Loomba et al67 investigated the occurrence of chronic cardiac arrhythmias in heterotaxy patients. Comparing left and right isomerism, the authors found no significant differences in cardiac malformations and sinus node position. In patients with left isomerism, the atrioventricular node more frequently was positioned posteriorly (86% vs 18%). Patients with right isomerism more frequently had duplicated atrioventricular nodes (82% vs 14%). Tachycardias were more frequently encountered in patients with left isomerism (atrial flutter, atrial tachycardia, junctional tachycardia, supraventricular tachycardia, ventricular tachycardia), whereas patients with right isomerism showed frequent conduction blocks (first-/second-degree atrioventricular block, complete atrioventricular block, intraventricular conduction delay, sick sinus syndrome).
A recent descriptive epidemiologic study conducted by Lin et al68 shed some light on the prevalence of heterotaxy. By querying the National Birth Defects Prevention Study database in the time frame of 1998 to 2007, the authors identified 517 cases with nonsyndromic laterality defects. Those cases included 378 cases with heterotaxy and 139 cases with situs inversus totalis, yielding an estimated birth prevalence of 0.81 per 10 000 live births. With regard to the distribution of congenital heart disease among individuals with heterotaxy, the study reported simple congenital heart disease (atrial septal defect, ventricular septal defect, mild pulmonary valve stenosis, mild aortic stenosis) in 9.3%, complex congenital heart disease in 67.7%, and no congenital heart disease in 23.0%. The most frequent cardiac malformation was a complete atrioventricular canal defect (48.4%), followed by conotruncal defects (truncus arteriosus, tetralogy of Fallot, transposition of great arteries, double-outlet right ventricle [47.4%]) and interrupted inferior vena cava, as well as right-sided defects (Ebstein anomaly, pulmonary stenosis, pulmonary atresia with intact ventricular septum, non-tetralogy of Fallot pulmonary atresia with ventricular septal defect) in 40.5% of cases.68
Few cases of heterotaxy can be traced to a monogenic etiology. These include autosomal dominant heterotaxy,69–72 X-linked heterotaxy,73–75 and autosomal recessive heterotaxy in the form of Kartagener syndrome (primary ciliary dyskinesia).76–78 Genes associated with heterotaxy include ZIC3, CRYPTIC, NODAL, CFC1, ACVR2B, LEFTY2, CITED2, and GDF1.18,57 The majority of cases can be caused by a variety of disruptions in the left-right axis patterning process.
Cardiac Outflow Tract Anomalies
Cardiac outflow tract anomalies represent a spectrum of heart development disorders that share etiologic features. Cardiac neural crest cells are instrumental in shaping the outflow tract by controlling its remodeling process. Disruption of neural crest cell induction, specification, endothelial-to-mesenchymal transformation, migration, cell-cell interaction, and condensation to form the outflow tract are thought to explain the major factor in the genesis of conditions, such as persistent truncus arteriosus, tetralogy of Fallot, transposition of the great arteries, and double-outlet right ventricle.79,80 Recall that the outflow tract is populated initially by resident first heart field cells, which are joined by migratory second heart field cells. Later, cardiac neural crest cells begin migrating from the dorsal neural tube into the outflow tract where they are involved in the formation of the aorticopulmonary septum by contributing cells for the outflow tract structure and shape. They also influence neighboring cells, specifically cells of the second heart field, by modulating secreted signaling factors such as FGF.81 Furthermore, cardiac neural crest cells contribute to the endocardial cushion mass, which is formed by endothelial cells that undergo epithelial-to-mesenchymal transformation. Defects in cardiac neural crest cells can occur at multiple levels. As a result, many of the different cardiac outflow tract malformation phenotypes can be traced back to cardiac neural crest cells, but the presence of multiple other cell types adds a layer of complexity and often precludes identification of a “single defect.” Chromosome 22q11.2 deletion syndrome serves as an interesting example for cardiac outflow tract anomalies.82 It is associated with a variety of cardiac outflow tract anomalies such as tetralogy of Fallot (most common cyanotic congenital heart disease), truncus arteriosus, double-outlet right ventricle, transposition of the great arteries, coarctation of the aorta, and interrupted aortic arch. The commonly deleted region on chromosome 22q11.2 harbors >35 genes, including TBX1, ERK2 (alias for mitogen-activated protein kinase [MAPK1]) and CRKL. TBX1 is required for growth and septation of the conotruncus,83 whereas developing neural crest cells require ERK2 signaling to be able to aid in conotruncal development.84 The role of CRKL, a member of the adaptor protein family that participates in multiple signaling pathways (including the MAPK pathway), is less defined.
Persistent Truncus Arteriosus
Persistent truncus arteriosus describes the failure of septum formation that divides the truncus arteriosus into aorta and pulmonary artery, leaving only 1 combined outflow tract for the blood that is ejected by each ventricle (Figure 9B). Mixing of blood occurs via a ventricular septal defect. The combined outflow tract can be positioned either above the right or the left ventricle, or can override the ventricular septal defect. Persistent truncus arteriosus is associated with chromosome 22q11.2 deletion syndrome and TBX1 deficiency caused by point mutations.
Double-Outlet Right Ventricle
During development of the outflow tract, malalignment defects trigger the development of a double-outlet right ventricle. The aorticopulmonary septum forms normally within the truncus arteriosus and separates the great vessels (aorta and pulmonary artery), but incorrect alignment of the aorta over the right ventricle leads to the final position in which both great vessels arise from the right ventricle (Figure 9C). This defect is frequently associated with a ventricular septal defect and pulmonary stenosis, causing cyanosis because of a significant right-to-left shunt after birth. Obler et al85 analyzed the underlying genetic makeup in 149 individuals diagnosed with double-outlet right ventricle. The majority of cases (56%) were found to have a nonchromosomal disorder, and but the condition often occurred in conjunction with several syndromes that included Adams-Oliver, Ellis-van Creveld, Gardner-Silengo-Wachtel, Kabuki, Kalmann, Melnick-Needles, Noonan, Opitz, Ritscher-Schinzel, and Robinow syndromes. A specific gene mutation was only identified in very few cases (10/149). Eight individuals showed a disrupted CFC1 gene (encoding extracellular signaling proteins involved in development of lateral plate mesoderm), whereas 2 individuals had a mutation in the CSX gene (encoding the transcription factor NKX2.5). A smaller subset of cases (41%) had associated chromosomal abnormalities, mainly Trisomy 18 and 13.85
Transposition of Great Arteries
D-Transposition of the great arteries, which stands for “dextro-loop transposition,” describes the relationship of the ventricles to the atria after cardiac looping to the right (Figure 9D). In D-transposition of the great arteries, there are concordant atrioventricular and discordant ventriculoarterial connections: the morphologic left ventricle is connected to the pulmonary artery, whereas the right ventricle connects to the ascending aorta. This creates 2 parallel circulations: blood is pumped from the right ventricle into the systemic circulation (aorta) and returns back to the right ventricle via the right atrium. The left ventricle ejects blood into the pulmonary circulation (pulmonary artery), which returns to the left ventricle via the left atrium. In contrast, congenitally corrected transposition of the great arteries must be separated strictly from D-transposition of the great arteries because of its different pathophysiology and pathogenesis. Congenitally corrected transposition arises because of dysfunctional cardiac looping to the left instead of the right side. The most common manifestation (94%) of this physiology occurs in patients with [S,L,L] segmental anatomy. That is, there is atrial situs solitus, L-loop ventricles, and L-loop great arteries. A right-sided right atrium connects via a right-sided mitral valve and left ventricle to a right-sided and posterior pulmonary artery. A left-sided left atrium connects via a left-sided tricuspid valve and right ventricle to a left-sided and anterior aorta.
Transposition of the great arteries is a complex lesion, and an understanding of its pathogenesis is incomplete. Two theories have been formulated. Goor and Edwards86 proposed that a defect in the infundibular rotation causes transposition of the great arteries by preventing the clockwise rotation of the aorta toward the left ventricle. De la Cruz et al87,88 hypothesizes that, instead of the normal, spiral-like movement of the aortopulmonary septum, it develops in a linear fashion in patients with transposition of the great arteries, thereby connecting the aortic arch to the anterior conus on the right ventricle. Heterotaxy is the only genetic syndrome with which transposition of the great arteries is strongly associated. This explains the association with genes involved in establishment of laterality such as ZIC3, CFC1, and NODAL. 89
Tetralogy of Fallot
With an incidence of approximately 0.3%, tetralogy of Fallot is the most common form of cyanotic congenital heart diseases. The 4 distinguishing features include ventricular septal defect, overriding of the aorta, right ventricular outflow obstruction, and right ventricular hypertrophy (Figure 9E).90 Tetralogy of Fallot is associated with syndromes sharing a deletion of chromosome 22q11 (DiGeorge syndrome, velocardiofacial syndrome). More commonly, it occurs sporadically but its genetic etiology is poorly understood. Tetralogy of Fallot has been associated with rare copy number variations of TBX1,91 SNX8,92 PLXNA2,93 NOTCH1, and JAG1.94
Bicuspid Aortic Valve
The incidence of bicuspid aortic valve disease varies between studies but is commonly quoted to be 0.4% to 2.25%.1 It is an important anatomic entity as its presence increases the risk for development of aortic valve stenosis, regurgitation, or infective endocarditis, as well as ascending aorta aneurysm and/or dissection.95–97 Bicuspid aortic valve disease can arise as a new mutation or can be inherited in an autosomal dominant fashion; unfortunately, it shows considerable heterogeneity and neither the genetic basis nor the phenotypic expression can always be attributed to a simple, single-gene defect.
The presence of bicuspid aortic valve disease in combination with genetic syndromes mostly affects females such as those with Turner syndrome (Monosomy X), DiGeorge syndrome (del 22q11.2), Loeys-Dietz syndrome (TGFBR1/2), Andersen-Tawil syndrome (KCNJ2), Larsen syndrome (FLNB), Kabuki syndrome (KMT2D, KDM6A), and familial thoracic aortic aneurysms and dissection [TAAD] (ACTA2).98 Bicuspid aortic valve disease can result from familial inheritance, although, with the exception of NOTCH1, in a very small proportion of familial cases as no single trigger gene has so far been implicated.99,100 Linkage analysis has identified multiple genes including TGFBR2, TGFBR1, NOTCH1, ACTA2, KCNJ2,98 MYH11, GATA5, FLNA, and SMAD3 101 that are associated with aortic valve development.
It is clear that the majority of non–syndromic-related cases of bicuspid aortic valve disease are not because of a single genetic variant. More likely, its inheritance results from a combination of numerous rare or uncommon genetic variants including copy number variants, epigenetic modifications, and environmental causes.97 Because most animal models of bicuspid aortic valve disease are created from NOTCH1 and GATA5/6 genes, both proteins seen in the developing heart, it is likely that many variants in a single pathway are responsible for an overall likelihood of developing a bicuspid aortic valve.
Mitral Valve Prolapse
Mitral valve prolapse is a common disorder that affects 2% to 3% of the population. It is caused by fibromyxomatous degeneration resulting in thickening and lengthening of the mitral valve leaflets. This, in turn, leads to displacement of one or both leaflets into the left atrium past the mitral annulus during systole with associated poor coaptation. The genetic basis of syndromic mitral valve prolapse has been traced to TGF-β signaling.102,103 The final common pathway of TGF-β signaling dysregulation leads to differentiation of valvular interstitial cells to myofibroblasts with subsequent extracellular matrix production and deposition resulting in myxomatous degeneration and altered mitral valve architecture.104 Mitral valve prolapse is strongly associated with Marfan syndrome caused by mutations in fibrillin 1 (FBN1). FBN1 usually inhibits TGF-β signaling; loss-of-function mutations therefore lead to an increase in active TGF-β, increased matrix deposition, and thickened valve leaflets. Loeys-Dietz syndrome, another syndrome with strong association to mitral valve prolapse, is caused by mutations in TGFBR1 and TGFBR2. A nonsyndromic cause of mitral valve prolapse has been identified in mutations of the filamin A gene (FLNA), which also affects TGF-β signaling.13
Ebstein Anomaly of the Tricuspid Valve
Ebstein anomaly is a rare congenital heart defect that involves the right ventricle, right atrium, and tricuspid valve. During normal development, the superficial layer of the right myocardium delaminates to form the septal and posterior leaflets of the tricuspid valve. Failure of delamination results in adherence of the leaflets to the ventricular myocardium causing apical displacement of the tricuspid valve leaflet hinge points with normal position of the tricuspid valve orifice. The area of the right ventricle between the tricuspid valve orifice and the resultant apically displaced tricuspid leaflet hinge points becomes atrialized and varying degrees of tricuspid valve insufficiency ensue.105,106 Ebstein anomaly is associated with atrial tachyarrhythmias including atrial fibrillation and flutter, as well as accessory conduction pathways such as Wolff-Parkinson-White syndrome.107,108 Although the genetic basis for this condition is largely unknown, recent investigations have identified an association of familial Ebstein anomaly with mutations in MYH7, a sarcomere gene encoding the cardiac β-myosin heavy chain.109,110 It is not clear why a sarcomeric protein is responsible for Ebstein anomaly, but a reasonable working hypothesis is that embryonic cell migration may be impaired by MYH7 mutations.
Patent Ductus Arteriosus
The ductus arteriosus is the physiological connection between the pulmonary arteries and the proximal descending aorta that serves as a right-to-left shunt to allow oxygenated blood from the placenta to bypass the nonventilated lungs and reach the systemic circulation.
Ductal closure after birth occurs in 2 steps: initially, functional closure is achieved by constriction of the vascular smooth muscles, typically within 72 hours of birth in 90% of term and 81% to 87% of healthy preterm infants.111 Removal of the placenta leads to a drop in prostaglandin E2 levels, a potent ductal vasodilator. In addition, the postpartum increase in arterial oxygen tension activates a ductal constrictor mechanism via cytochrome P450 hemoprotein acting as the sensor and endothelin-1 acting as the effector complex, as well as via inhibition of voltage-gated potassium channels resulting in depolarization and activation of voltage-dependent calcium channels.112
The second step in ductal closure involves tissue remodeling and leads to permanent, structural closure. Coceani and Baragatti113 describe evidence for involvement of 4 distinct mechanisms in this step: development of intimal cushions, mechanical solicitation from turbulent blood flow along the narrowing lumen, intramural hypoxia due to the collapse of vasa vasorum in the constricting ductus, and interaction of platelets with the vessel wall.
Adult patency of the ductus arteriosus occurs in about 1 in 2000 individuals.114 Patent ductus arteriosus usually occurs sporadically, but syndromic associations of this condition have been identified. Chromosomal abnormalities are found in 8% to 11% of cases of patent ductus arteriosus. Furthermore, an association of isolated patent ductus arteriosus with Down syndrome, CHARGE syndrome (acronym for coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth/development, genital and/or urinary abnormalities, and ear abnormalities/deafness), Cri-du-chat syndrome, Noonan syndrome, Char syndrome, and Holt-Oram syndrome has been documented. The importance of the contractile apparatus in vascular smooth muscle cells for ductal closure is shown by patent ductus arteriosus being associated with mutations in the MYH11 (smooth muscle myosin heavy chain) and ACTA2 genes (α-actin).111
Ventricular Septal Defect
Ventricular septal defects are the most common nonvalvular congenital heart defect that occurs in 1.56 to 53.2 per 1000 live births.115 Characterized by location, ventricular septal defects are classified into membranous ventricular septal defect, muscular ventricular septal defect, inlet ventricular septal defect, and infundibular ventricular septal defect.115 Similar to atrial septal defects, ventricular septal defects are associated with aneuploidy syndromes (Patau, Edwards), abnormal chromosomal structure syndromes (del22q11), single-gene mutations syndromes (Holt-Oram, Noonan), nonsyndromic congenital heart disease with copy number variations, and single-gene mutations causing isolated congenital heart disease (GATA4, IRX4, TDGF1). As with atrial septal defects, the same 3 genes involved in cardiac septation (TBX5, NKX2.5, and GATA4) are associated with ventricular septal defects.
Hypoplastic Left Heart Syndrome
Hypoplastic left heart syndrome presents with different degrees of stenosis or atresia of the aortic and mitral valve along with hypoplasia of the left ventricle and ascending aorta. It manifests in 3 forms classified by the extent of stenosis of the 2 valves (mitral stenosis/aortic stenosis, mitral stenosis/aortic atresia, mitral atresia/aortic atresia), which differ in prognosis and presentation.
To allow survival of the newborn, especially in the atresia forms, 2 shunts must be present. One shunt arises at the atrial level, allowing mixing of pulmonary venous blood with blood in the right atrium that ultimately is ejected by the right ventricle into the pulmonary artery where the second shunt, an intact ductus arteriosus, provides flow to the systemic circulation (and retrograde flow to the coronary arteries). Chromosomal abnormalities that have been linked to hypoplastic left heart syndrome include Trisomy 13, 18, Turner syndrome (Monosomy X), and Jacobsen syndrome (terminal 11q deletion). Sporadic cases were found to have mutations that cause dysfunctions in connexin protein 43 or NKX2. 116
Noonan syndrome is a complex of congenital heart defects that can be traced to environmental and genetic etiologies. The latter are again subdivided into syndromic congenital heart disease, nonsyndromic congenital heart disease, or congenital heart disease secondary to mutations in 1 gene. But even a “defined” syndrome has a tremendous amount of heterogeneity in the phenotypic expression. Noonan syndrome is associated with cardiac malformations in 80% to 90% of cases. Defects range from valvular pulmonic stenosis, hypertrophic cardiomyopathy, and secundum atrial septal defect (most common) to ventricular septal defect, atrioventricular septal defect, aortic stenosis, aortic coarctation, peripheral pulmonary stenosis, mitral valve abnormalities, and coronary artery abnormalities.117,118 It is triggered by a defect in the RAS-MAPK signaling pathway; within this pathway, 6 genes have been identified as possible mutation targets for Noonan syndrome (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF), whereas mutations in 2 genes (SHOC2, CBL) yield a Noonan syndrome-like phenotype.118 Although mutation carriers in the PTPN11 gene are predominantly afflicted with pulmonary stenosis, hypertrophic cardiomyopathy is more frequently seen in individuals with an RAF1 mutation.118 This collection of genetic variants and clinical phenotypes has been historically coalesced as a single syndrome; yet, it is likely that we will see these further defined and subtyped in the next decade.
Holt-Oram syndrome has an incidence of 1 in 100,000 live births and presents with bilateral forelimb deformities with congenital heart disease in 75% of individuals.114 Heart defects include atrial septal defect, ventricular septal defect, cardiac arrhythmias, hypoplastic left heart syndrome, persistent superior vena cava, and mitral valve prolapse. The disease arises from a variety of mutations in the T-box transcription factor TBX5, which causes a spectrum of alterations (introduction of premature stop codon that yields a truncated protein that cannot bind to DNA, intragenic duplications that increase gene dosage, etc), depending on the specific genetic abnormality. The interaction of TBX5 with NKX2-5 and GATA4 is required for normal septal development, whereas interaction with MEF2C activates MYH6 expression required for myocardial development.119
Heart development is a complex process that can be disrupted in many ways, leading to congenital heart disease. With an incidence of 0.4% to 5% of live births, children afflicted by these disorders are frequently encountered by the anesthesiologist. Gains in knowledge of genetics, embryology, and molecular medicine provide insights into the mechanisms of congenital heart disease. This progress may eventually give rise to novel therapies that specifically target genes or signal transduction pathways involved in these conditions. Unfortunately, congenital heart disease can rarely be tracked to one defined etiology (such as a simple gene mutation), and different influencing factors have to be taken into account.
We thank James Bell for the design and creation of figures and illustrations that appear throughout this manuscript.
Name: Benjamin Kloesel, MD, MSBS.
Contribution: This author helped write the manuscript.
Name: James A. DiNardo, MD.
Contribution: This author helped write the manuscript.
Name: Simon C. Body, MBChB, MPH.
Contribution: This author helped write the manuscript.
This manuscript was handled by: Charles W. Hogue, MD.
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