Genetics of Cardiac Development and Congenital Heart Disease.

Composed of diverse cell lineages, the heart is among the first organs to form and function in vertebrate embryos. Cardiac morphogenesis involves a myriad of genes and is tightly

regulated to ensure an effective embryonic circulation. Key steps involve specification of cardiac cell fate, morphogenesis and looping of the heart tube, segmentation and growth of the

cardiac chambers, cardiac valve formation, and connection of the great vessels to the heart.[26] The genetic regulation of heart formation has been widely studied in model organisms,

including chick, frog, mouse, and zebrafish. In recent years, the zebrafish, an organism that is transparent and has external fertilization, a brief generation time, and no requirement of a

functional cardiovascular system for survival during embryogenesis, has permitted detailed genetic analysis of both normal development and cardiac defects. [27] [28] The molecular

pathways controlling cardiac development provide a foundation for understanding the basis of some congenital heart defects and can be used to reveal pathways and interactions important

in human disease.[29]

Several congenital heart diseases are associated with mutations in transcription factors. For example, mutation of the gene that encodes the transcription factor, TBX5, has been shown to

cause the ASD and VSD observed in the Holt-Oram syndrome, a rare hereditary condition associated with heart, arm, and hand defects.[30] Another gene, encoding the transcription factor

NKX2.5, causes nonsyndromic (isolated) ASD in humans when one copy is missing. This gene is the human counterpart of the tinman gene of the fruit fly (so named because, like the Tin

Man in The Wizard of Oz, fruit fly embryos lacking both copies of tinman have no hearts). Nevertheless, most ASDs do not have an identifiable genetic etiology, and the mechanisms by

which mutated transcription factors cause clinically important heart defects are just beginning to be understood.[31]

Until recently, in most studies, defects were classified by their pathology; for example, all VSDs were considered as one group. A major advance has been to examine familial aggregation

of defects based on presumed pathogenesis. Since some cardiac structures share developmental pathways, anatomically and clinically distinct lesions may be related by a common genetic

defect. Thus, the occurrence of distinct defects in the same family remains consistent with a genetic model. Defects unrelated by pathogenesis would require a different interpretation.

Developmental errors in mesenchymal tissue migration exemplify the concept that distinct syndromes share a common pathogenesis. Included in this category is a wide range of anomalies

of the outflow tract, some due to failure of fusion and others due to failure of septation. These lesions include isolated interruption of the aortic arch, persistent truncus arteriosus (failure of

separation of aorta and pulmonary arteries), and tetralogy of Fallot (malalignment of aorta and pulmonary artery with the ventricles). Comprising 15% of congenital heart defects, outflow

tract defects may be caused by the abnormal development of neural crest-derived cells, whose migration into the embryonic heart is required for formation of the outflow tracts of the heart

( Fig. 12-5 ). Considerable progress has been made during the past few years in identifying a region of chromosome 22 that has a major role in development of the conotruncus, the

branchial arches, and the face. Chromosome 22q11.2 deletions are seen in 15% to 50% of these disorders, rendering this abnormality a common genetic cause of congenital heart defects

(see also Chapter 5 ). This condition includes developmental anomalies of the fourth branchial arch and derivatives of the third and fourth pharyngeal pouches. Hypoplasia of the thymus

and parathyroids causes immune deficiency (Di George syndrome, Chapter 5 ) and hypocalcemia.

Other common mechanisms of congenital heart disease include extracellular matrix abnormalities and situs and looping defects. The endocardial cushions have received the most attention

as an area where defects in cell-cell and cell-extracellular matrix interactions might produce malformations, as evidenced by a high frequency of endocardial cushion defects and

atrioventricular septal defects in Down syndrome. Situs and looping defects may arise from single genes that have a major effect on determining laterality.

Clinical Features.

The varied structural anomalies in congenital heart disease fall primarily into three major categories:

• Malformations causing a left-to-right shunt

• Malformations causing a right-to-left shunt

• Malformations causing an obstruction.

A shunt is an abnormal communication between chambers or blood vessels. Abnormal channels permit the flow of blood from left to right or the reverse, depending on pressure

relationships. When blood from the right side of the heart enters the left side (right-to-left shunt), a dusky blueness of the skin and mucous membranes (cyanosis) results because there is

diminished pulmonary blood flow, and poorly oxygenated blood enters the systemic circulation (called cyanotic congenital heart disease). The most important examples of right-to-left

shunts are tetralogy of Fallot, transposition of the great arteries, persistent truncus arteriosus, tricuspid atresia, and total anomalous pulmonary venous connection. Moreover, with right-toleft

shunts, bland or septic emboli arising in peripheral veins can bypass the normal filtration action of the lungs and thus directly enter the systemic circulation (paradoxical embolism);

brain infarction and abscess are potential consequences. Clinical findings frequently associated with severe, long-standing cyanosis include clubbing of the tips of the fingers and toes

(hypertrophic osteoarthropathy) and polycythemia.

In contrast, left-to-right shunts (such as ASD, VSD, and patent ductus arteriosus [PDA]) increase pulmonary blood flow and are not initially associated with cyanosis. However, they

expose the postnatal, low-pressure, low-resistance pulmonary circulation to increased pressure and/or volume, which can result in right ventricular hypertrophy and, potentially, failure.

Shunts associated with increased pulmonary blood flow include ASDs; shunts associated with both increased pulmonary blood flow and pressure include VSDs and PDA. The muscular

pulmonary arteries (<1 mm diameter) first respond to increased pressure by medial hypertrophy

Figure 12-5Cardiac defects related to neural crest abnormalities. A, Biologic pathways for cardiac neural crest-related defects. B, Disease phenotypes. DORV, double-outlet right

ventricle; TGA, transposition of the great arteries. (Reproduced by permission from Chien KR: Genomic circuits and the integrative biology of cardiac diseases. Nature 407:227, 2000.)

Figure 12-6Schematic diagram of congenital left-to-right shunts. A, Atrial septal defect (ASD). B, Ventricular septal defect (VSD). With VSD the shunt is left-to-right, and the pressures

are the same in both ventricles. Pressure hypertrophy of the right ventricle and volume hypertrophy of the left ventricle are generally present. C, Patent ductus arteriosus (PDA). D,

Atrioventricular septal defect (AVSD). E, Large VSD with irreversible pulmonary hypertension. The shunt is right-to-left (shunt reversal). Volume hypertrophy and pressure hypertrophy

of the right ventricle are present. Arrow indicates the direction of blood flow. The right ventricular pressure is now sufficient to yield a right-to-left shunt (Ao, aorta; LA, left atrium; LV,

left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle.)

Figure 12-7Gross photograph of a ventricular septal defect (membranous type); defect denoted by arrow. (Courtesy of William D. Edwards, M.D., Mayo Clinic, Rochester, MN.)

Figure 12-8Schematic diagram of the most important right-to-left shunts (cyanotic congenital heart disease). A, Tetralogy of Fallot. Diagrammatic representation of anatomic variants,

indicating that the direction of shunting across the VSD depends on the severity of the subpulmonary stenosis. Arrows indicate the direction of the blood flow. B, Transposition of the great

vessels with and without VSD. (Ao, aorta; LA, left atrium; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle.) (Courtesy of William D. Edwards, M.D., Mayo

Clinic, Rochester, MN.)

Figure 12-9Transposition of the great arteries. (Courtesy of William D. Edwards, M.D., Mayo Clinic, Rochester, MN.)

Figure 12-10Diagram showing coarctation of the aorta with and without PDA. (Ao, aorta; LA, left atrium; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle;

PDA, persistent ductus arteriosus.) (Courtesy of William D. Edwards, M.D., Mayo Clinic, Rochester, MN.)

Figure 12-11Atherosclerotic plaque rupture. A, Plaque rupture without superimposed thrombus, in patient who died suddenly. B, Acute coronary thrombosis superimposed on an

atherosclerotic plaque with focal disruption of the fibrous cap, triggering fatal myocardial infarction. C, Massive plaque rupture with superimposed thrombus, also triggering a fatal

myocardial infarction (special stain highlighting fibrin in red). In both A and B, an arrow points to the site of plaque rupture. (B, reproduced from Schoen FJ: Interventional and Surgical

Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, W.B. Saunders, 1989, p. 61.)

Figure 12-12Schematic representation of sequential progression of coronary artery lesion morphology, beginning with stable chronic plaque responsible for typical angina and leading to

the various acute coronary syndromes. (Modified and redrawn from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles.

Philadelphia, W.B. Saunders Co., 1989, p. 63.)

TABLE 12-3-- Coronary Artery Pathology in Ischemic Heart Disease

Syndrome Stenoses

Plaque

Date: 2016-04-22; view: 844