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Congenital Heart Disease (CHD)

Congenital Heart DiseaseCSBR.Prasad, MD.,JAN-2015-CSBRP

Congenital Heart Disease - CHDCHD is a general term designating abnormalities of the heart or great vessels that are present at birthCHD arises from faulty embryogenesis during 3-8 weeks of gestationIncidence - 5%

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Twelve disorders account for about 85% of cases

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Table 12-2 is from Robbins path 9Ed.Table 11-1 is from Emanual Rubens Path.3

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Congenital Heart Disease Cardiac DevelopmentThe fetal heart consists of a single chamber until the fifth week of gestationThen, it is divided by the development of interatrial and interventricular septa and by theformation of atrioventricular valves from endocardial cushionsA muscular interventricular septum grows upward from the apex toward the base of the heart. It is joined by the down-growing membranous septum, thereby separating right and left ventricles

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CHD - Cardiac DevelopmentDay 15: Multipotent progenitor cells originate in lateral mesoderm and migrate to the midlineDay 20: beating tube Day 28: Migration of neural crest cells, out flow tract & aortic arch formationEndocardial cushion formationDay 50: Formation of four chambered heart

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CHD - Cardiac DevelopmentThis well orchestrated event involves many genes, transcription factors, signaling pathwaysEach heart field is differentially marked by the expression of distinct set of genes1st heart field: Hand1 (most of the left ventricle derived from this field)2nd heart field: Hand2 and FGF-10 (Out flow tract, right ventricle and atria are derived from this field)Pathways involved: Wnt, Hedghog, Notch-DeltaGrowth factors involved: VEGF, TGF-beta, FGFSpecific micro-RNAsOthers: Hemodynamic forces in the developing heart

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Hand1: Heart- and neural crest derivatives-expressed protein 1Chr#5

Hand2: Heart- and neural crest derivatives-expressed protein 2Chr#47

CHD - Cardiac Development

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Figure 12-3 Human cardiac development, emphasizing three main sources of cells. A, Day 15. First heart field (FHF) cells (shown in red) form a crescent shape in the anterior embryo with second heart field (SHF) cells (shown in yellow) near the FHF. B, Day 21. SHF cells lie dorsal to the straight heart tube and begin to migrate (arrows) into the anterior and posterior ends of the tube to form the right ventricle, conotruncus (CT), and part of the atria (A). C, Day 28. Following rightward looping of the heart tube, cardiac neural crest cells (shown in blue) also migrate (arrow) into the outflow tract from the neural folds to septate theoutflow tract and pattern the bilaterally symmetric aortic arch arteries. D, Day 50. Septation of the ventricles, atria, and atrioventricular valves (AVV) results inthe appropriately configured four-chambered heart. Ao, Aorta; AS, aortic sac; DA, ductus arteriosus; LA, left atrium; LCA, left carotid artery; LSCA, left subclavianartery; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RCA, right carotid artery; RSCA, right subclavian artery; V, ventricle. (Modified withpermission from Srivastava D: Making or breaking the heart: from lineage determination to morphogenesis. Cell 126:1037, 2006.)8

CATCH-22Downs syndromeTrisomies (13,18, 21)

Most common genetic cause of congenital heart disease is Trisomy 21 (Downs Syndrome)

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GATA4, TBX5, and NKX2-5, three transcription factors that are mutated in some patients with atrialand ventricular septal defects, all bind to one another and co-regulate the expression of target genes required forproper cardiac development. Of further interest, GATA4 and TBX20 are also mutated in rare forms of adult-onsetCardiomyopathy, indicating important roles not only in development but also in maintainingnormal function of the postnatal heart.

Thus, mutations in genes encoding various components of the Notch pathway (Chapter 1) are associated with a variety of congenital heart defects, including bicuspid aortic valve (NOTCH1, discussed later) and tetralogy of Fallot (JAG1 and NOTCH2). As described in Chapter 11, fibrillin mutations underlie Marfan syndromeassociated with valvular defects and aortic aneurysms. Although fibrillin is an important structural protein in the ECM, it is also an important negative regulator of TGF- signaling, and hyperactive TGF- signaling contributes to the cardiovascular abnormalities in Marfan syndrome and Loeys-Dietz syndrome.

The Di George syndrome is associated with multiple deficits (memorable through the mnemonic CATCH-22: cardiac abnormality, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia, all on chromosome 22). Of the 30 or so genes present on this chromosome segment, deletion specifically of the TBX1 transcription factor gene is probably the culprit lesion. TBX1 regulates neural crest migration, as well as the expansion of cardiac progenitors in the second heart field. Interestingly, deletions in this region are also associated with mental illness, including schizophrenia.9

Congenital Heart Disease Environmental factorsMutations in Csx/Mkx2-5Down syndrome (trisomy 21) and other trisomiesTurner syndrome and Di George syndromeIntrauterine influencesRubellaAlcoholPhenytoinAmphetaminesLithiumEstrogenic steroids and, Thalidomide (historical)Maternal diabetes

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Congenital Heart Disease - gistCHD is a consequence of faulty embryonic developmentEither as misplaced structures OREg: transposition of the great vessels) or As an arrest in the progression of a normal structure (from an early stage to one that is more mature)Eg: ASDJAN-2015-CSBRP

Congenital Heart Disease Clinical featuresCHDs can be organized into three major categories:Malformations causing a left-to-right shuntMalformations causing a right-to-left shuntMalformations causing an obstructionDefinition:SHUNT: is an abnormal communication between chambers or blood vessels.JAN-2015-CSBRP

Congenital Heart Disease Clinical featuresCHDs can be organized into three major categories:1-Malformations causing a left-to-right shuntNot initially associated with cyanosisHowever, over the course of years, the patient may develop right to left shunt EISENMENGER syndrome

Left to right shunt results in pulmonary hypertension and associated changes in the pulmonary circulation. After the development of PHT the structural defects in CHDs are considered irreparable.

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Eventually, pulmonary vascular resistance approaches systemic levels, and the original left-to-rightshunt becomes a right-to-left shunt that introduces poorly oxygenated blood into the systemic circulation (Eisenmenger syndrome). Once irreversible pulmonary hypertension develops, the structural defects of congenital heart disease are consideredirreparable; subsequent right heart failure can lead to the patients death. This provides the rationale for earlyintervention to close significant left-to-right shunts.13

Common congenital left-to-right shunts

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Figure 12-4 Common congenital left-to-right shunts (arrows indicate the direction of blood flow). 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). Ao, Aorta; LA, left atrium; LV, left ventricle; PT,pulmonary trunk; RA, right atrium; RV, right ventricle. 14

Congenital Heart Disease Clinical featuresCHDs can be organized into three major categories:2-Malformations causing a right-to-left shuntAssociated with cyanosisParadoxical embolismHypertrophic osteoarthropathyPolycythemiaJAN-2015-CSBRP

Severe, long-standing cyanosis also causes a peculiar distal blunting and enlargement (clubbing) of the tips of the fingers and toes (called hypertrophic osteoarthropathy)15

Congenital Heart Disease Clinical features -Hypertrophic osteoarthropathy

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Severe, long-standing cyanosis also causes a peculiar distal blunting and enlargement (clubbing) of the tips of the fingers and toes (called hypertrophic osteoarthropathy)

Primary hypertrophic osteoarthropathy is a rare hereditary disorder that occurs predominantly in males. Affected patients typically display skin hypertrophy and skeletal abnormalities, known as pachydermoperiostosis. Note the thickened furrowed skin of the forehead (leonine facies), clubbing of the fingers and toes, and the large effusion of the right knee.

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Tetralogy of FallotTransposition of the great arteriesPersistent truncus arteriosusTricuspid atresia, and Total anomalous pulmonary venous connectionCommon congenital right-to-left shunts

Atresia:Absence of a normal opening, or failure of a structure to be tubular. Atresia can affect many structures in the body. For example, esophageal atresia is a birth defect in which part of the esophagus is not hollow, and withanal atresia, there is no hole at the bottom end of the intestine.

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Congenital Heart Disease Clinical featuresCHDs can be organized into three major categories:3-Malformations causing an obstructionAbnormal narrowing of chambers, valves or blood vesselsComplete obstruction is called Atresia

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Eventually, pulmonary vascular resistance approaches systemic levels, and the original left-to-rightshunt becomes a right-to-left shunt that introduces poorly oxygenated blood into the systemic circulation (Eisenmenger syndrome). Once irreversible pulmonary hypertension develops, the structural