Cyanotic heart defect pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Keri Shafer, M.D. [2], Atif Mohammad, M.D.; Kalsang Dolma, M.B.B.S.[3]

## Overview

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## Pathophysiology

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### Tetrology of Fallot

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* It is understood that tetralogy of fallot is the result of improper positioning of the outlet septum.[1][2][3]
* In the normal heart, the outlet septum is an indistinguishable component of the crista supraventricularis that communicates with the septomarginal trabeculae to divide the right and left ventricular cavities.
* In Tetralogy of Fallot, proper ventricular septation is perturbed by anterocephalad displacement of the outlet septum relative to the septomarginal trabecula.
* The direct consequence of this misalignment is an overriding aortic orifice and a ventricular septal defect, resulting in an intracardiac right to left shunt of blood.
* In addition, anterocephalad displacement of the outlet septum indirectly predisposes the pulmonary trunk to stenosis in the setting of septoparietal trabecular hypertrophy.
* Together, the displacement of the outlet septum coupled with the hypertrophic arrangement of the septoparietal trabeculae account for the three anatomical cardinal defects in Tetralogy of Fallot - aortic dextroposition, interventricular communication (VSD), and pulmonary stenosis.
* The fourth defect \- right ventricular hypertrophy \- is a hemodynamic consequence of these three morphologic changes, as the right ventricle physiologically adapts to the increased resistance of a stenotic pulmonary trunk.

### Total Anomalous Pulmonary Venous Connection

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* In this condition,the right side of heart is receiving blood both from pulmonary and systemic circulation.[4][5]
* There is a mixing of oxygenated pulmonary venous blood with deoxygenated blood from systemic circulation.
* The mixing of blood could occur at three levels i.e. supracardiac, infracardiac and cardiac.
* In the former two the mixing occurs outside the heart and in latter inside the heart (right atrium)

### Transpostion of Great Arteries

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* In the TGA the aorta arises from the morphologic right ventricle via a subaortic infundibulum and the pulmonary artery arises from the morphologic left ventricle, without a subpulmonary infundibulum.[6][7][8][9]
* These ventriculoarterial connection is known as ventriculoarterial discordance.
* As a consequence, there is a a fibrous continuity between the mitral and pulmonary valve, but no continuity between the tricuspid and aortic valve.
* The abnormal origin of the great arteries results in an altered spiral relationship.
* Therefore, the aorta and pulmonary artery run parallel to each other
* In normal heart thus the circulation is in series.
* However, in transposition of the great vessels circulation is in parallel

### Truncus Arteriosus

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* In truncus arteriosus, the pulmonary arteries are connected to the aorta.
* A decrease in PVR at birth causes a left to right shunt with evidence of congestive heart failure.
* These patients have a very high incidence of pulmonary hypertension and vascular disease.

### Tricuspid Atresia

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* In tricuspid atresia, there is no continuity between the right atrium and right ventricle. Blood from superior vena cava and inferior vena cava is forced across intra atrial connection into the left heart.
* As a consequence, oxygen saturation in the left atrial blood is diminished.

### Hypoplastic Left Heart Syndrome

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* In patients with hypoplastic left heart syndrome, the left side of the heart is unable to send enough blood to the body.
* As a result, the right side of the heart must maintain the circulation for both the lungs and the body.
* The right ventricle can support the circulation to both the lungs and the body for a while, but this extra workload eventually causes the right side of the heart to fail.

## Genetics

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* Genes involved in the pathogenesis of tetralogy of fallot include:[10][11][12][13][14][15][16]
* The cellular processes that underlie cardiogenesis are extensively regulated in the developing heart.
* Proper cardiac development requires the complex orchestration of cardiac transcription factors and signaling pathways in a spatiotemporal specific manner.
* Previous genetic studies demonstrated that mutations in numerous genes encoding cardiac transcription factors and cell signaling proteins have a role in the development of Tetralogy of Fallot.
* Specifically, heterozygous mutations in NKX2-5, HAND1, TBX5, and GATA4 have been reported in familial forms of disease.
* Many of these single gene mutations result in haploinsufficiency and suggest a dose dependent relationship between genetic expression and disease.
* While the mechanistic basis of this relationship is currently poorly understood, it is hypothesized that disruption of the direct protein-protein interactions that allow these transcription factors to work synergistically impedes the activation of downstream targets and signaling pathways central to cardiac morphogenesis.
* In addition, recent whole-exome sequencing investigations have introduced a novel role for epigenetic dysregulation in the pathogenesis of Tetralogy of Fallot.
* Aberrant epigenetic modifications are thought to provide an alternative mechanism to perturb normal spatiotemporal expression of these essential developmental genes.

* Genetic mutations associated with total anomalous pulmonary venous connection include:[17][18]

## Associated Conditions

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* Conditions associated with tetralogy of fallot include:[19][20][21][22]
* Left superior vena cava
* Anomalies of the mitral valve
* Anomalies of the tricuspid valve
* Stenosis of the left pulmonary artery, in 40% of patients
* A bicuspid pulmonary valve, in 40% of patients
* Right sided aortic arch, in 25% of patients
* Coronary artery anomalies, in 10% of patients
* An atrial septal defect, in which case the syndrome is sometimes called a pentalogy of Fallot.
* An atrioventricular septal defect
* Partially or totally anomalous pulmonary venous return
* Forked ribs and scoliosis
* Associated abnormalities include cleft lip, cleft palate, hypospadias, skeletal and craniofacial abnormalities.

* Conditions associated with total anomalous pulmonary venous connection
* Patent foramen ovale
* Atrial septal defect
* Patent ductus arteriosus
* Pulmonary hypertension
* Conditions associated with TGA include:
* Ventricular septal defect
* Pulmonary stenosis
* Left atrioventricular valve regurgitation (tricuspid or systemic)
* Complete heart block
* Conditions associated with truncus arteriosus include:
* DiGeorge syndrome

## Gross Pathology

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On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

## Microscopic Pathology

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On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

## References

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1. ↑ Anderson RH, Jacobs ML (2008). "The anatomy of tetralogy of Fallot with pulmonary stenosis". Cardiol Young. 18 Suppl 3: 12–21. doi:10.1017/S1047951108003259. PMID 19094375.
2. ↑ Bashore TM (2007). "Adult congenital heart disease: right ventricular outflow tract lesions". Circulation. 115 (14): 1933–47. doi:10.1161/CIRCULATIONAHA.105.592345. PMID 17420363.
3. ↑ Bailliard F, Anderson RH (2009). "Tetralogy of Fallot". Orphanet J Rare Dis. 4: 2. doi:10.1186/1750-1172-4-2. PMC 2651859. PMID 19144126.CS1 maint: PMC format (link)
4. ↑ NEILL CA (December 1956). "Development of the pulmonary veins; with reference to the embryology of anomalies of pulmonary venous return". Pediatrics. 18 (6): 880–7. PMID 13378917.
5. ↑ CRAIG JM, DARLING RC, ROTHNEY WB (1957). "Total pulmonary venous drainage into the right side of the heart; report of 17 autopsied cases not associated with other major cardiovascular anomalies". Lab. Invest. 6 (1): 44–64. PMID 13386206.
6. ↑ Warnes CA (December 2006). "Transposition of the great arteries". Circulation. 114 (24): 2699–709. doi:10.1161/CIRCULATIONAHA.105.592352. PMID 17159076.
7. ↑ Levin, Daniel L. (1977). "d-Transposition of the Great Vessels in the Neonate". Archives of Internal Medicine. 137 (10): 1421. doi:10.1001/archinte.1977.03630220061015. ISSN 0003-9926.
8. ↑ Rashkind, William J. (1966). "Creation of an Atrial Septal Defect Without Thoracotomy". JAMA. 196 (11): 991. doi:10.1001/jama.1966.03100240125026. ISSN 0098-7484.
9. ↑ Hornung TS, Bernard EJ, Celermajer DS, Jaeggi E, Howman-Giles RB, Chard RB, Hawker RE (November 1999). "Right ventricular dysfunction in congenitally corrected transposition of the great arteries". Am. J. Cardiol. 84 (9): 1116–9, A10. doi:10.1016/s0002-9149(99)00516-0. PMID 10569681.
10. ↑ Olson EN (2006). "Gene regulatory networks in the evolution and development of the heart". Science. 313 (5795): 1922–7. doi:10.1126/science.1132292. PMID 17008524.
11. ↑ Yang YQ, Gharibeh L, Li RG, Xin YF, Wang J, Liu ZM; et al. (2013). "GATA4 loss-of-function mutations underlie familial tetralogy of fallot". Hum Mutat. 34 (12): 1662–71. doi:10.1002/humu.22434. PMID 24000169.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
12. ↑ Bruneau BG (2008). "The developmental genetics of congenital heart disease". Nature. 451 (7181): 943–8. doi:10.1038/nature06801. PMID 18288184.
13. ↑ Bruneau BG, Srivastava D (2014). "Congenital heart disease: entering a new era of human genetics". Circ Res. 114 (4): 598–9. doi:10.1161/CIRCRESAHA.113.303060. PMID 24526674.
14. ↑ Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R; et al. (2001). "Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation". Nat Genet. 28 (3): 276–80. doi:10.1038/90123. PMID 11431700.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
15. ↑ Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA; et al. (2003). "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature. 424 (6947): 443–7. doi:10.1038/nature01827. PMID 12845333.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
16. ↑ Sheng W, Qian Y, Wang H, Ma X, Zhang P, Diao L; et al. (2013). "DNA methylation status of NKX2-5, GATA4 and HAND1 in patients with tetralogy of fallot". BMC Med Genomics. 6: 46. doi:10.1186/1755-8794-6-46. PMC 3819647. PMID 24182332.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
17. ↑ Phelan, K.; McDermid, H.E. (2011). "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)". Molecular Syndromology. doi:10.1159/000334260. ISSN 1661-8777.
18. ↑ Bleyl, Steven B.; Saijoh, Yukio; Bax, Noortje A.M.; Gittenberger-de Groot, Adriana C.; Wisse, Lambertus J.; Chapman, Susan C.; Hunter, Jennifer; Shiratori, Hidetaka; Hamada, Hiroshi; Yamada, Shigehito; Shiota, Kohei; Klewer, Scott E.; Leppert, Mark F.; Schoenwolf, Gary C. (2010). "Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: integrating evidence from human genetics and model organisms". Human Molecular Genetics. 19 (7): 1286–1301. doi:10.1093/hmg/ddq005. ISSN 0964-6906.
19. ↑ Dabizzi RP, Caprioli G, Aiazzi L, Castelli C, Baldrighi G, Parenzan L, Baldrighi V (January 1980). "Distribution and anomalies of coronary arteries in tetralogy of fallot". Circulation. 61 (1): 95–102. doi:10.1161/01.cir.61.1.95. PMID 7349946.
20. ↑ Satyanarayana Rao, B.N.; Anderson, Ray C.; Edwards, Jesse E. (1971). "Anatomic variations in the tetralogy of Fallot". American Heart Journal. 81 (3): 361–371. doi:10.1016/0002-8703(71)90106-2. ISSN 0002-8703.
21. ↑ Muster, Alexander J.; Paul, Milton H.; Nikaidoh, Hisashi (1973). "Tetralogy of Fallot Associated with Total Anomalous Pulmonary Venous Drainage". Chest. 64 (3): 323–326. doi:10.1378/chest.64.3.323. ISSN 0012-3692.
22. ↑ Saifi, Comron; Matsumoto, Hiroko; Vitale, Michael G.; Roye, David P.; Hyman, Joshua E. (2012). "The incidence of congenital scoliosis in infants with tetralogy of Fallot based on chest radiographs". Journal of Pediatric Orthopaedics B. 21 (4): 313–316. doi:10.1097/BPB.0b013e3283536872. ISSN 1060-152X.

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Congenital malformations and deformations of circulatory system (Q20-Q28, 745-747)

Cardiac chambers and connections|

Persistent truncus arteriosus \- Double outlet right ventricle (Taussig-Bing syndrome) - Transposition of the great vessels (dextro, levo)

Cardiac septa|

Ventricular septal defect \- Atrial septal defect (Lutembacher's syndrome) - Atrioventricular septal defect (Ostium primum) - Tetralogy of Fallot \- Eisenmenger's syndrome

Right: pulmonary and tricuspid valves|

pulmonary valves (stenosis, insufficiency) - tricuspid valves (stenosis, atresia) - Ebstein's anomaly

Left: aortic and mitral valves|

aortic valves (stenosis, insufficiency, bicuspid) - mitral valves (stenosis, regurgitation) - Hypoplastic left heart syndrome

Other congenital malformations
of heart|

Dextrocardia \- Levocardia \- Cor triatriatum

Great arteries|

aorta (Patent ductus arteriosus, Aortic coarctation, Interrupted aortic arch, Overriding aorta, Aneurysm of sinus of Valsalva, Vascular ring) - Pulmonary atresia

Great veins|

Persistent left superior vena cava \- Total anomalous pulmonary venous connection \- Scimitar syndrome

Other|

Arteriovenous malformation (Cerebral arteriovenous malformation)

See also non-congenital conditions (I, 390-459)

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