Tetralogy of Fallot pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Fahimeh Shojaei, M.D., Priyamvada Singh, M.B.B.S. [2], Keri Shafer, M.D. [3]; Omar Toubat; Assistant Editor-In-Chief: Kristin Feeney, B.S. [4]

Overview

Tetralogy of Fallot is a congenital heart lesion characterized by a constellation of four morphologic abnormalities present in the newborn heart. It is understood that tetralogy of fallot is the result of improper positioning of the outlet septum. 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. These features include a ventricular septal defect, overriding aorta, pulmonary stenosis, and right ventricular hypertrophy. The obstruction of right ventricular outflow in tetralogy of Fallot causes blood to shunt or flow from the right to left side of heart through the ventricular septal defect. This causes right ventricular hypertrophy and eventual right sided heart failure. There is flow of deoxygenated venous blood from the right side of the heart to the systemic circulation resulting in cyanosis.

Pathophysiology

Physiology

The normal physiology of heart development can be understood as follows:


Pathogenesis


Anatomy

  • This defect in outlet septum in turn leads to the four characteristic features:
  • A: Pulmonic Stenosis
    • Pulmonic stenosis is a right ventricular outflow tract obstruction
      • A narrowing at (valvular stenosis, seen in approximately 20-25% case) or just below (infundibular stenosis, seen in around 50% of cases) the pulmonary valve.
      • The stenosis is mostly the result of hypertrophy of the septoparietal trabeculae,[4] however the deviated outlet septum is believed to play a role.
      • The stenosis is the major cause of the malformations, with the other associated malformations acting as compensatory mechanisms to the pulmonic stenosis.[5]
      • The degree of stenosis varies between individuals with TOF, and is the primary determinant of symptoms and severity. This malformation is infrequently described as sub-pulmonary stenosis or subpulmonary obstruction.[6]
      • Tetralogy of Fallot with pulmonary atresia or pseudotruncus arteriosus is a severe variant in which there is complete obstruction of the right ventricular outflow tract and absence of the pulmonary trunk. In these individuals, there is complete right-to-left shunting of blood. The lungs are perfused via extensive collaterals from the systemic arteries.
  • B: Overriding Aorta
  • C: Ventricular Septal Defect
    • Ventricular septal defect is a hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the outlet septum, the most superior aspect of the septum, and in the majority of cases is single and large. In some cases septal hypertrophy can narrow the margins of the defect.[4]
  • D: Right Ventricular Hypertrophy
    • The right ventricle is more muscular than normal, causing a characteristic coeur-en-sabot (boot-shaped) appearance as seen by chest x-ray. Due to the misarrangement of the external ventricular septum, the right ventricular wall increase in size to deal with the increased obstruction to the right outflow tract. This feature is now generally agreed to be a secondary anomaly, as the level of hypertrophy generally increases with age.[7]
  • There is anatomic variation between the hearts of individuals with tetralogy of Fallot.
  • The degree of right ventricular outflow tract obstruction varies between patients and is generally determines clinical symptoms and disease progression.

Embrylogy

Genetics

Associated Conditions

Gross Pathology


Microscopic Pathology

There is no characteristic findings of tetralogy of fallot on microscopic histopathological analysis.


References

  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.
  4. 4.0 4.1 4.2 Gatzoulis MA, Webb GD, Daubeney PE. (2005) Diagnosis and Management of Adult Congenital Heart Disease. Churchill Livingstone, Philadelphia. ISBN 0443071039.
  5. Bartelings M, Gittenberger-de Groot A (1991). "Morphogenetic considerations on congenital malformations of the outflow tract. Part 1: Common arterial trunk and tetralogy of Fallot". Int. J. Cardiol. 32 (2): 213–30. PMID 1917172.
  6. Anderson RH, Weinberg. The clinical anatomy of tetralogy of Fallot. Cardiol Young. 2005 15;38-47. PMID 15934690.
  7. Anderson RH, Tynan M. Tetralogy of Fallot – a centennial review. Int J Cardiol. 1988 21; 219-232. PMID 3068155.
  8. 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.
  9. 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.
  10. Bruneau BG (2008). "The developmental genetics of congenital heart disease". Nature. 451 (7181): 943–8. doi:10.1038/nature06801. PMID 18288184.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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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