Cyanotic heart defect pathophysiology: Difference between revisions
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==Genetics== | ==Genetics== | ||
[ | *[[Genes]] involved in the [[pathogenesis]] of tetralogy of fallot include:<ref name="pmid17008524">{{cite journal| author=Olson EN| title=Gene regulatory networks in the evolution and development of the heart. | journal=Science | year= 2006 | volume= 313 | issue= 5795 | pages= 1922-7 | pmid=17008524 | doi=10.1126/science.1132292 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17008524 }} </ref><ref name="pmid24000169">{{cite journal| author=Yang YQ, Gharibeh L, Li RG, Xin YF, Wang J, Liu ZM et al.| title=GATA4 loss-of-function mutations underlie familial tetralogy of fallot. | journal=Hum Mutat | year= 2013 | volume= 34 | issue= 12 | pages= 1662-71 | pmid=24000169 | doi=10.1002/humu.22434 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24000169 }} </ref><ref name="pmid18288184">{{cite journal| author=Bruneau BG| title=The developmental genetics of congenital heart disease. | journal=Nature | year= 2008 | volume= 451 | issue= 7181 | pages= 943-8 | pmid=18288184 | doi=10.1038/nature06801 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18288184 }} </ref><ref name="pmid24526674">{{cite journal| author=Bruneau BG, Srivastava D| title=Congenital heart disease: entering a new era of human genetics. | journal=Circ Res | year= 2014 | volume= 114 | issue= 4 | pages= 598-9 | pmid=24526674 | doi=10.1161/CIRCRESAHA.113.303060 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24526674 }} </ref><ref name="pmid11431700">{{cite journal| author=Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R et al.| title=Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. | journal=Nat Genet | year= 2001 | volume= 28 | issue= 3 | pages= 276-80 | pmid=11431700 | doi=10.1038/90123 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11431700 }} </ref><ref name="pmid12845333">{{cite journal| author=Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA et al.| title=GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. | journal=Nature | year= 2003 | volume= 424 | issue= 6947 | pages= 443-7 | pmid=12845333 | doi=10.1038/nature01827 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12845333 }} </ref><ref name="pmid24182332">{{cite journal| author=Sheng W, Qian Y, Wang H, Ma X, Zhang P, Diao L et al.| title=DNA methylation status of NKX2-5, GATA4 and HAND1 in patients with tetralogy of fallot. | journal=BMC Med Genomics | year= 2013 | volume= 6 | issue= | pages= 46 | pmid=24182332 | doi=10.1186/1755-8794-6-46 | pmc=PMC3819647 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24182332 }} </ref> | ||
** The [[cellular]] processes that underlie cardiogenesis are extensively regulated in the developing [[heart]]. | |||
** Proper [[Heart|cardiac]] development requires the complex orchestration of [[cardiac]] [[Transcription factor|transcription factors]] and [[Signaling pathway|signaling pathways]] in a spatiotemporal specific manner. | |||
** Previous [[Genetics|genetic]] studies demonstrated that [[mutations]] in numerous [[genes]] encoding [[Heart|cardiac]] [[transcription factors]] and [[cell]] [[Signaling protein|signaling proteins]] have a role in the [[development]] of Tetralogy of Fallot. | |||
** Specifically, [[Heterozygous|heterozygous mutations]] in [[NKX2-5]], [[HAND1]], [[TBX5 (gene)|TBX5]], and [[GATA4]] have been reported in familial forms of [[disease]]. | |||
** Many of these single [[Gene mutation|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 pathway]]<nowiki/>s central to [[cardiac]] morphogenesis. | |||
** In addition, recent whole-exome sequencing investigations have introduced a novel role for [[Epigenetics|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]]. | |||
==Associated Conditions== | ==Associated Conditions== | ||
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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
Pathophysiology
Tetrology of Fallot
- 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
- In this condition,the right side of heart is receiving blood both from pulmonary and systemic circulation.
- 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)
Hypoplastic Left Heart Syndrome
- 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.
Transpostion of Great Arteries
- The pulmonary and systemic circulations function in parallel, rather than in series.
- Oxygenated pulmonary venous blood returns to the left atrium and left ventricle but is recirculated to the pulmonary vascular bed and deoxygenated systemic venous blood returns into right atrium and ventricle which is subsequently pumped back into systemic circulation.[4]
Truncus Arteriosus
- 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
- 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.
Genetics
- Genes involved in the pathogenesis of tetralogy of fallot include:[5][6][7][8][9][10][11]
- 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.
Associated Conditions
Conditions associated with [disease name] include:
- [Condition 1]
- [Condition 2]
- [Condition 3]
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Warnes CA (December 2006). "Transposition of the great arteries". Circulation. 114 (24): 2699–709. doi:10.1161/CIRCULATIONAHA.105.592352. PMID 17159076.
- ↑ 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.
- ↑ 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.
- ↑ Bruneau BG (2008). "The developmental genetics of congenital heart disease". Nature. 451 (7181): 943–8. doi:10.1038/nature06801. PMID 18288184.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.