Abstract
The right ventricle (RV) is exposed to numerous stressors in patients with congenital heart defects. The ability of the RV to adapt to stress is important in maintaining long term structure and function. Genetic factors play an important role in influencing RV adaptation. These include variations in genes involved in hypoxia signaling, metabolic regulation and neurohormonal regulation. Variants in these genes influence the RV response to hypoxia, pressure or volume overload and surgical injury. Knowledge of patient genotype may help identify those at highest risk for adverse RV remodeling and RV failure, and importantly in guiding choice and timing of interventions to preserve RV function.
Keywords
This is a preview of subscription content, log in via an institution.
Abbreviations
- CHD:
-
Congenital heart disease
- HCM:
-
Hypertrophic cardiomyopathy
- HIF1A:
-
Hypoxia inducible factor 1α
- LV:
-
Left ventricle
- RAAS:
-
Renin-angiotensin-aldosterone system
- RV:
-
Right ventricle
- SNP:
-
Single nucleotide polymorphism
- TGFB1:
-
Transforming growth factor β1
- TOF:
-
Tetralogy of Fallot
References
Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506(7487):185–90.
Michaelson JJ, Shi Y, Gujral M, Zheng H, Malhotra D, Jin X, et al. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell. 2012;151(7):1431–42.
Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013;498(7453):220–3.
Al Turki S, Manickaraj AK, Mercer CL, Gerety SS, Hitz MP, Lindsay S, et al. Rare variants in NR2F2 cause congenital heart defects in humans. Am J Hum Genet. 2014;94(4):574–85.
Buckingham M, Meilhac S, Zaffran S. Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet. 2005;6(11):826–35.
Stevens KN, Hakonarson H, Kim CE, Doevendans PA, Koeleman BP, Mital S, et al. Common variation in ISL1 confers genetic susceptibility for human congenital heart disease. PLoS One. 2010;5(5):e10855.
Greenway SC, Pereira AC, Lin JC, DePalma SR, Israel SJ, Mesquita SM, et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet. 2009;41(8):931–5.
Silversides CK, Lionel AC, Costain G, Merico D, Migita O, Liu B, et al. Rare copy number variations in adults with tetralogy of Fallot implicate novel risk gene pathways. PLoS Genet. 2012;8(8):e1002843.
Semenza GL, Agani F, Feldser D, Iyer N, Kotch L, Laughner E, et al. Hypoxia, HIF-1, and the pathophysiology of common human diseases. Adv Exp Med Biol. 2000;475:123–30.
Sun S, Ning X, Zhang Y, Lu Y, Nie Y, Han S, et al. Hypoxia-inducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition. Kidney Int. 2009;75(12):1278–87.
Kim Y-M, Barnes EA, Alvira CM, Ying L, Reddy S, Cornfield DN. Hypoxia-inducible factor-1α in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation. Circ Res. 2013;112(9):1230–3.
Reddy S, Osorio JC, Duque AM, Kaufman BD, Phillips AB, Chen JM, et al. Failure of right ventricular adaptation in children with tetralogy of fallot. Circulation. 2006;114(1 Suppl):I37–42.
Jeewa A, Manickaraj AK, Mertens L, Manlhiot C, Kinnear C, Mondal T, Smythe J, Rosenberg H, Lougheed J, McCrindle BW, van Arsdell G, Redington AN, Mital S. Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair. Pediatr Res. 2012;72(4):407–13.
Russell MW, Wilder NS. Getting personal: understanding how genetic variation affects clinical outcomes in patients with tetralogy of Fallot. Pediatr Res. 2012;72(4):334–6.
Alkon J, Friedberg MK, Manlhiot C, Manickaraj AK, Kinnear C, McCrindle BW, Benson LN, Addonizio LJ, Colan SD, Mital S. Genetic variations in hypoxia response genes influence hypertrophic cardiomyopathy phenotype. Pediatr Res. 2012;72(6):583–92.
Zhang H, Gong DX, Zhang YJ, Li SJ, Hu S. Effect of mitochondrial aldehyde dehydrogenase-2 genotype on cardioprotection in patients with congenital heart disease. Eur Heart J. 2012;33(13):1606–14.
Ortlepp JR, Vosberg HP, Reith S, Ohme F, Mahon NG, Schroder D, et al. Genetic polymorphisms in the renin-angiotensin-aldosterone system associated with expression of left ventricular hypertrophy in hypertrophic cardiomyopathy: a study of five polymorphic genes in a family with a disease causing mutation in the myosin binding protein C gene. Heart. 2002;87(3):270–5.
Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, et al. Enalapril in infants with single ventricle: results of a multicenter randomized trial. Circulation. 2010;122(4):333–40.
Mital S, Chung WK, Colan SD, Sleeper LA, Manlhiot C, Arrington CB, et al. Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle. Circulation. 2011;123(21):2353–62.
Wypij D, Newburger JW, Rappaport LA, duPlessis AJ, Jonas RA, Wernovsky G, et al. The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: The Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg. 2003;126(5):1397–403.
Gaynor JW, Gerdes M, Zackai EH, Bernbaum J, Wernovsky G, Clancy RR, et al. Apolipoprotein E genotype and neurodevelopmental sequelae of infant cardiac surgery. J Thorac Cardiovasc Surg. 2003;126(6):1736–45.
Gaynor JW, Nord AS, Wernovsky G, Bernbaum J, Solot CB, Burnham N, et al. Apolipoprotein E genotype modifies the risk of behavior problems after infant cardiac surgery. Pediatrics. 2009;124(1):241–50.
Zeltser I, Jarvik GP, Bernbaum J, Wernovsky G, Nord AS, Gerdes M, Zackai E, Clancy R, Nicolson SC, Spray TL, Gaynor JW. Genetic factors are important determinants of neurodevelopmental outcome after repair of tetralogy of Fallot. J Thorac Cardiovasc Surg. 2008;135(1):91–7.
Gaynor JW, Kim DS, Arrington CB, Atz AM, Bellinger DC, Burt AA, Ghanayem NS, Jacobs JP, Lee TM, Lewis AB, Mahle WT, Marino BS, Miller SG, Newburger JW, Pizarro C, Ravishankar C, Stolle CA, Wilder NS, Jarvik GP, Mital S, Russell MW. Validation of association of the apo-lipoprotein E (APOE) ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants. J Thorac Cardiovasc Surg. 2014;148(6):2560–6.
Ashley EA, Hershberger RE, Caleshu C, Ellinor PT, Garcia JGN, Herrington DM, et al. Genetics and cardiovascular disease: a policy statement from the american heart association. Circulation. 2012;126(1):142–57.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this chapter
Cite this chapter
Mital, S. (2018). Genetic Variation and Outcomes in Right Ventricular Congenital Heart Disease. In: Friedberg, M., Redington, A. (eds) Right Ventricular Physiology, Adaptation and Failure in Congenital and Acquired Heart Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-67096-6_4
Download citation
DOI: https://doi.org/10.1007/978-3-319-67096-6_4
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-67094-2
Online ISBN: 978-3-319-67096-6
eBook Packages: MedicineMedicine (R0)