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Genetic determinants in right-ventricular fibrosis and remodeling after tetralogy of Fallot repair

Grant number: 14/12006-6
Support type:Scholarships abroad - Research
Effective date (Start): October 06, 2014
Effective date (End): October 05, 2015
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal researcher:Paulo Henrique Manso
Grantee:Paulo Henrique Manso
Host: Elizabeth Golmuntz
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: Children's Hospital of Philadelphia (CHOP), United States  


Congenital heart defects (CHDs) are the most common, serious type of birth defect, occurring in 1 in 200 live births. Despite medical and surgical advances, CHDs remain the leading cause of birth defect related infant mortality and, as survival improves, become of increasing prevalence and healthcare concern in adults. Tetralogy of Fallot (TOF) is the most common cyanotic heart defect and accounts for 7% of all CHDs. All patients with TOF require open-heart surgery in the first year of life to relieve the associated right ventricular (RV) outflow tract obstruction and to close the ventricular septal defect. Although most patients with TOF survive the initial surgery, many require re-interventions throughout their lifetime and experience substantial morbidity and early mortality, such that one in ten die before age 30. The late morbidity and mortality in TOF are in large part caused by the obligatory surgical disruption of the pulmonary valve with consequent pulmonary insufficiency (PI) and RV remodeling that involves geometric (dilation and hypertrophy) and functional changes. The response of the RV to the increased pressure and volume load afforded by residual outflow tract obstruction, pulmonary artery stenosis and/or PI is highly variable and the mechanisms poorly understood. We hypothesize that the variability in RV remodeling is in part regulated by genetic factors, be they genetic variants that contribute to the etiology of TOF or that modify RV remodeling. In TOF the operated RV has been found to have a significant degree of fibrosis detected by late gadolinium enhancement on cardiac magnetic resonance, which itself has been associated with ventricular dysfunction, exercise intolerance and ventricular arrhythmias (including sudden death). To test our hypothesis, we propose to study the association of genotype with the process of RV remodeling, with a particular focus on fibrosis as described in the following aims: 1. Assess the association of the extent of fibrosis in the operated RV in cases with TOF with measures of RV remodeling. 2.Assess the association of genotype conferring risk for TOF to the extent of RV fibrosis. 3.Assess the association of variants in genes (HIF1A and ACE) regulating fibrosis to the extent of RV fibrosis and measures of RV remodeling.To accomplish these aims, we will use a previously ascertained and consented cohort of cases with TOF who have undergone cardiac MRI from which the extent of fibrosis can be measured retrospectively. Measures of RV remodeling are already available from these studies. This same cohort has already been tested for trisomy 21 and 22q11.2 deletion status. Furthermore, this cohort has already either been genotyped on a dense SNP-array, and/or have DNA available for genotyping for specific variants of interest if not represented on the arrays and/or in additional cases that have not yet been array genotyped. Thus, the study cohort and materials (ie: CMR images and DNA for additional genotyping) required for these proposed analyses are already readily available. As such, these studies should be readily performed within the proposed fellowship period. These studies will not only advance our understanding of factors that contribute to RV fibrosis in particular, RV remodeling in general, and associated outcomes, but will also identify potential avenues for intervention to improve long term clinical outcomes. In addition, these studies serve as a paradigm for the study of the impact of genetic variability on clinical outcome in TOF specifically and CHDs in general.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
HOANG, THANH T.; MANSO, PAULO HENRIQUE; EDMAN, SHARON; MERCER-ROSA, LAURA; MITCHELL, LAURA E.; SEWDA, ANSHUMAN; SWARTZ, MICHAEL D.; FOGEL, MARK A.; AGOPIAN, A. J.; GOLDMUNTZ, ELIZABETH. Genetic variants of HIF1 alpha are associated with right ventricular fibrotic load in repaired tetralogy of Fallot patients: a cardiovascular magnetic resonance study. JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE, v. 21, n. 1 AUG 19 2019. Web of Science Citations: 0.

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