Methylenetetrahydrofolate Reductase C677T And Reduced Folate Carrier80G>A Polymorphisms And Conotruncal Heart Defects Effects Of Mitochondrial Aldehyde Dehydrogenase-2Genotype On Cardioprotection In Conotruncal Heart Defect Patients Undergoing Open-hea

Background:Folic acid plays an important role during embryologic development, including the development of the cardiovascular system. Enzymes and carrier proteins involved in the metabolism of folic acid is crucial in the maintenance of body folic acid level. Polymorphisms of the genes encoding these proteins can alter the functions of them.Methods and Results:We analyze the involvement of8polymorphisms in genes related to folic acid metabolism,5,10-methylenetetrahydrofolate reductase(MTHFR), MTHFD1, TCN2, RFC (SLC19A1), NNMT and NPPA as risk factors of conotruncal heart defects. In the single locus analyses, the genotype frequencies of MTHFR rs1801133C>T were18.4%(CC),50.4%(CT), and31.1%(TT) in the conotruncal heart defects patients and31.6%(CC),52.9%(CT), and15.4%(TT) in the control subjects, and the difference was statistically significant (p=0.001). Logistic regression analyses revealed that when the MTHFR rs1801133CC homozygote genotype was used as the reference group, subjects carrying the TT variant homozygote had a significantly3.46fold (adjusted OR=3.46;95%CI=1.83-6.55) increased risk of conotruncal heart defects. When the RFC rs1051266GG homozygote genotype was used as the reference group, subjects carrying the GA variant heterozygote had a significantly1.68fold (OR=1.68;95%CI=1.02-2.78) increased risk of conotruncal heart defects. In stratification analyses, the MTHFR rs1801133C>T genotype was associated with an increased risk for Tetralogy of Fallot (TOF) and Transposition of Great Artery (TGA) both in homozygote comparison, dominant genetic model and recessive genetic model. In addition, RFC rs1051266GA genotype was associated with an increased risk for TGA compared with wild-type homozygotes and in dominant genetic model, the RFC rs1051266GA/AA genotype was also associated with a significantly increased risk of TGA compared with the RFC rs1051266GG genotypes.Conclusions:Our research suggests that genotypes for the MTHFR C677T and RFC rs1051266polymorphism might be associated with the risk of conotruncal heart defects. Background:About40%of East Asians carry an ALDH2*2allele, and the influence of ALDH2*2allele on human cardioprotection has not been studied. This study was designed to evaluate the effect of aldehyde dehydrogenase-2*2(ALDH2*2) allele on cardioprotection of patients with congenital heart diseases after open heart surgery.Methods and Results:Right atrial appendage was harvested before performing cardiopulmonary bypass in cyanotic and acyanotic congenital heart disease groups (n=20per group). Tissues were assayed to determine the impact of cyanosis on metabolic remodeling. A prospective cohort of Tetralogy of Fallot (TOF) patients (n=118) were recruited to investigate the influence of ALDH2*2allele on cardioprotection after surgical repair. Myocardium samples were dissected after cardioplegia. ALDH2activity, oxidative stress and GSH levels, and activating transcription factor-4(ATF4) were analyzed. After genotyping and grouping, all of the experimental and clinical results were compared between ALDH2*2carriers and non-carriers. The ALDH2activity, GSH level, tissue4-HNE adducts content, and MDA level of acyanotic ALDH2*2non-carriers and carriers were:2.58±0.71and1.11±0.25U/mg,1.29±0.45and1.25±0.23nmol/mg,1.14±0.59and1.54±0.65ug/mg,70.17±35.19and93.90±51.66nmol/mg respectively. The ALDH2activity, GSH level, tissue4-HNE adducts content, and MDA level of cyanotic ALDH2*2non-carriers and carriers were:1.56±0.34and0.70±0.15U/mg,1.14±0.32and2.35±0.40nmol/mg,1.73±0.75and2.83±0.77ug/mg,77.31±40.01and264.13±116.97nmol/mg respectively. Both ALDH2*2genotype and cyanosis can significantly inhibit ALDH2activity (P=0.01and P<0.01). The inhibited ALDH2activity led to aldehydes accumulations in ALDH2*2carriers. This accumulation in turn increased ATF4expressions and resulted in larger myocardium glutathione (GSH) pools (P<0.01). ALDH2activity differences between carriers and non-carriers disappeared during cardioplegic arrest (ALDH2*2carriers:0.58±0.30U/mg Vs. ALDH2*2carriers:0.61±0.33; P=0.935), and more aldehydes accumulated in the non-carriers. Consequently, ALDH2*2carriers showed lower post-operative troponin I (Corrected P=0.026), inotrope (Corrected P=0.001), and shorter postoperative length of ICU and hospital stay (Corrected P=0.009and0.023respectively). Conclusions:ALDH2*2carriers with cyanotic congenital heart disease were associated with an induced metabolic remodeling and a compensatory myocardium GSH pool. When ALDH2activity was impaired during open-heart surgery, this larger GSH pool could lead to unexpectedly better cardioprotection. This may aid in the prediction of cardioprotection outcomes and identification of individualized cardioprotective strategies.