Effect of mitochondrial aldehyde dehydrogenase-2 genotype on cardioprotection in patients with congenital heart disease

About 40 of East Asians carry an aldehyde dehydrogenase-22 (ALDH22) allele, and the influence ofthe ALDH22 allele on human cardioprotection has not been studied. This study was designed to evaluate the effect of ALDH22 allele on cardioprotection of patients with congenital heart diseases after open-heart surgery. The right atrial appendage was harvested before performing cardiopulmonary bypass in cyanotic and acyanotic congenital heart disease groups (n 20 per group). Tissues were assayed to determine the impact of cyanosis on metabolic remodelling. A prospective cohort of Tetralogy of Fallot (TOF) patients (n 118) was recruited to investigate the influence of the ALDH22 allele on cardioprotection after surgical repair. Myocardium samples were dissected after cardioplegia. ALDH2 activity, oxidative stress and glutathione (GSH) levels, and activating transcription factor-4 (ATF4) were analysed. After genotyping and grouping, all of the experimental and clinical results were compared between ALDH22 carriers and non-carriers. Cyanosis inhibited ALDH2 activity and led to aldehyde accumulation in ALDH22 carriers. This accumulation in turn increased expression of ATF4 and resulted in larger myocardium GSH pools. The differences in ALDH2 activity and GSH level between carriers and non-carriers disappeared during cardioplegic arrest, and more aldehydes accumulated in the non-carriers. Consequently, ALDH22 carriers showed lower postoperative troponin I, inotrope score, and shorter postoperative length of ICU and hospital stay. ALDH22 carriers with cyanotic congenital heart disease were associated with an induced metabolic remodelling phenotype and a compensatory myocardium GSH pool. When ALDH2 activity 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.