Molecular Genetic Studies in Atrial Fibrillation

Atrial fibrillation (AF) is now recognized to be the most common sustained cardiac arrhythmia and a major public health burden. By genetic association study, some genetic variants or polymorphisms and derived biomarkers related to the mechanism of AF have been found to be associated with common AF. For example, accumulating evidence suggests that there is a link between oxidative processes and AF. Many works revealed that accumulation of cytotoxic and reactive aldehydes derived from reactive oxygen species (ROS) can also severely impair cardiac functions. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a key enzyme that detoxifies ROS-generated aldehyde adducts. The rs671, a common polymorphism in the ALDH2 gene, results in a dramatic reduction in the enzymatic activity and has been linked to an increased risk of cancer and heart disease. We hypothesize that the rs671 is associated with the risk of AF in Taiwanese by modifying atrial remodeling derived from oxidative stress. Therefore, we plan to investigate whether: 1. The rs671 polymorphism in the ALDH2 gene is associated with the risk of atrial fibrillation. 2. Plasma 4-HNE levels are higher in AF patients than in healthy controls, and Plasma 4-HNE levels are higher in AF patients with the ALDH2*2 allele than in AF patients with the ALDH2*1 allele. 3. 4-HNE-modified protein adducts by immunohistochemistry and western bot in atrial tissue increase in AF patients than in patients with sinus rhythm, and 4-HNE-modified protein adducts by immunohi stochemi stry and western bot in atrial tissue increase in AF patients with the ALDH2*2 allele than in AF patients with the ALDH2* 1 allele. 4. Rapid activation of HL-1 atrial myocytes generates 4-HNE and MDA derived from ROS-induced stress. 5. Overexpression or knockdown of ALDH2 modulates the oxidative stress induced by rapid-pacing in HL-1 cells. 6. Overexpression or knockdown of ALDH2 modulates the atrial structure remodeling induced by rapid-pacing in HL-1 cells. 7. Overexpression of ALDH2 attenuates oxidative stress induced by rapid-pacing in HL-1 cells and PKCs is involved in this protection. Hopefully, our study will offer a deeper understanding about oxidative stress-induced cellular structural and electrical remodeling in AF. The results of our study may help define the role of ALDH2 in AF and provide a useful target for therapeutic intervention in AF.

Project ID:PC10408-2384
External Project ID:MOST104-2314-B182-054