East Asians Variant Mitochondrial Aldehyde Dehydrogenase 2 Genotype Exacerbates Nitrate Tolerance in Patients With Coronary Spastic Angina

Abstract

Background: Aldehyde dehydrogenase 2 (ALDH2) plays a central role in the biotransformation of glyceryl trinitrate (GTN) or nitroglycerin, which is widely used for the treatment of coronary artery disease (CAD). The deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. This study examined whether there are differences in nitroglycerine-mediated dilation (NMD) and flow-mediated dilation (FMD) response between wild ALDH2*1/*1 and variant ALDH2*2 patients with CAD. Methods and Results: The study subjects comprised 55 coronary spastic angina (CSA) patients, confirmed by coronary angiography and intracoronary injection of acetylcholine (42 men and 13 women, mean age 68.0±9.0 years). They underwent NMD and FMD tests in the morning before and after continuous transdermal GTN administration for 48 h. NMD was lower at baseline in ALDH2*2 than in the ALDH2*1/*1 group (P=0.0499) and decreased significantly in both groups (P<0.0001 and P<0.0001, respectively) after GTN, with significantly lower levels in the ALDH2*2 group (P=0.0002). FMD decreased significantly in both ALDH2*1/*1 and ALDH2*2 groups (P<0.0001and P=0.0002, respectively) after continuous GTN administration, with no significant differences between the 2 groups both before and after GTN. Conclusions: Continuous administration of GTN produced endothelial dysfunction as well as nitrate tolerance in both ALDH2*1/1 and ALDH2*2 patients with CSA. ALDH2*2 attenuated GTN response and exacerbated GTN tolerance, but not endothelial dysfunction, as compared to ALDH2*1/*1 in patients with CSA.