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

• Published in: Circulation Journal Vol. 84; no. 3; pp. 479 - 486
• Main Authors: Mizuno, Yuji, Harada, Eisaku, Kinoshita, Kenji, Kusumegi, Izumi, Yoshimura, Michihiro, Kugimiya, Fumihito, Shono, Makoto, Yasue, Hirofumi
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Circulation Society 25.02.2020
• Subjects: Aged; Aldehyde Dehydrogenase, Mitochondrial - genetics; Angina Pectoris - drug therapy; Angina Pectoris - ethnology; Angina Pectoris - genetics; Angina Pectoris - physiopathology; Asian People - genetics; Coronary spastic angina; Coronary Vasospasm - drug therapy; Coronary Vasospasm - ethnology; Coronary Vasospasm - genetics; Coronary Vasospasm - physiopathology; Drug Resistance - genetics; East Asian variant aldehyde dehydrogenase 2 genotype; Endothelial dysfunction; Female; Humans; Japan - epidemiology; Male; Middle Aged; Nitrate tolerance; Nitroglycerin; Nitroglycerin - administration & dosage; Nitroglycerin - adverse effects; Polymorphism, Genetic; Vasoconstriction - drug effects; Vasoconstriction - genetics; Vasodilator Agents - administration & dosage; Vasodilator Agents - adverse effects; Japan; Nitrate tolerance; Endothelial dysfunction; Coronary spastic angina; Nitroglycerin; East Asian variant aldehyde dehydrogenase 2 genotype
• ISSN: 1346-9843; 1347-4820; 1347-4820
• DOI: 10.1253/circj.CJ-19-0989

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 wildALDH2*1/*1and variantALDH2*2patients 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 inALDH2*2than in theALDH2*1/*1group (P=0.0499) and decreased significantly in both groups (P<0.0001 and P<0.0001, respectively) after GTN, with significantly lower levels in theALDH2*2group (P=0.0002). FMD decreased significantly in bothALDH2*1/*1andALDH2*2groups (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 bothALDH2*1/1andALDH2*2patients with CSA.ALDH2*2attenuated GTN response and exacerbated GTN tolerance, but not endothelial dysfunction, as compared toALDH2*1/*1in patients with CSA.