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

Circ J. 2020 Feb 25;84(3):479-486. doi: 10.1253/circj.CJ-19-0989. Epub 2020 Jan 31.


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.

Keywords: Coronary spastic angina; East Asian variant aldehyde dehydrogenase 2 genotype; Endothelial dysfunction; Nitrate tolerance; Nitroglycerin.

MeSH terms

  • Aged
  • Aldehyde Dehydrogenase, Mitochondrial / genetics*
  • Angina Pectoris / drug therapy*
  • Angina Pectoris / ethnology
  • Angina Pectoris / genetics*
  • Angina Pectoris / physiopathology
  • Asian Continental Ancestry Group / genetics*
  • Coronary Vasospasm / drug therapy*
  • Coronary Vasospasm / ethnology
  • Coronary Vasospasm / genetics*
  • Coronary Vasospasm / physiopathology
  • Drug Resistance / genetics*
  • Female
  • Humans
  • Japan / epidemiology
  • Male
  • Middle Aged
  • Nitroglycerin / administration & dosage*
  • Nitroglycerin / adverse effects
  • Polymorphism, Genetic*
  • Vasoconstriction / drug effects*
  • Vasoconstriction / genetics
  • Vasodilator Agents / administration & dosage*
  • Vasodilator Agents / adverse effects


  • Vasodilator Agents
  • ALDH2 protein, human
  • Aldehyde Dehydrogenase, Mitochondrial
  • Nitroglycerin