To determine whether polymorphisms at codon 487 (*1, GAA=Glu; *2, AAA=Lys) of mitochondrial aldehyde dehydrogenase 2 (ALDH2) influence nitroglycerine (glyceryl trinitrate (GTN))-induced vasodilation, and whether GTN or isosorbide dinitrate (ISDN) is a more effective antianginal agent in each ALDH2 genotype.
A randomised, open-label, crossover trial with 117 healthy Japanese (20–39 years) whose genotypes were determined (*1/*1, n=47; *1/*2, n=48; *2/*2, n=22) was performed at Kyushu University Hospital, Fukuoka, Japan. Participants were randomly assigned to treatment: sublingual spray of GTN (0.3 mg) or ISDN (1.25 mg). After ≥1 week, measurements were repeated using the other drug. The main outcome measures were the maximal rate of increase in the brachial artery diameter determined by ultrasonography, the time required to attain maximal dilation (Tmax) and the time required to attain 90% maximal dilation (T0.9).
The maximal artery diameter increase in response to GTN or ISDN did not differ among genotypes. However, GTN Tmax was significantly longer for *2/*2 (299.7 s, 269.0–330.4) than *1/*1 (254.7 s, 238.6–273.4; p=0.0190). GTN T0.9 was significantly longer in the *1/*2 (206.1 s, 191.7–219.3) and *2/*2 (231.4 s, 211.8–251.0) genotypes than *1/*1 (174.9 s, 161.5–188.3; p=0.0068, p<0.0001, respectively). In contrast, the time-course of ISDN-induced vasodilation did not differ among genotypes. GTN Tmax and T0.9 among *1 allele carriers (*1/*1 and *1/*2) were significantly shorter than those of ISDN, whereas the time course of GTN and ISDN vasodilation did not differ among participants carrying *2/*2.
The amplitude of GTN-induced vasodilation was not influenced by the ALDH2 genotype, but the response was significantly delayed in *2 allele carriers, especially *2/*2. GTN dilated the artery more quickly than ISDN in *1/*1 and *1/*2, but not in *2/*2.
Trial registration number
UMIN000001492 (UMIN-CTR database).
There were few reliable human studies on the influence of aldehyde dehydrogenase 2 (ALDH2) polymorphisms at codon 487 on the response to nitroglycerine (GTN). In particular, there was no information about the response to GTN in *2/*2 homozygotes.
It was unclear whether GTN or isosorbide dinitrate (ISDN) is a more effective antianginal agent in each ALDH2 genotype.
We aimed at comparing vasodilation induced by GTN and ISDN in individuals with different ALDH2 genotypes.
The maximal rate of increase in arterial diameter after GTN treatment did not differ among ALDH2 genotype groups.
The time required to attain 90% maximal vasodilation was longer in the *1/*2 and *2/*2 groups than in the *1/*1 group.
GTN (0.3 mg) induced vasodilation more rapidly than ISDN (1.25 mg) in the *1/*1 and *1/*2 groups, but there was no difference between GTN and ISDN in the *2/*2 group.
Strengths and limitations of this study
The choice of healthy young individuals as participants may have strengthened the validity of the study; the participants' backgrounds were likely to be more homogeneous by excluding the influence of multiple concomitant factors that could not be controlled when studying patients or older subjects. However, the results could have been different if the study had been performed with patients with angina, because haemodynamic changes in patients might alter the response to nitrates.
Sublingual spray formulations of nitrates were used instead of tablets to minimise the fluctuation in absorption rate. However, this may have made the dosage slightly unreliable.
A randomised crossover design was used, and arterial diameter was determined by a single measurer blinded to genotype. However, the participants and investigators were not blinded to treatment.
Arterial diameter was accurately measured using a semiautomatic ultrasonography system. However, the brachial artery diameter was measured instead of the coronary artery diameter, and moreover, we did not evaluate venous dilation.