Common genetic mutation blunts response to nitroglycerin

Shelley Wood

January 27, 2006

Shanghai, China - Chinese researchers have identified a common genetic mutation in Asians that reduces responsiveness to nitroglycerin [1]. The mutation, found in mitochondrial aldehyde dehydrogenase-2 (ALDH2)—an enzyme used to metabolize alcohol—is found in 30% to 50% of Asians and should be taken into account when prescribing antianginal medication, the authors of a new study say.

The paper, by Dr Yifeng Li (Fudan University, Shanghai, China) and colleagues, is published online January 26, 2006 in the Journal of Clinical Investigation.

In their study, Li et al note that ALDH2 is responsible for formation of nitric oxide (NO), the metabolite required for nitroglycerin efficacy. In people with a specific polymorphism of ALDH2 (known as ALDH2*2), the activity of this enzyme is reduced. As Li explained to heart wire , "This mutation reduces the activity of the enzyme that plays a key role in transforming the drug to release pharmacologically active NO, which then relaxes vascular smooth muscle."

To appreciate the impact of this reduced ALDH2 activity, Li et al examined 80 Chinese coronary artery disease patients who were taking nitroglycerin for angina attacks. In all, 59 (74%) subjects reported feeling pain relief within 10 minutes of taking the drug (responders) while the remainder had no pain relief (nonresponders). When stratified according to whether or not they carried at least one mutant allele, 57.6% of patients with the mutation (19 out of 33 subjects) responded well to nitroglycerin therapy, as opposed to 85.1% of subjects without the polymorphism (40 out of 47 subjects).

The authors acknowledged that ALDH2 does not tell the whole story; after all, some of the people carrying the polymorphism obtained anginal relief from nitroglycerin, while others without the mutant form did not.

"We postulate that other pathways may also be involved in the metabolism of nitroglycerin such as glutathione S-transferase [GST], the cytochrome p450 system, although the catalytic efficiency of ALDH2 is much higher than that of other enzymes," Li told heart wire .

Nevertheless, given the prevalence of this particular polymorphism in people of Asian descent, physicians should probably consider testing for ALDH2*2 when prescribing nitroglycerin, the authors say. Since DNA testing may not be feasible, physicians can resort to alcohol, so to speak. Earlier research has shown that people whose face and skin tends to become flushed during alcohol consumption are usually carriers of the inactive form of ALDH2. As such, a "flushing response" determined by self-report, after ingestion of a small amount of alcohol, or a local reaction to an ethanol patch test may be helpful in determining whether a patient will respond to nitroglycerin.

Such a strategy, however, would need to be tested in clinical trials, Li emphasized to heart wire . If confirmed, Li added, "It [would be] advisable not to give nitroglycerin to those who show a flush response to alcohol."


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