Genetic Predisposition to Neurohumoral Activation Following Myocardial Infarction: Effects of the Angiotensin Converting Enzyme I/D Polymorphism

Recent studies suggest that deletion polymorphism of the angiotensin converting enzyme (ACE) gene is associated with increased plasm ACE activity and an increased risk for both, myocardial infarction (MI) and left ventricular hypertrophy (LVH). To test the hypothesis whether the deletion ACE genotype also affects neurohumoral activation following MI, we studied 96 patients, 59 ± 9 years of age, with acute anterior MI, no overt heart failure, or need for ACE-inhibition. Subjects were randomized to treatment with either captopril or placebo following thrombolytic therapy. Bloodsamples for plasm norepinephrine and ACE activity were taken at baseline (before thrombolysis) and 1, 12 and 24 hours after thrombolysis. ACE genotyping (polymerase chain reaction; specific primers amplifying 190 bp and 490 bp fragments of deletion [D] and insertion [I] alleles, respectively) was carried out at the end of follow-up, without knowledge of clinical parameters. At baseline, norepinephrine levels were equal in DD, I/D and II groups. In contrast, the increase of norepinephrine levels was more pronounced in MI patients with DD (n = 34; 556 ± 189 pg/ml) as compared to ID and II genotype (n = 62; 96 ± 98 pg/ml; p < 0.01). Furthermore, baseline ACE activity was higher in the DD genotype group (29 ± 3 vs 23 ± 2 U/I; P = 0.01). This increased response in DD genotype patients was blunted by captopril. Association of the DD genotype and adverse neurohumoral activation was still evident after correction for infarct size and captopril treatment (p < 0.01). Thus, the ACE/DD genotype appears to increase the risk for neurohumoral activation after anterior MI and DD genotype patients benefit most from early ACE inhibition.