DD angiotensin-converting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans

A polymorphism within the angiotensin-converting enzyme (ACE) gene may incr ease the risk of myocardial infarction in individuals previously thought to be at low cardiovascular risk. The mechanism through which it exerts this effect is unknown but may be due to increased angiotensin II-induced nitric oxide (NO) breakdown and/or reduced bradykinin-mediated NO release. We inv estigated whether endothelial function was different between different ACE genotypes. We performed a cross-sectional study comparing the endothelial f unction of the 3 genotypes (II: n=25; ID: 31; DD: n=12). Mean+/-SD ages of the subjects were 24+/-4 (IT), 25+/-6 (ID), and 25+/-6 (DD) years. We asses sed the impact of the genotypes on endothelial function and found that the DD genotype was associated with a significant blunting in endothelial-depen dent vasodilatation (forearm blood flow data are presented as mean+/-SD rat io of blood flow in response to 3 incrementally increasing doses of each va soactive agent in the test arm to blood flow in the control arm; the compar ison is between DD versus ID versus II; the P value is an expression of an overall difference by ANOVA, and the 95% CIs are of a pairwise comparison b etween genotypes): acetylcholine, 2.88+/-1.45 versus 3.81+/-1.93 versus 4.2 3+/-2.37 (P=0.002; 95% CI [II versus ID], -0.19 to 0.91; 95% CI [II versus DD], 0.36 to 1.80; 95% CI [ID versus DD], 0.02 to 1.42). There was also a s ignificant difference with the endothelial-independent vasodilator sodium n itroprusside, with values of 2.11+/-1.00 versus 2.55+/-1.36 versus 2.75+/-1 .18 (P<0.05; 95% CI [II versus ID], -0.15 to 0.51; 95% CI [II versus DD], 0 .03 to 0.89; 95% CI [ID versus DD], -0.13 to 0.71), but not with verapamil. There was no effect of the ACE genotype on endothelial-dependent or -indep endent vasoconstrictors NG-monomethyl-L-arginine or norepinephrine. Investi gating the effects of cigarette smoking on each genotype demonstrated that for II and DD genotypes, acetylcholine responses were further blunted if su bjects smoked. These data demonstrate that the DD ACE genotype in a young p opulation is associated with a blunting of stimulated endothelial NO and do nated NO responses but not to non-NO vasodilators or vasoconstrictors.