The paradoxical association of common polymorphisms of the renin-angiotensin system genes with risk of myocardial infarction.

BACKGROUND: The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) and the A1166C polymorphism of the angiotensin-II AT1 receptor (AT1R) have been extensively investigated as possible risk factors for myocardial infarction (MI). DESIGN AND METHODS: Genetic association, case-control study, specifically designed to investigate the association of the above-mentioned polymorphisms with risk of MI in a homogeneous, low coronary risk, Caucasian population. The study population consisted of 1603 consecutive patients with acute MI who were recruited from nine clinics, located in three cities, and 699 unrelated adults who were randomly selected from the city catalogues. RESULTS: In univariate analysis, the DD genotype was found to be more prevalent among controls (40.8 vs. 35.2%, P=0.011). In multivariate analysis adjusted for age, gender, smoking status, diabetes mellitus, hypercholesterolaemia, hypertension and family history of coronary artery disease, the presence of the DD genotype was independently and negatively associated with risk of AMI (RR=0.743, 95% CI=0.595-0.927, P=0.008). The CC genotype was not found to be significantly associated with risk of MI, either in univariate (6.2 vs. 6.4%, P=0.856), or in multivariate analysis adjusted for the same confounders (RR=0.743, 95% CI=0.473-1.167, P=0.197). CONCLUSIONS: Contrary to previous reports, in this study the DD genotype of the ACE gene, but not the CC genotype of the AT1R gene, was associated with a lower risk of MI. Our results emphasize the complexity of genotype-phenotype interactions in the pathogenesis of ischaemic heart disease and question the previously hypothesized role of the DD genotype on risk of acute myocardial infarction.

Effect of enalapril and losartan on cytokines in patients with stable angina pectoris awaiting coronary artery bypass grafting and their interaction with polymorphisms in the interleukin-6 gene.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may have anti-inflammatory actions, an effect that could explain some of their beneficial effects on cardiovascular events in clinical trials. Coronary artery bypass grafting (CABG) is associated with a systemic inflammatory response and provides a convenient model to examine the effects of such agents. Genetic polymorphisms may be important in influencing the expression of cytokines, such as interleukin-6 (IL-6). We randomized men awaiting CABG to treatment with enalapril, losartan, or control for 2 months before surgery. Systemic IL-6, IL-8, IL-10, and IL-1 receptor agonists were measured before and after surgery, and genotypes for the -174 G/C and -572 G/C IL-6 gene polymorphisms were determined. Total release of the IL-1 receptor agonist was decreased 29% by enalapril and 31% by losartan (adjusted p = 0.041). IL-6 was decreased 17% by enalapril and 20% by losartan. Subjects possessing the -174 GG genotype produced 20% more IL-6 (adjusted p = 0.029). In these high producers of IL-6, release of IL-6 was decreased 51% by enalapril (adjusted p = 0.001) and 32% by losartan (adjusted p = 0.068). Release of IL-10 was nonsignificantly decreased 26% by enalapril and 21% by losartan, whereas IL-8 was not detected. In conclusion, enalapril and losartan significantly decreased release of the IL-1 receptor agonist after CABG. Enalapril produced a highly significant decrease of 51% in the release of IL-6 in patients identified as high producers of IL-6 by the -174 G/C polymorphism, whereas losartan has a similar but less marked effect. The production of IL-6 in this setting is influenced by the -174 G/C polymorphism.

Impact of the recommendations for the redefinition of myocardial infarction on diagnosis and prognosis in an unselected United Kingdom cohort with suspected cardiac chest pain.

We prospectively and blindly assessed the diagnostic and prognostic impact of implementation of the European Society of Cardiology/American College of Cardiology recommendations for redefinition of myocardial infarction (MI) in an unselected cohort of patients with suspected cardiac chest pain, with particular attention to prespecified clinical groups. All patients admitted to our institute with suspected cardiac chest pain were enrolled. Physicians provided usual care using serial electrocardiograms/creatine kinase (CK)/aspartate transaminase according to World Health Organization (WHO) criteria for MI, while blinded to additional measurements of cardiac troponin T (cTnT) and CK-MB mass. After discharge, diagnoses based on WHO and new criteria were compared, and major adverse cardiac events monitored for 6 months. Implementation of the new recommendations classified an additional 26.1% of patients as having MI compared with WHO criteria, and produced an overall diagnostic alteration in 11.5%. Two thirds of the additional patients with MI were previously diagnosed with unstable angina, whereas one third had "other cardiac" or "noncardiac" diagnoses. A similar MI cohort to the cTnT diagnosis was identified using a CK-MB mass discriminator value of 5 microg/L, but not 10 microg/L. The 6-month prognosis was similar in patients diagnosed with MI by new (cTnT) and WHO criteria, with the new criteria thus identifying a further high-risk cohort in the WHO negative group. In our cohort, the new Joint European Society of Cardiology/American College of Cardiology recommendations identify one fourth more patients as having MI. The 6-month prognosis of those patients reclassified as having MI was similar to those diagnosed with MI by both criteria.