Abstract
BackgroundEndothelial dysfunction plays a central role in atherosclerotic progression and cardiovascular complications of type 2 diabetes mellitus (T2DM). Given the role of nitric oxide in the vascular system, we aimed to test hypotheses of synergy between the common endothelial nitric oxide synthase (eNOS) Asp298 allele and T2DM in predisposing to acute myocardial infarction (AMI).MethodsIn a population-based patient survey with 403 persons with T2DM and 799 healthy subjects from the population without diabetes or hypertension, we analysed the relation between T2DM, sex and the eNOS Asp298 allele versus the risk for AMI.ResultsIn an overall analysis, T2DM was a significant independent risk factor for AMI. In patients with T2DM, homozygosity for the eNOS Asp298 allele was a significant risk factor (HR 3.12 [1.49–6.56], p = 0.003), but not in subjects without diabetes or hypertension.Compared to wild-type non-diabetic subjects, all patients with T2DM had a significantly increased risk of AMI regardless of genotype. This risk was however markedly higher in patients with T2DM homozygous for the Asp298 allele (HR 7.20 [3.01–17.20], p < 0.001), independent of sex, BMI, systolic blood pressure, serum triglycerides, HDL -cholesterol, current smoking, and leisure time physical activity. The pattern seemed stronger in women than in men.ConclusionWe show here a strong independent association between eNOS genotype and AMI in patients with T2DM. This suggests a synergistic effect of the eNOS Asp298 allele and diabetes, and confirms the role of eNOS as an important pathological bottleneck for cardiovascular disease in patients with T2DM.
Highlights
Endothelial dysfunction plays a central role in atherosclerotic progression and cardiovascular complications of type 2 diabetes mellitus (T2DM)
This suggests a synergistic effect of the endothelial nitric oxide synthase (eNOS) Aspartate at position 298 (Asp298) allele and diabetes, and confirms the role of eNOS as an important pathological bottleneck for cardiovascular disease in patients with T2DM
In order to test the hypothesis that the genotype effect is manifested in the subgroup of patients with T2DM, we analysed the effect of the eNOS Asp298 allele using the subjects with Glutamate at position 298 (Glu298)/Glu298 as reference group, stratifying for diabetes, and adjusting for age, Body Mass Index (BMI), systolic blood pressure, serum triglycerides, high density lipoprotein (HDL) -cholesterol, current smoking, and leisure time physical activity
Summary
Endothelial dysfunction plays a central role in atherosclerotic progression and cardiovascular complications of type 2 diabetes mellitus (T2DM). Endothelial Nitric Oxide (NO) is a critical actor in the pathophysiology of the vascular system [1,2,3] and is involved in preventing the oxidation of lipoproteins, in down-regulating inflammatory mediators, preventing the adhesion of monocytes to the endothelium, controlling the expression of proteins involved in atherogenesis, and in inhibiting the proliferation of vascular smooth muscle cells [1,2] It has a protective effect in angina and the acute coronary syndrome by promoting vessel vasodilation and by inhibiting platelet adhesion and aggregation [1,2,4]. Several risk factors for coronary artery disesase (CAD) such as smoking, elevated homocysteine, free fatty acids, hypertension, insulin resistance, and diabetes depress eNOS [2,6,8]
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