Evaluation of coronary microvascular function and nitric oxide synthase intron 4a/b polymorphism in patients with coronary slow flow

Abstract

Slow coronary flow (SCF) is reported to be associated with increased risk of cardiovascular disease. We have used coronary flow reserve measurement by transthoracic Doppler echocardiography to determine coronary microvascular function in patients with SCF and to determine whether the intron 4a/b polymorphism of the eNOS gene influences coronary endothelial function. Overall, 96 patients with SCF and 79 controls were enrolled in the study. Coronary flow was quantified according to the thrombolysis in myocardial infarction (TIMI) frame count (TFC) on angiogram. Coronary diastolic peak flow velocities (DPFV) were measured with color Doppler flow mapping at baseline and after dipyridamole infusion. Coronary flow reserve was calculated as the ratio of hyperemic to baseline DPFV. The eNOS 4a/b polymorphism was detected by PCR. Patients with diabetes were excluded from the study. The SCF group was comparable to the control group in terms of demographic and clinical characteristics, except for hemoglobin and HDL-cholesterol levels, TFC of the left anterior descending artery, the circumflex artery, and the right coronary artery; the mean TFC was higher in the SCF group. Hyperemic DPFV and the hyperemic/baseline DPFV ratio were significantly lower in the SCF group when compared with the control group. However, baseline DPFV were similar in both groups. The number of patients with eNOS4 a/a and eNOS4 a/b phenotypes was statistically higher in SCF groups. The frequency of allele 'a' of the eNOS4 gene was also statistically higher in the SCF group. When patients were grouped according to the presence or absence of allele 'a' of the eNOS4 gene, statistically significant differences were found in the TFC of the left anterior descending artery, the circumflex artery; mean TFC; baseline DPFV; and hyperemic/baseline DPFV. Univariate analysis in which eNOS4 b/b was used as the referent group showed that the presence of allele 'a' of the eNOS4 gene significantly predicted SCF (odds ratio: 2.79, 95% confidence interval: 1.32-5.89; P=0.007). In multivariate analysis using a model adjusted for variables with a P value lower than 0.10 in univariate analyses, the presence of allele 'a' of the eNOS4 gene was found to be an independent predictor of SCF (odds ratio: 3.22, 95% confidence interval: 1.28-8.82; P=0.013). The presence of allele 'a' may be a risk factor for microvascular endothelial dysfunction and higher TFCs in SCF patients.