Lutai Y. Endothelium-dependent vascular reactivity in patients with acute myocardial infarction: clinical and genetic determinants, importance for risk stratification, prognosis and choice of therapy

The aim of the study was to develop new approaches to risk stratification and treatment of patients with acute myocardial infarction (AMI) based on the study of genetic and acquired features of endothelium-dependent vascular reactivity. 817 patients with AMI were examined. The study had two stages. The first evaluated the frequency of registration, pathogenetic and prognostic value of three polymorphisms of promoter T-786C (rs2070744), 7th exon G894T (rs1799983) and 4th intron 4b / 4a (rs869109213) of the endothelial NO-synthetase (eNOS) gene, on the second - assessed the role of endothelial dysfunction in the development of AMI and reperfusion complications to develop new approaches to their prevention and treatment. T-786C polymorphism of the eNOS gene promoter was more common in patients with AMI than in the control group, contributed to the development of endothelial dysfunction (according to FMD and laboratory markers) and was associated with in-hospital and out-hospital complications after AMI. Noninvasive signs of the infarct-related coronary artery reperfusion during thrombolytic therapy with streptokinase were more often observed in patients with the -786TT genotype (peak of СK-MB within 12 hours from the symptoms onset was observed in 69.8 % of patients with T/Т vs 40.7 % in patients with T/C and C/C genotypes, p <0.01). Statins’ lipid-lowering effects and their impact on endothelial function was not affected by the polymorphism of eNOS gene promoter, but their clinical efficacy (prevention of in-hospital complications) was realized only in patients with the -786TT genotype, which allowed us to hypothesize "clinical resistance" to moderate doses of statins in STEMI patients with eNOS gene polymorphism. An increase in the diameter of the brachial artery during FMD < 5 % revealed a category of patients with a predisposition to the development of no-reflow (MBG 3 after primary PTCA 66.7 % in patients with FMD < 5 % vs 83.7 % in patients with FMD ≥ 5 % p = 0.047), in-hospital complications, systolic and diastolic LV dysfunction and early post-MI LV dilatation (46.4 % vs 22.5 %, p = 0.038) after STEMI. FMD≤4.9 % was associated with the development of intramyocardial hemorrhage after revascularization for STEMI according to cardio-MRI (HR 3.5; 95 % CI 1.0–13.5). The prescription of high-intensity (atorvastatin 80 mg or a combination of atorvastatin 40 mg and ezetimibe 10 mg) lipid-lowering therapy (LLT) before the primary coronary intervention in STEMI patients had a positive effect on endothelial function (when target LDL levels were reached) and prevented the development of no-reflow after primary PTCA (MBG-3 was confirmed in 75.6 % of patients on high-intensity LLT vs 52.0 % in patients on LLT of moderate intensity, p<0.01), which was accompanied by fewer in-hospital complications. The addition of intravenous Quercetin to the recommended therapy of STEMI was accompanied by: 1. the improvement of FMD results (9.96±0.94 % on the 10th day vs 6.45±1.02 % on the 1st day, p = 0.004); 2. a significant increase in the level of vascular endothelial growth factor on the 7th day of AMI (396.0 ± 64.7 pg/ml in Quercetin group vs 196.4 ± 49.9 pg/ml in control group, p = 0.022); 3. a decrease in the mean level of myeloperoxidase in blood plasma (611.7±83.3 ng/ml on the 1st day vs 382.4±65.4 ng/ml on the 7th day, p = 0.013). According to cardio-MRI, patients with STEMI who received Quercetin therapy in addition to standard treatment were significantly less likely to develop intramyocardial hemorrhage after revascularization (HR 0.21; 95 % CI 0.03-1.10).