P4626Neuronal nitric oxide sintetase polymorphism increases sympathetic activity and recurrent cardiovascular events after myocardial infarction

Abstract

Abstract Background The expression and activity of neuronal nitric oxide sintetase (nNOS) in central and peripheral nervous system attenuate the sympathetic response and promote other cardioprotective effects in animal models. However, in humans those effects are uncertain. Recently, a polymorphism at the sequence rs41279104 G/T has been associated with a reduced expression of nNOS, but its clinical impact has never been studied in the context of ST elevation myocardial infarction (STEMI) in humans. Purpose We investigated the impact of the T allele at rs41279104 in sympathetic activation after STEMI and its influence in the incidence of recurrent major cardiovascular events (MACE). We sought to determine a pathway to autonomic nervous system modulation during STEMI and its possible clinical impact. Methods 297 patients were admitted in the first 24h (D1) after STEMI and followed prospectively. Blood samples and an electrocardiogram were obtained upon D1 and fifth day (D5). We assessed glycosylated hemoglobin, glucose, insulin, C-peptide, lipid profile and nitric oxide (NOx) plasma levels. We genotyped rs41279104 and grouped patients according to carrier status (GT+TT vs. GG). The heart rate variability was obtained with a 15min electrocardiogram recording and processed into spectral analysis variables including low (LF) and high frequencies (HF) and LF/HF ratio. Flow-mediated dilation (FMD) was performed after 30 days. Clinical follow–up was carried over until two years after MI and the endpoint was a composite of major cardiovascular events (MACE) consisting of fatal MI, non-fatal MI, unstable angina with hospitalization and cardiac sudden death. Results T-allele carriers showed a decreased parasympathetic activity and an increased sympathetic activity between D1 and D5 (ΔLF −68.43 (median) [IQR −324.76 to −6.29] vs −4.49 [−190.29 to 72.03], p<0.001; ΔHF −19.40 [−185.55 to 6.21] vs −10.73 [−79.53 to 137.53], p=0.004; ΔLF/HF 0.07 [−2.32 to 1.44] vs −0.11 [−1.14 to 0.96], p<0.001). Decreased FMD (6.9±4.7 vs 7.5±4.9, p=0.046) was also detected among T-allele carriers. In the Cox -regression analysis adjusted by sex, age, betablocker use and mean simvastatin dose, T-allele carriers had a relative risk for MACE of 2.112 (95% CI: 1.133–3.938; p=0.019). Conclusions The presence of the T allele at nNOS gene rs41279104 sequence is associated with increased sympathetic tone at acute phase of STEMI and a higher incidence of recurrent MACE.