Einfluss des eNOS-G-894-T-Polymorphismus auf die 5-Jahres-Mortalität und-Morbidität kardiochirurgischer Patienten
The eNOS 894 G/T gene polymorphism and its role on 5-year-mortality and- morbidity after on-pump cardiac surgery.
by Christina Lipke
Date of Examination:2015-04-14
Date of issue:2015-03-25
Advisor:Dr. PD Aron F. Popov
Referee:Prof. José Dr. Hinz
Referee:Prof. Dr. Heike Bickeböller
Referee:Prof. Dr. Jürgen Brockmöller
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EnglishNitric oxide (NO), an endothelium-derived relaxing factor (EDRF), plays a crucial role in regulating the mammalian cardiovascular system. The endothelial NO Synthase (eNOS) is a key enzyme that synthesizes NO from L-Arginin. Apart from influencing the relaxation of vascular smooth muscle cells, NO inhibits platelet adhesion to the vascular endothelium and regulates the microcirculation in several organs. Interestingly, changes in NO bioavailability have been associated with vascular diseases, such as coronary artery disease and hypertension, or with metabolic diseases such as diabetes mellitus. Several genetic polymorphism of the eNOS gene can influence the functional activity of the enzyme and accordingly the NO-bioavailability. The eNOS 894 G/T polymorphism is associated with a decreased eNOS activity, thus with a reduced constitutive NO production. Its role in influencing intraoperative hemodynamics during cardiopulmonary bypass (CPB) surgery has been investigated, however with debating results. In the current study we have analyzed the impact of eNOS 894 G/T polymorphism on long term mortality and morbidity in a CBP patient cohort. The study was based on a 500 patient cohort following cardiac surgery with CPB (approval by local ethics committee 30/7/05). Preoperative EDTA blood samples were used for genomic DNA extraction and eNOS G/T 894 polymorphism genotyping by real time PCR. The patients were divided in three genotype subgroups: GG, GT and TT. The 5-year-mortality and- morbidity was ascertained by a designed questionnaire addressed to the corresponding general practitioner. In case of non-response we try to establish a direct patient contact or get in touch with the local registration office. The long-mortality was reported in all investigated cases (100%) within a follow-up time of approximately 5 years. We observed an overall mortality of 25% (n=125) without statistically significant difference across genotypes (p=0,88). We conclude that homozygous TT-carriers are not predisposed to a significantly higher postoperative mortality after CPB surgery. Protocol dropouts did not allow for a safe 5-year-morbiditiy statement. Therefore this study cannot identify the eNOS 894 G/T polymorphism as a relevant high-risk biomarker for cardiac surgery. Nevertheless, the socioeconomic challenge to investigate the complex pathogenesis of cardiovascular diseases and the necessity to cross-over between genetic and surgical achievements motivate towards a further engagement in the field of combined studies, aiming to define high risk groups between CPB-candidates.
Keywords: polymorphism; cadiac surgery; enos 894G/T polymorphism; long-term mortality; nitric oxide; NO Synthase (NOS); eNOS
Schlagwörter: Stickstoffmonoxid (NO); Polymorphismus; eNOS 894 G/T Polymorphismus; Herzchirurgie; Langzeitmortalität; Langzeitmorbidität; eNOS