European Heart Journal Advance Access published online on March 5, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp046
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Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor-mediated oxidative stress and microvascular flow abnormalities in the ventricles
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1 Division of Cardiology, University Hospital Magdeburg, Otto-von-Guericke University, Leipzigerstr. 44, 39120 Magdeburg, Germany
2 Institute of Medical Biochemistry and Molecular Biology, Ernst-Moritz-Arndt University, Greifswald, Germany
3 Institute of Clinical Chemistry, Department of Pathobiochemistry, Otto-von-Guericke University, Magdeburg, Germany
4 Institute of Biometrics, Otto-von-Guericke University, Magdeburg, Germany
5 Department of Vascular Endothelium and Microcirculation, Dresden University of Technology, Germany
6 Department of Clinical Chemistry and Laboratory Medicine, Dresden University of Technology, Germany
7 Department of Pharmacology and Toxicology, Dresden University of Technology, Germany
Received 27 April 2008; revised 13 December 2008; accepted 16 January 2009 * Corresponding author. Tel: +49 391 6713225, Fax: +49 391 6713202, Email: andreas.goette{at}med.ovgu.de
Aims: Patients with paroxysmal atrial fibrillation (AF) often present with typical angina pectoris and mildly elevated levels of cardiac troponin (non ST-segment elevation myocardial infarction) during an arrhythmic event. However, in a large proportion of these patients, significant coronary artery disease is excluded by coronary angiography. Here we explored the potential underlying mechanism of these events.
Methods and results: A total of 14 pigs were studied using a closed chest, rapid atrial pacing (RAP) model. In five pigs RAP was performed for 7 h (600 b.p.m.; n = 5), in five animals RAP was performed in the presence of angiotensin-II type-1-receptor (AT1-receptor) inhibitor irbesartan (RAP+Irb), and four pigs were instrumented without intervention (Sham). One-factor analysis of variance was performed to assess differences between and within the three groups. Simultaneous measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) before, during, and after RAP demonstrated unchanged FFR (P = 0.327), but decreased CFR during RAP (RAP: 67.7 ± 7.2%, sham: 97.2 ± 2.8%, RAP+Irb: 93.2 ± 3.3; P = 0.0013) indicating abnormal left ventricular (LV) microcirculation. Alterations in microcirculatory blood flow were accompanied by elevated ventricular expression of NADPH oxidase subunit Nox2 (P = 0.039), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1, P = 0.004), and F2-isoprostane levels (P = 0.008) suggesting RAP-related oxidative stress. Plasma concentrations of cardiac troponin-I (cTn-I) increased in RAP (RAP: 613.3 ± 125.8 pmol/L vs. sham: 82.5 ± 12.5 pmol/L; P = 0.013), whereas protein levels of eNOS and LV function remained unchanged. RAP+Irb prevented the increase of Nox2, LOX-1, and F2-isoprostanes, and abolished the impairment of microvascular blood flow.
Conclusion: Rapid atrial pacing induces AT1-receptor-mediated oxidative stress in LV myocardium that is accompanied by impaired microvascular blood flow and cTn-I release. These findings provide a plausible mechanism for the frequently observed cTn-I elevation accompanied with typical angina pectoris symptoms in patients with paroxysmal AF and normal (non-stenotic) coronary arteries.
Key Words: Angina pectoris • Angiotensin • Atrial fibrillation • Microvascular flow • Oxidative stress
These authors contributed equally to this study.
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