Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor-mediated oxidative stress and microvascular flow abnormalities in the ventricles.
OBJECTIVE
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.


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 (AT(1)-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 F(2)-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 F(2)-isoprostanes, and abolished the impairment of microvascular blood flow.


CONCLUSIONS
Rapid atrial pacing induces AT(1)-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.
Goette
Andreas
A
Division of Cardiology, University Hospital Magdeburg, Otto-von-Guericke University, Leipzigerstr. 44, 39120 Magdeburg, Germany. andreas.goette@med.ovgu.de
Bukowska
Alicja
A
Dobrev
Dobromir
D
Pfeiffenberger
Jan
J
Morawietz
Henning
H
Strugala
Denis
D
Wiswedel
Ingrid
I
Röhl
Friedrich-Wilhelm
FW
Wolke
Carmen
C
Bergmann
Sybille
S
Bramlage
Peter
P
Ravens
Ursula
U
Lendeckel
Uwe
U
D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D003326:Coronary Circulation / Q000502:physiology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008833:Microcirculation / Q000502:physiology; D009249:NADP / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013552:Swine; D013610:Tachycardia / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D009249:NADP