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

Abstract

AimsPatients 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 resultsA 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.ConclusionRapid 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.

Long-Term Mortality of Nonvalvular Atrial Fibrillation

“…It has yet to be established whether uncomplicated coronary artery disease alone (atrial ischaemia) predisposes to AF and how AF affects coronary perfusion (14) . Coronary heart disease was seen in 29.9% of our study group.…”

Atrial fibrillation in outpatients with stable coronary artery disease : results from the multicenter RECENT study

“…28 We also demonstrated that the longer history of CAD, independently of the presence of overt HF, is associated with the higher prevalence of AF. Of note, the hypothesis that uncomplicated CAD favors the occurrence of AF, eg, by triggering atrial ischemia, has not been verified yet, 29 and further research is needed to confirm this.…”

Erectile dysfunction in atrial fibrillation: A risk factor for stroke or a reflection of stroke risk factors?

“…For example, permanent AF has been shown to be an independent predictor of impaired brachial artery flow mediated dilatation [11] whilst plasma levels of soluble E-selectin and vWF are raised in all forms of AF [12]. Furthermore, in porcine models, rapid atrial tachycardia (simulated by pacing) has been shown to enhance the local release of vasoactive substances such as angiotensin II [13], whilst also down-regulating the expression of nitric oxide synthase (NOS) expression and subsequent nitric oxide production [14]. This not only creates oxidative stress leading to subsequent left ventricular microvascular flow abnormalities but also leads to loss of the antithrombotic properties of NOS, thus contributing to hypercoagulability.…”