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Oxidative stress and microcirculatory flow abnormalities in the ventricles during atrial fibrillation

*, , Christopher H. Lillig 3 and
1 Department of Cardiology and Intensive Care Medicine, St. Vincenz-Hospital Paderborn, Paderborn, Germany2 Working Group: Molecular Electrophysiology, University Hospital Magdeburg, Magdeburg, Germany3 Institute of Medical Biochemistry and Molecular Biology, Ernst-Moritz-Arndt University, Greifswald, Germany Patients with atrial fibrillation (AF) often present with typical angina pectoris and mildly David R. Van Wagoner, Cleveland elevated levels of cardiac troponin (non-ST-segment elevation myocardial infarction) during Clinic Lerner College of Medicine of an acute episode of AF. However, in a large proportion of these patients, significant coro- Case Western Reserve University,USA nary artery disease is excluded by coronary angiography, which suggests that AF itself influences myocardial blood flow. The present review summarizes the effect of AF on the Barbara Casadei, University of occurrence of ventricular oxidative stress, redox-sensitive signaling pathways and gene Oxford, UK expression, and microcirculatory flow abnormalities in the left ventricle.
David R. Van Wagoner, ClevelandClinic Lerner College of Medicine of Keywords: angiotensin, atrial fibrillation, microvascular flow, oxidative stress
Case Western Reserve University,USAGeorge John Rozanski, University ofNebraska Medical Center, USA *Correspondence:
Andreas Goette, Department of
Cardiology and Intensive Care
Medicine, St. Vincenz-Hospital
Paderborn, Am Busdorf 2, 33098
Paderborn, Germany.
e-mail:
VENTRICULAR OXIDATIVE STRESS AND SIGNAL
Angina pectoris is a typical symptom in patients with parox- TRANSDUCTION DURING AF
ysmal atrial fibrillation (AF). In most of these patients, angina Reactive oxygen species (ROS) are generated under physiologi- pectoris is associated with mildly elevated cardiac troponin (cTn) cal conditions in the cardiovascular system and act as second levels suggesting a non-ST-segment elevation myocardial infarc- messengers in numerous redox-sensitive signal transduction path- tion (NSTEMI). However, in a large proportion of these patients, ways However, under pathophysiological conditions, significant coronary artery disease can be excluded by coronary chronically elevated amounts of ROS may exert oxidative stress.
angiography despite clinical symptoms Historically, the term "oxidative stress" was defined as an imbal- Although the elevated ventricular rate during AF ance between the generation of ROS and the capacity of the defense may contribute to the symptoms of angina pectoris systems During the past decade, this model angina pectoris develops also in patients with a slow ven- has evolved based on some key findings: the production of dif- tricular rate and most patients tolerate fast ventricular rates in ferent oxidants affects distinct presets of target proteins through sinus rhythm without any clinical symptoms modifications that are specific both with respect to the oxidant Recent reports suggest that myocar- and the site of modification, most frequently well-defined cys- dial blood flow is reduced, whereas coronary vascular resistance teinyl side chains. The so-called antioxidant redox systems in the is elevated in patients with AF different cellular compartments, e.g., glutathione, NADPH, thiore- One potential link between AF, abnormal ventric- doxin (Trx), and peroxidases such as the peroxiredoxins (Prx), are, ular perfusion, and cardiomyocyte dysfunction is the occurrence however, not in equilibrium and independently maintained at dis- of oxidative stress and the disruption of redox signaling through tinct redox potentials. Oxidative stress may thus, more timely, be activation of the nicotinamide adenine dinucleotide phosphate defined as the chronic disturbance of redox circuits and redox- oxidase (NADPH oxidase; responsive signal transduction pathways Repetitive episodes of AF-induced ventricular ischemia may contribute to the development of a Oxidative stress has been implicated as playing a critical pathological vicious cycle combining AF and left ventricular (LV) role in the pathophysiology of heart and cardiovascular dis- eases such as heart failure, LV hypertrophy, coronary heartdisease,

Goette et al.
Ventricular oxidative stress during AF FIGURE 1 Schematic summary of different interactions between atrial fibrillation, oxidative stress, and flow abnormalities. Abbreviations should be
included here are explained in the text.
cardiac arrhythmia. It appears that the oxidative events initiate as reoxygenation-induced PV burst firing represent important the disease-dependent tissue remodeling and promote its prop- proarrhythmogenic mechanisms agation. Oxidative stress is associated with microvascular flow Coronary flow can be estimated in vivo using wire-based sys- abnormalities and occurs immediately after new-onset AF likely tems Coronary flow representing key initiator mechanisms of AF-related ventricular reserve (CFR) measurements can be measured using a pressure remodeling. This has been shown in patients with lone recur- temperature sensor-tipped guidewires, which allow the simulta- rent AF and for rapid atrial pacing models neous determination of the fractional flow reserve (FFR). CFR measurements are influenced by flow abnormalities in the epicar- ular RR intervals are considered to be responsible for compro- dial arteries and the microcirculation. In contrast, reduced FFR is mised coronary blood flow reserve, thus preventing the adequate specific to epicardial lesions. Recent studies can clearly show that attainment of the increased oxygen demand due to tachycardia acute episodes of AF induce oxidative stress in the LV myocardium In addition, increased catecholamine and compromise microvascular blood flow levels via α-adrenergic vasoconstriction may further contribute to AF-induced ischemia AF- Although it is well established that ischemia creates a sub- dependent cardiac remodeling, especially fibrosis, may well con- strate for AF maintenance tribute to long-term restriction of microcirculation the effects of AF on ventricular microcirculation and underlying Resulting imbalances of myocardial oxygen supply and pathways are less well understood. Impaired intracellular Ca2+- myocardial oxygen demand lead to the specific activation of redox- handling as described above together with elevated cardiac and sensitive signaling pathways, that are either protective or part systemic angiotensin II levels are two important factors which very of the pathophysiological process causing onset and progression likely contribute to the AF-dependent activation of redox-sensitive signaling pathways in the ventricles. These will be discussed in Ischemia facilitates the onset of AF by altering cellular ionic more detail below.
homeostasis, in particular via tachycardia-induced intracellularcalcium and sodium overload. Increased spontaneous ectopy is VASOCONSTRICTORY PEPTIDES REGULATING CORONARY FLOW
due to increased NCX currents and spontaneous Ca2+-release events In pulmonary veins (PV), hypoxia- Vasoactive peptides such as angiotensin II (AngII) and endothe- induced EAD, and delayed after-depolarizations (DAD) as well lin (ET) play important roles in the regulation of cardiovascular Goette et al.
Ventricular oxidative stress during AF function as well as in the pathogenesis of heart and cardiovascular of hypercholesterolemic animals In a recent diseases. AF has been associated with increased plasma and tissue study it was shown that application of irbesartan prevents ventric- levels of angiotensin II (AngII) ular oxidative stress and microvascular flow abnormalities during which are resulting from increased expression/activity of 7 h of AF Nevertheless, clinical trials like the ACTIVE study failed to demonstrate a measurable benefit of long- Angiotensin II mediates its major hemodynamic and patho- term ARB therapy in patients with AF physiological effects via the AT1 receptor. Six hours of rapid atrial pacing is sufficient to elevate plasma AngII levels suggesting thevery early involvement of this vasoactive molecule in the patho- genesis of AF The activation of the AT1 Endothelin-1 (ET-1) exerts its proarrhythmogenic effects by two receptor induces a cascade of phosphorylation events that even- different ways. First, due to its strong vasoconstrictory activity, tually activates MAP kinases, which stimulate the proliferation ET-1 may induce ischemia which facilitates arrhythmia. Second, of fibroblasts, cellular hypertrophy, and apoptosis. Furthermore, upon binding to endothelin receptor A (ET-A), ET-1 affects intra- activation via the AT1 receptor releases calcium from intracellu- cellular calcium handling and, in particular, provokes intracellular lar stores and activates protein kinase C (PKC). PKC regulates Ca2+-waves via IP3-dependent Ca2+-release leading to DAD the function of calcium and potassium channels, and phosphory- Furthermore, ET-1 activates PKC and MAP kinases lates p47phox regulatory subunit. The phosphorylation of p47phox Atrial stretch is a potent factor promoting the plays a pivotal role in the activation of NOX2/NOX1 by providing production and release of ET-1 ET-1 acti- physical binding domains to another regulatory subunit p67phox vates NADPH oxidase via the ET receptor-proline-rich tyrosine It is noteworthy that both the MAP kinase kinase-2 (Pyk2)-rac1 pathway as well as the calcium/PKC signaling pathways respond to ROS The GTPase, rac1, binds to p67phox and activates NADPH oxidase themselves and are regulated by redox effector molecules from the in its GTP-bound state Trx family of proteins valvular disease At the atrial level, it is well established that AngII upon bind- primary pulmonal hypertension but ing to its preferred receptor, AT1R, leads to the activation of also AF are all associated with increased plasma and cardiac tissue levels of ET-1. Atrial ET-1 levels were correlated with atrial rhythm, In blood vessels, AngII infusion resulted in increased atrial size, and hypertension and were associated with hypertro- expression and activity of NADPH oxidase, which was dependent phy, fibrosis, and atrial dilatation Changes on PKC to some extent In the murine heart, in cardiac and circulating levels of ET-1 have been described in AngII increased superoxide generation and cardiac hypertrophy experimental models of myocardial ischemia and in patients with involving NOX2 Increased NADPH oxidase acute myocardial infarction activity contributes to elevated ROS production, protein modi- Accordingly, a dual ET receptor antago- fication, and redox-related gene expression patterns observed in nist has been demonstrated to prevent coronary vasoconstriction AF Moreover, it has been identified as an during reperfusion of ischemic heart AF- independent risk factor for post-operative AF dependent negative changes in the microcirculation Pre-operative treatment with ascorbate prevented AF to a signifi- contribute to and further enhance cant extent Similarly, ascorbate reduced the increased gene expression and release of ET-1 which, in turn, recurrence of AF after cardioversion aggravates coronary vasoconstriction Less is known about the effects of AF on ventricular func- and leads to oxidative stress tion and underlying changes in redox-signaling pathway activity Although the AngII/ET-1-induced increase of ROS generation is and related gene expression. AF is associated with increased coro- mostly associated with hemodynamic response and development nary resistance, compromised vasodilation of hypertension, solid evidence shows that these vasoactive pep- reduced coronary flow or flow reserve tides via activation of NADPH oxidase mediate changes in vascular As these changes can be largely architecture and heart damage attenuated by the administration of sartans AngII seems to be a major factor linking AF with LV malperfusionand dysfunction. In support of this view, the RAP-induced Ang-II- dependent activation of NADPH oxidase and down-stream effec- It has been suggested that the NADPH oxidase is an important tors of redox-activated signaling cascades, e.g., LOX-1 expression source of ROS in the left ventricle during atrial tachyarrhyth- and F2-isoprostane formation, were all attenuated by irbesartan mia NADPH oxidase was originally discovered in neutrophils, where, during phago- At the molecular level, ANG-II-receptor blockers (ARBs) have cytosis, millimolar quantities of superoxide can be released into been shown to increase NO availability and it is possible that this the extracellular (phagosomal) compartment. In non-phagocytic effect is mediated by a stronger ANG-II-dependent activation of cells such as cardiomyocytes, fibroblasts, and endothelial cells, AT2-receptors. ARBs also attenuate aortic intimal proliferation the amounts of produced superoxide are much lower and occur and markedly decrease the enhanced LOX-1 expression in the aorta mostly intracellularly The neutrophil NADPH Goette et al.
Ventricular oxidative stress during AF oxidase is composed of membrane-associated subunits: p22phox, ROS production is shifted from NADPH oxidase to mitochon- and NOX, and four cytosolic regulatory subunits: p47phox, p67phox, drial oxidases and uncoupled eNOS in the right atrium p40phox, and the small GTPase rac1 or rac2. NOX is the key cat- This is in full accordance with the observation that alytic subunit of the NADPH oxidase and in non-phagocytic cells statins, which reduce ROS production by NADPH oxidases via possess several isoforms. Beside the phagocyte NADPH oxidase inhibition of Rac1, are effective in acute models of AF and in (NOX2; gp91phox), the expression of six homologs (NOX1, NOX3, patients with post-operative AF, but fail to reduce ROS production NOX4, NOX5, Duox1, and Duox2) has been identified in models of long-lasting AF or patients with permanent AF. Pre- While the cytosolic regulatory components translocate to operative statin-treatment was shown to reduce myocardial O − the membrane to form the active NADPH oxidase complex upon and ONOO− production by reducing NADPH oxidase activity activation in the neutrophil in the non- phagocytic cells preassembled functional enzyme complex is partlypresent intracellularly VENTRICULAR MICROCIRCULATION DURING AF
Although the non-phagocyte NADPH oxidase is consti- An induced episode of AF of up to 6 h has no effect on FFR (marker tutively active, its activity can be further up-regulated in response for epicardial flow) in pigs In contrast, to vasoactive peptides (AngII, ET-1), hormones, growth factors, CFR (index of microvascular abnormalities if FFR is normal) is cytokines, and mechanical stress substantially reduced (about 50%) after an AF episode of 6 h. Inter- estingly, application of irbesartan and dronedarone could prevent The NOX-dependent ROS signaling is an important factor microcirculatory flow abnormalities to occur whereas amiodarone responsible for development of many pathological processes in has no effect on CRF These results correspond to latest the ventricles during cardiac hypertrophy, remodeling, and heart findings that dronedarone reduces the size and volume of induced failure Recently, in an animal model of cerebral and myocardial infarcts acute AF, increased expression of NOX2, NOX1, and enhanced Patients without previously documented coro- expression of NOX4 were shown in the left ventricle after 6 h of nary artery disease sometimes develop chest discomfort with the atrial pacing The AT1 onset of AF Furthermore, patients with AF receptor antagonist, irbesartan, and the multichannel inhibitor, have ventricular-flow abnormalities and a higher incidence of car- dronedarone, efficiently prevented the up-regulation of NOX2 diac events Consistent The elevated expres- with this notion, coronary artery resistance is markedly elevated sion of NOX2 and superoxide production in the left ventricle was (by 62%), whereas myocardial blood flow is substantially reduced also observed in a rabbit model of chronic heart failure in AF patients Vasodilatation in response Several studies have shown a crucial role of NOX2 to exercise is also compromised during AF in the response to AngII-induced LV hypertrophy The Doppler-derived coronary vascular resistance index has been It was found that the regu- reported to be increased by 67% in an experimental AF model latory compound rac1 initiated hypertrophic response Induction of AF for up to 6 h has no effect on Amounts of the regulatory p47phox FFR (marker of epicardial flow) in pigs increase after myocardial by contrast, CFR (index of microvascular abnormalities if FFR infarction in the left ventricle and contribute to the NADPH oxi- is normal) is substantially reduced (about 50%) by short-term dase dependent tissue remodeling NOX2 AF. Interestingly, irbesartan and dronedarone could prevent the and NOX4 are the main isoforms expressed in the cardiac cells.
occurrence of microcirculatory flow abnormalities whereas amio- NOX4, in contrast to NOX2, does not require the presence of darone had no effect These results are in keeping with regulatory oxidase proteins p47phox or the GTPase rac. Moreover, recent findings indicating that dronedarone reduces the size and NOX4 produces mainly hydrogen peroxide and only very small volume of induced cerebral and myocardial infarcts amounts of superoxide intracellularly and was found on internal membranes, in mitochondria and also in perinuclear endoplasmic AF ALTERS VENTRICULAR EXPRESSION OF
reticulum The up-regulation in NOX4 expres- ISCHEMIA/HYPOXIA-RELATED GENE PANELS
sion was accompanied by mitochondrial dysfunction and apop- Atrial fibrillation provokes rapid and profound changes in the ven- tosis in the cardiomyocytes tricular expression of ischemia/hypoxia-related genes NOX1 is an important isoform expressed particularly in vascular These expression changes were associated with and smooth muscle cells and is responsible for extracellular superox- may result partially from microcirculatory abnormalities. Both ide production in coronary arterial myocytes. Several studies have the observed RAP-dependent limitation of flow reserve and the provided evidence that NOX1 oxidase is involved in mediating the expression changes could be prevented by dronedarone. Interest- hypertensive response to AngII in particular ingly, amiodarone does not reduce AF-induced flow abnormal- ities in the microvascular tree The positive effect of Recent data suggests, however, that induction of atrial NADPH dronedarone in brief episodes of AF is supported by the ATHENA oxidase activity or subunit expression is an early but transient trial, which found a reduced rate of acute coronary syndromes and mechanism in the natural course of AF development and pro- reduced cardiovascular mortality in patients with AF gression With increasing duration of AF,

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Ventricular oxidative stress during AF A recent study could show that acute application of were HIF-1, VEGFA, and PPARGC1α, all of them known to be dronedarone during an induced myocardial infarction reduced induced in response to hypoxia or deprivation of nutrients the infarct size substantially Nevertheless, in long- The regulation of VEGF expression in response lasting (6 month) AF, myocardial NADPH is not activated to hypoxia is mediated by HIF-1α Under and thereby, positive effects through inhibition of the same conditions, and independent of this canonical HIF- NADPH are unrealistic to exist. Thus, the antioxidant effects of pathway, increased PPARGC1α exerts its strong angiogenic activity dronedarone should not be present in permanent AF. This is sup- and induces VEGF expression by co-activating ERR-α ported by the PALLAS trial, which showed negative outcome if Thus, both HIF-1α and PPARGC1α appear to be criti- patients with permanent AF are treated with dronedarone. In PAL- cally involved in the angiogenic response to AF-dependent flow LAS, rates of stroke, myocardial infarction, and heart failure were alterations and may provide protection against ischemic damage.
almost doubled in dronedarone treated patients Rapid atrial pacing also led to an activation of the NF-κB Thus, the therapeutic effect of dronedarone depends on the pathway in the left ventricle ROS as intra- duration of AF, which is quite a unique finding.
cellular messengers and redox effector molecules such as Trx and Transcriptome analyses provided a first mechanistic insight glutaredoxin (Grx) lead to the activation and nuclear translocation into the pathophysiological processes mediating or even counter- of this redox-sensitive transcription factor acting coronary and ventricular dysfunction during AF. Among Consistent with the RAP-dependent ventricular activation the genes the expression of which was changed in response to RAP of NF-κB, the expression of a panel of established down-streamtargets of NF-κB including VEGFA Fn14, CCL2 HIF1A as well as DnaJ fam-ily members, DNAJA4 and DNAJB9, that have been describedas co-chaperones for the ATPase activity of Hsp70 and func-tion to protect stressed cells from apoptosis was up-regulated in the left ventricle Both DNAJA4 and DNAJB9, but also thioredoxin (Trx1; and peroxiredoxin I (PrxI; are antioxidant response element (AREs) regulated genes acti-vated through nuclear factor-erythroid 2-related factor 2 (Nrf2) inresponse to oxidative stress. After phosphorylation by, e.g., PKC,Nrf2 translocates to the nucleus where it binds to AREs and trans-activates target genes of, e.g., enzymes such as PrxI that regulate theintracellular amounts of ROS It seems FIGURE 2 Induction of ventricular-flow abnormalities in the ventricles
reasonable to assume that increased expression of anti-oxidative during rapid atrial pacing (RAP) in comparison to unpaced controls
response genes, e.g., peroxiredoxins and DnaJ family members, is using a porcine model. Effects of dronedarone and amiodarone
aimed at limiting stress-mediated tissue-damage. In this in vivo demonstrated. Abbreviations are explained in the text adopted from model of acute AF, dronedarone attenuated most of the ven- tricular changes in gene expression. In addition, RAP-dependent FIGURE 3 Effect of dronedarone on size of acute myocardial infarctions adopted from .
Goette et al.
Ventricular oxidative stress during AF PKC phosphorylation, NADPH isoform expression, isoprostane generally mediate the shift from aerobic metabolism and fatty acid release, and IκBα phosphorylation were decreased. This, together utilization to glucose utilization via pyruvate oxidation or even with the attenuation of negative flow alterations may indicate that to glycolytic metabolism dronedarone beneficially affects very early steps of RAP-associated HIF-1, together with c-myc, mediates the induction of HK2 ventricular pathology, very likely by preventing ischemia/hypoxia which contributes to shift glucose away from mitochondrial uti- lization and has also anti-oxidative effects PPARGC1, the multi-functional co-activator, is also involved On this background, the observed ventricular induc- in the regulation of cardiac mitochondrial functional capacity tion of glycolytic gene expression during AF completely fits to the and cellular energy metabolism. In accordance with the observed increased expression levels of HIF-1α and PPARGC1 and, most increase in PPARGC1 and HIF-1α expression, RAP provoked importantly, demonstrate that the compromised microcirculatory profound changes in the ventricular expression of important flow leads to ischemia-like conditions. The latter activate multiple metabolic genes including hexokinase 2 (HK2), glycogen syn- signaling pathways that are aimed at the improvement of oxygen thase kinase 3β (GSK-3β), muscle isoform of glycogen phospho- supply, angiogenesis, cell survival, and adaption of metabolism rylase (PYGM), and acyl-coenzyme A dehydrogenase (ACADL; Interestingly, these metabolic changes werenot affected by dronedarone, which suggests that other factors than deprivation of oxygen and nutrients contribute to the overall AT induces oxidative stress in the atrial and ventricular change of ventricular gene expression during AF.
myocardium. In the ventricles, AF causes alterations in gene It is fully established that even mild ischemia is associated expression and activation of specific signal transduction pathways.
with compromised mitochondrial function and requires meta- As a consequence, microcirculation is impaired, troponin can be bolic adaption to maintain adequate ATP generation and cardiac released, which is associated with causing clinical symptoms like output Again, the activation of redox- angina pectoris and dyspnea. It remains to be determined if these sensitive transcription factors, namely HIF-1α and PPARGC1, is alterations are also related to the increased rate of death in AF responsible for these protective changes in the metabolism that patients shown by several epidemiologic studies.
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