Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits

Laszlo, Roman; Menzel, K; Bentz, Kerstin; Schreiner, B; Kettering, Klaus; Eick, Christian; Schreieck, Jüergen

doi:10.1016/j.lfs.2010.09.010

Cited by 14 publications

(12 citation statements)

References 54 publications

(63 reference statements)

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“…Recent studies demonstrate statin therapy can attenuate nerve sprouting and sympathetic hyperinnervation in a rapid pacinginduced AF animal model (25,27), which eventually improves ion-channel expression (15). In the present study, the increased Pmax and Pd, as well as shortened AERP, especially impaired rate adaptation of AERP, occurred in the MI group, all of which are considered to result from the electrical remodeling process after MI.…”

Section: Discussionsupporting

confidence: 54%

“…In addition, it has been shown that statins can modulate atrial ion currents of both L-type calcium current and transient outward potassium (K ϩ ) current (I to ), which are altered by rapid atrial pacing (15) and could account for their prevention of AF. The effects of simvastatin on prevention of AF have also been shown in a rapid pacing animal model, possibly through inhibiting fibroblast proliferation, and this effect is not shared by activation of peroxisome proliferator-activated receptor-␣ using fenofibrate (24).…”

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confidence: 99%

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Simvastatin attenuates sympathetic hyperinnervation to prevent atrial fibrillation during the postmyocardial infarction remodeling process

Zhu

et al. 2012

Journal of Applied Physiology

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Simvastatin attenuates sympathetic hyperinnervation to prevent atrial fibrillation during the postmyocardial infarction remodeling process. J Appl Physiol 113: 1937-1944, 2012. First published September 13, 2012 doi:10.1152/japplphysiol.00451.2012.-Statin, as a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor, has been shown to prevent atrial fibrillation (AF) due to its anti-inflammatory and antioxidant effects. However, it is still not known whether statin can improve autonomic remodeling to prevent AF. In the present study, using an in vivo rat myocardial infarction (MI) model, we aimed to test whether simvastatin can attenuate nerve sprouting and sympathetic hyperinnervation to prevent AF during the post-MI remodeling process. Our data demonstrate that simvastatin, delivered 3 days after MI for 4 wk, can result in significant decreases in plasma levels of both TNF-␣ (239 Ϯ 23 pg/ml) and IL-1␤ (123 Ϯ 11 pg/ml) compared with MI rats without therapy (TNF-␣, 728 Ϯ 57 pg/ml; IL-1␤, 213 Ϯ 21 pg/ml; P Ͻ 0.05), which, however, were still higher than sham-operated rats (TNF-␣, 194 Ϯ 20 pg/ml; IL-1␤, 75 Ϯ 8 pg/ml; P Ͻ 0.05). The similar pattern of changes in inflammation responses was also observed in TNF-␣ and IL-1␤ protein expression in the left atrium free wall. The suppressed inflammation responses were associated with reduced superoxide and malondialdehyde generation in the atrium. These changes account for decreases in neural growth factor expression at levels of both mRNA (1.2 Ϯ 0.09 AU vs. MI group, 1.78 Ϯ 0.16 AU) and protein (1.57 Ϯ 0.17 AU vs. MI group, 2.24 Ϯ 0.19 AU; P Ͻ 0.05), thus resulting in reduced nerve sprouting and sympathetic hyperinnervation. Accordingly, the rate adaptation of the atrial effective refractory period also recovered, leading to the decreased inducibility of AF. These data suggest that simvastatin administration after MI can prevent AF through reduced sympathetic hyperinnervation. atrial fibrillation; autonomic remodeling; inflammation; statin ATRIAL FIBRILLATION (AF) IS a common cardiac arrhythmia in clinical practice, which is associated with a higher mortality as well as an increased morbidity due to a significantly higher incidence of stroke, congestive heart failure, and tachycardiainduced cardiomyopathy, leading to an impaired quality of life (4). In the patients with myocardial infarction (MI), a cardiacremodeling process often results in a high incidence of AF (3).A growing body of evidence shows that inflammation and/or oxidative stress play an important role in the pathological process of AF (20); however, the underlying mechanism via which inflammation causes AF is still not well known. Interestingly, in a tachycardiac pacing-induced AF animal model, there shows a significant increase in nerve sprouting and sympathetic hyperinnervation, characterized by a higher density of GAP-43-and tyrosine hydroxylase (TH)-positive staining nerves in the atrium (6, 27). Furthermore, nerve sprouting and sympathetic hyperinnervation are also observed in MI animal models where GAP-43...

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Section: Discussionsupporting

confidence: 54%

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confidence: 99%

Simvastatin attenuates sympathetic hyperinnervation to prevent atrial fibrillation during the postmyocardial infarction remodeling process

Zhu

et al. 2012

Journal of Applied Physiology

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“…Different regional heterogeneity of ionic currents and gap junctions in the AV node explain the electrophysiological heterogeneity of the AV node (Efimov et al 2004) and provide a molecular basis to reveal the mechanism through which SV affects the AV node. Several previous studies have demonstrated widespread patterns of modulation of various ion channels by statins Laszlo et al 2010). SV directly inhibits I CaL, I Na + , and I to in ventricular tissue during an acute ischemia-reperfusion model Ding et al 2008).…”

Section: Sv Effects On Basic Av Nodal Propertiesmentioning

confidence: 96%

Protective role of simvastatin on isolated rabbit atrioventricular node during experimental atrial fibrillation model: role in rate control of ventricular beats

Khori

Najafi

Alizadeh

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

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The purpose of the present study was to determine (1) whether simvastatin (SV) modifies the rate-dependent conduction time and refractoriness of the atrioventricular (AV) node and (2) how it can change the protective mechanism of the AV node during atrial fibrillation (AF). Predefined stimulation protocols were applied to detect the electrophysiological parameters of the AV node, including atrial-His conduction time, effective refractory period (ERP), functional refractory period (FRP), concealed conduction, excitable index, and fatigue in two groups of isolated, perfused rabbit AV nodal preparations (N=16). The stimulation protocols (fatigue, recovery) were carried out during control and in the presence of SV (0.5, 0.8, 3, and 10 μM). Simulated AF was executed in a separate group (N=8), and specific indexes, including H-H mean, zone of concealment (ZOC), and concealed beats were recorded. SV, in a concentration-dependent manner, prolonged ERP, FRP, and Wenckebach cycle lengths. It (10 μM) significantly increased fatigue and the excitable index. In addition, SV elicited prolongation of ZOC and H-H mean at 3 and 10 μM. SV-evoked prolongation of nodal refractoriness and concealed conduction caused rate-dependent ventricular slowing effects during AF. The ability of simvastatin to decrease the excitable gap by its heterogeneous effects on nodal dual pathways proposes its protective role in AF.

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“…Ischemia-reperfusion had been shown to induce significant upregulation of the L-type calcium current (I Ca,L ), and simvastatin pretreatment could attenuate I Ca,L without lowering the serum cholesterol level [7]. Laszlo et al [8] found that atorvastatin treatment decreased I Ca,L , similar to rapid atrial pacing in atrial myocytes. These studies indicated that the effect of statin treatment on arrhythmia is mediated through different ion channels independent of a decrease in cholesterol [9].…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin blocks increased l-type Ca<sup>2+</sup> current and cell injury elicited by angiotensin II via inhibiting oxide stress

Kong

et al. 2016

ABBS

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The L-type Ca 2+ current (I Ca,L ) plays a crucial role in shaping action potential and is involved in cardiac arrhythmia. Statins have been demonstrated to contribute to anti-apoptotic and anti-arrhythmic effects in the heart. Here, we examined whether atorvastatin regulates the I Ca,L and cell injury induced by angiotensin II (AngII) as well as the putative intracellular cascade responsible for the effects. Cultured neonatal rat ventricular myocytes were incubated with AngII for 24 h, and then cell injury and expression levels of Nox2/gp91 phox , p47 phox , and Cav1.2 were analyzed. In addition, I Ca,L was recorded using the whole-cell patch-clamp technique, and mechanisms of atorvastatin actions were also investigated. It was found that the number of apoptotic cardiomyocytes was increased and cell viability was significantly decreased after AngII administration. AngII also augmented the expressions of Nox2/gp91 phox and p47 phox compared with control cardiomyocytes. Exposure to AngII evoked I Ca,L in a voltage-dependent manner without affecting the I-V relationship. In addition, AngII enhanced membrane Cav1.2 expression. These effects were abolished in the presence of the reactive oxygen species (ROS) scavenger, manganese (III)-tetrakis 4-benzoic acid porphyrin [Mn(III) TBAP], or the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, atorvastatin. These results suggested that atorvastatin mediates cardioprotection against arrhythmias and cell injury by controlling the AngII-ROS cascade.

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Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits

Cited by 14 publications

References 54 publications

Simvastatin attenuates sympathetic hyperinnervation to prevent atrial fibrillation during the postmyocardial infarction remodeling process

Simvastatin attenuates sympathetic hyperinnervation to prevent atrial fibrillation during the postmyocardial infarction remodeling process

Protective role of simvastatin on isolated rabbit atrioventricular node during experimental atrial fibrillation model: role in rate control of ventricular beats

Atorvastatin blocks increased l-type Ca<sup>2+</sup> current and cell injury elicited by angiotensin II via inhibiting oxide stress

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Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits

Cited by 14 publications

References 54 publications

Simvastatin attenuates sympathetic hyperinnervation to prevent atrial fibrillation during the postmyocardial infarction remodeling process

Simvastatin attenuates sympathetic hyperinnervation to prevent atrial fibrillation during the postmyocardial infarction remodeling process

Protective role of simvastatin on isolated rabbit atrioventricular node during experimental atrial fibrillation model: role in rate control of ventricular beats

Atorvastatin blocks increased l-type Ca&lt;sup&gt;2+&lt;/sup&gt; current and cell injury elicited by angiotensin II via inhibiting oxide stress

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Atorvastatin blocks increased l-type Ca<sup>2+</sup> current and cell injury elicited by angiotensin II via inhibiting oxide stress