CaMKII-Dependent Diastolic SR Ca
            <sup>2+</sup>
            Leak and Elevated Diastolic Ca
            <sup>2+</sup>
            Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation

Neef, Stefan; Dybkova, Nataliya; Sossalla, Samuel; Ort, Katharina; Fluschnik, Nina; Neumann, K.; Seipelt, Ralf; Schöndube, Friedrich A.; Hasenfuß, Gerd; Maier, Lars S.

doi:10.1161/circresaha.109.203836

Cited by 351 publications

(392 citation statements)

References 54 publications

(59 reference statements)

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“…We next compared the role of CaMKII on basal I Ca,L and the activation of I Ca,L by NE in myocytes from patients with SR and patients with AF. As reported previously (13,19), the CaMKII inhibitor KN-93, but not its inactive analog KN-92, reduced basal I Ca,L in myocytes from patients with SR but not in those from patients with AF. In addition, KN-93 reduced the NE-evoked I Ca,L responses in myocytes from patients with SR but not in those from patients with AF, consistent with a loss in AF of the NE-facilitated phosphorylation of the L-type Ca 2+ channel by CaMKII (Fig.…”

Section: Kn-93 Reduces Ne-evoked Increases Of I Cal In Patients Withsupporting

confidence: 79%

“…Spontaneous impulse generation could be related to increased activity of PKA and/or CaMKII, with subsequent uncoordinated release of Ca 2+ from the sarcoplasmic reticulum. Such a concept is attractive, because Ca 2+ released from the "leaky" sarcoplasmic reticulum would activate the Na + -Ca 2+ exchanger to extrude Ca 2+ and to produce a arrhythmogenic depolarizing current, thereby explaining both the contractile dysfunction and the high recurrence rate (11)(12)(13).…”

Section: Fig 1 Bone Cells Express Avprs Immunofluorescence Microgrmentioning

confidence: 99%

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Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation

Christ

Rozmaritsa²,

Engel³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Fig. 1. Bone cells express Avprs. Immunofluorescence micrographs (A) and Western immunoblotting (B)show the expression of Avpr1α in osteoblasts and osteoclasts, and as a function of osteoblast (mineralization) and osteoclast (with Rankl) differentiation. The expression of Avp (ligand) and Avpr1α (receptor) in osteoblasts is regulated by 17β-estradiol, as determined by quantitative PCR (C) and Western immunoblotting (D). (Magnification: A, 63×.) Because Avp is a small peptide, its precursor neurophysin II is measured. Statistics: Student t test, P values shown compared with 0 h. Stimulation of Erk phosphorylation (p-Erk) as a function of total Erk (t-Erk) by Avp (10 −8 M) in osteoclast precursors (preosteoclasts), osteoclasts (OC), and osteoblasts establishes functionality of the Avpr1α in the presence or absence of the receptor inhibitor SR49059 (10 −8 M) (E). Western immunoblotting showing the expression of Avpr2 in preosteoclasts, OCs (F), and osteoblasts (G) isolated from Avpr1α −/− mice, as well as in MC3T3.E1 osteoblast precursors (G). Functionality of Avpr2 was confirmed by the demonstration that cells from Avpr1α −/− mice remained responsive to AVP in reducing the expression of osteoblast differentiation genes, namely Runx2, Osx, Bsp, Atf4, Opn, and Osteocalcin (quantitative PCR, P values shown) (H). Only relevant bands from Western blots are shown, with gaps introduced where empty lanes are excised to conserve space.

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Section: Kn-93 Reduces Ne-evoked Increases Of I Cal In Patients Withsupporting

confidence: 79%

Section: Fig 1 Bone Cells Express Avprs Immunofluorescence Microgrmentioning

confidence: 99%

Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation

Christ

Rozmaritsa²,

Engel³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Gergs et al (2010) thought that this evidence indicated that the spontaneous arrhythmias may be due to activation of CaMKII in the hearts of TG mice. This interesting suggestion is in line with a report by Neef et al (2010) of increased CaMKII expression and CaMKII-dependent phophorylation of ryanodine (RyR2) channels at Ser2814 in chronic atrial fibrillation (AF). The phosphorylation of RyR2 increased cytosolic Ca 2+ levels, attributed to an increased Ca 2+ leak from the sarcoplasmic reticulum, thereby facilitating arrhythmias that could trigger or maintain AF (Neef et al 2010).…”

supporting

confidence: 90%

Surprises from a cardiac 5-HT4 TG mouse: spontaneous atrial arrhythmias by endogenous 5-HT of atrial origin? Different mechanism of arrhythmias through 5-HT4 receptors and β-adrenoceptors?

Kaumann

2013

Naunyn-Schmiedeberg's Arch Pharmacol

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5-HT 4 receptors of human myocardium mediate cardiostimulant effects of 5-hydroxytryptamine (5-HT, serotonin) mainly through the G s protein→cAMP→PKA pathway. Several 5-HT 4 receptor splice variants are expressed in human heart but functional differences have not yet been detected (Reviewed in Kaumann and Levy 2006). 5-HT does not only increase myocardial force and hasten relaxation Sanders and Kaumann 1992;Brattelid et al. 2004), but can also elicit arrhythmic contractions in atrial trabeculae (Kaumann and Sanders 1994) and myocytes (Sanders et al. 1995) as well as in ventricular trabeculae (Brattelid et al. 2004). It has been proposed that 5-HT can initiate atrial fibrillation (Kaumann 1994) and facilitate arrhythmias in patients with ischaemic heart disease (Brattelid et al. 2004). Chronic treatment of patients with β-blockers potentiates the inotropic effects of 5-HT in atrial trabeculae and myocytes (Sanders et al. 1995). 5-HT increases the L-type Ca 2+ current (I Ca,L )in human atrial myocytes in a PKA-dependent manner (Ouadid et al. 1992). Chronic treatment of patients with β-blockers potentiates the effects of 5-HT on I Ca,L and arrhythmic activity of atrial myocytes (Pau et al. 2003). 5-HT causes also cardiostimulation in porcine heart (Kaumann 1990;Parker et al. 1994;Brattelid et al. 2004), but not in other non-primate species, at least under physiological conditions. Arrhythmias, probably mediated through 5-HT 4 receptors, have also been reported in porcine atrium (Rahme et al. 1999). Rat ventricular 5-HT 4 receptor expression and function is induced in rats with ischaemic heart failure but not in normal rats (Qvigstad et al. 2005), plausibly by reactivating a phenotype resembling late foetal development (Brattelid et al. 2012).Gergs et al. (2010) overexpressed human 5-HT 4a receptors in the heart of mice that normally do not express functional cardiac 5-HT 4 receptors. In these transgenic mice 5-HT produced sinoatrial tachycardia, increases in ventricular I Ca,L and Ca 2+ transients, positive inotropic and lusitropic effects in ventricle, associated with phosphorylation of phospholamban (PLB) at Ser16 in ventricular myocytes and Thr 17 in perfused working hearts. These features resemble the pharmacology of 5-HT 4 receptors in human heart. 5-HT, but hardly isoprenaline, also caused arrhythmic Ca 2+ transients in venricular myocytes from TG hearts. Interesting, in isolated hearts from these TG hearts Gergs et al. (2010) demonstrated episodes of spontaneous polymorphic atrial arrhythmias in the absence of exogenous 5-HT that resemble shortlasting episodes of atrial fibrillation.In an additional report of Gergs et al. (2013) in the present issue of Naunyn-Schmiedeberg's Archives of Pharmacology, the authors studied the effects of 5-HT on paced left atria and spontaneously beating right atria from their TG mouse. As expected, 5-HT produced sinoatrial tachycardia and increases in left atrial force, left atrial arrhythmias, phosphorylation of PLB at Ser16 and arrhythmias, which were antagonised by 5-HT 4 re...

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“…Indeed, human atrial myocytes isolated from patients with AF show increased CaMKII-dependent phosphorylation of RyR2 leading to increased SR Ca 2+ leak and elevated cytosolic Ca 2+ levels [39]. These altered subcellular calcium dynamics promotes EADs and DADs formation [26] in a positive feedback loop [38] promoting AF.…”

Section: Discussionmentioning

confidence: 99%

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Pezhouman¹,

Cao

Fishbein

et al. 2018

J Hear Health

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Background The mechanism of Atrial Fibrillation (AF) that emerges spontaneously during acute oxidative stress is poorly defined and its drug therapy remains suboptimal. We hypothesized that oxidative activation of Ca-calmodulin dependent protein kinase (CaMKII) promotes Early Afterdepolarization-(EAD)-mediated triggered AF in aged fibrotic atria that is sensitive to late Na current (INa-L) blockade. Method and Results High-resolution voltage optical mapping of the Left and Right Atrial (LA & RA) epicardial surfaces along with microelectrode recordings were performed in isolated-perfused male Fisher 344 rat hearts in Langendorff setting. Aged atria (23–24 months) manifested 10-fold increase in atrial tissue fibrosis compared to young/adult (2–4 months) atria (P<0001. Spontaneous AF arose in 39 out of 41 of the aged atria but in 0 out of 12 young/adult hearts (P<001) during arterial perfusion of with 0.1 mm of hydrogen peroxide (H2O2). Optical Action Potential (AP) activation maps showed that the AF was initiated by a focal mechanism in the LA suggestive of EAD-mediated triggered activity. Cellular AP recordings with glass microelectrodes from the LA epicardial sites showing focal activity confirmed optical AP recordings that the spontaneous AF was initiated by late phase 3 EAD-mediated triggered activity. Inhibition of CaMKII activity with KN-93 (1 μM) (N=6) or its downstream target, the enhanced INa-L with GS-967 (1 μM), a specific blocker of INa-L (N=6), potently suppressed the AF and prevented its initiation when perfused 15 min prior to H2O2 (n=6). Conclusions Increased atrial tissue fibrosis combined with acute oxidative activation of CaMK II Initiate AF by EAD-mediated triggered activity. Specific block of the INa-L with GS-967 effectively suppresses the AF. Drug therapy of oxidative AF in humans with traditional antiarrhythmic drugs remains suboptimal; suppressing INa-L offers a potential new strategy for effective suppression of oxidative human AF that remains suboptimal.

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CaMKII-Dependent Diastolic SR Ca ²⁺ Leak and Elevated Diastolic Ca ²⁺ Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation

Cited by 351 publications

References 54 publications

Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation

Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation

Surprises from a cardiac 5-HT4 TG mouse: spontaneous atrial arrhythmias by endogenous 5-HT of atrial origin? Different mechanism of arrhythmias through 5-HT4 receptors and β-adrenoceptors?

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

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CaMKII-Dependent Diastolic SR Ca 2+ Leak and Elevated Diastolic Ca 2+ Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation

Cited by 351 publications

References 54 publications

Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation

Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation

Surprises from a cardiac 5-HT4 TG mouse: spontaneous atrial arrhythmias by endogenous 5-HT of atrial origin? Different mechanism of arrhythmias through 5-HT4 receptors and β-adrenoceptors?

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

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Product

Resources

About

CaMKII-Dependent Diastolic SR Ca ²⁺ Leak and Elevated Diastolic Ca ²⁺ Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation