Triggered intracellular calcium waves in dog and human left atrial myocytes from normal and failing hearts

Aistrup, Gary L.; Arora, Rishi; Grubb, Søren; Yoo, Seung Hoon; Toren, Benjamin; Kumar, Meghan Bruce; Kunamalla, Aaron; Marszalec, William; Motiwala, Tej; Tai, Shannon; Yamakawa, Sean; Yerrabolu, Satya; Alvarado, Francisco; Valdivia, Héctor H.; Cordeiro, Jonathan M.; Shiferaw, Yohannes; Wasserstrom, J. Andrew

doi:10.1093/cvr/cvx167

Cited by 20 publications

(23 citation statements)

References 28 publications

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“…Voigt et al showed that CaMKII-p-RyR2 (S2814) leads to an increased propensity for spontaneous Ca 2+ release (Ca 2+ waves) -and consequent delayed afterdepolarizations -in atrial myocytes from patients with chronic AF (16). Very recently, we have shown that atrial myocytes demonstrate a propensity for Ca 2+ waves that occur in the setting of rapid heart rates (17). These TCWs occur during atrial systole and cause membrane depolarizations that are conducive to the genesis of early-afterdepolarizations (30).…”

Section: Discussionmentioning

confidence: 81%

“…Preliminary data indicate that these TCWs cause incomplete cellular repolarization on a beat-to-beat basis and, therefore, could contribute to afterdepolarizations and/or dispersion of repolarization (30). The incidence of TCWs increases significantly in HF myocytes, with Ca 2+ waves occurring at significantly longer cycle lengths than in normal myocytes (17). Since CaMKII-p-RyR2 (S2814) has been shown to alter SR Ca 2+ release (16), and as Ox-CaMKII -which is known to be enzymatically active in the absence of Ca 2 + / CaM -was increased in the HF PLA, we measured the level of CaMKII-p-RyR2 (S2814).…”

Section: Increased Incidence Of Tcws In Hf Pla Myocytes and Attenuatimentioning

confidence: 93%

“…Aberrant Ca 2+ cycling is thought to contribute to AF substrate formation (29). We recently described a unique form of aberrant sarcoplasmic reticulum (SR) Ca 2+ release in atrial myocytes, wherein atrial myocytes demonstrate the presence of Ca 2+ waves that occur during rapid atrial stimulation, not during diastole (17). Preliminary data indicate that these TCWs cause incomplete cellular repolarization on a beat-to-beat basis and, therefore, could contribute to afterdepolarizations and/or dispersion of repolarization (30).…”

Section: Increased Incidence Of Tcws In Hf Pla Myocytes and Attenuatimentioning

confidence: 99%

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Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure

Yoo¹,

Aistrup²,

Shiferaw³

et al. 2018

JCI Insight

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The precise mechanisms by which oxidative stress (OS) causes atrial fibrillation (AF) are not known. Since AF frequently originates in the posterior left atrium (PLA), we hypothesized that OS, via calmodulin-dependent protein kinase II (CaMKII) signaling, creates a fertile substrate in the PLA for triggered activity and reentry. In a canine heart failure (HF) model, OS generation and oxidized-CaMKII-induced (Ox-CaMKII-induced) RyR2 and Na v 1.5 signaling were increased preferentially in the PLA (compared with left atrial appendage). Triggered Ca 2+ waves (TCWs) in HF PLA myocytes were particularly sensitive to acute ROS inhibition. Computational modeling confirmed a direct relationship between OS/CaMKII signaling and TCW generation. CaMKII phosphorylated Na v 1.5 (CaMKII-p-Na v 1.5 [S571]) was located preferentially at the intercalated disc (ID), being nearly absent at the lateral membrane. Furthermore, a decrease in ankyrin-G (AnkG) in HF led to patchy dropout of CaMKII-p-Na v 1.5 at the ID, causing its distribution to become spatially heterogeneous; this corresponded to preferential slowing and inhomogeneity of conduction noted in the HF PLA. Computational modeling illustrated how conduction slowing (e.g., due to increase in CaMKII-p-Na v 1.5) interacts with fibrosis to cause reentry in the PLA. We conclude that OS via CaMKII leads to substrate for triggered activity and reentry in HF PLA by mechanisms independent of but complementary to fibrosis. insight.jci.org https://doi.org/10.1172/jci.insight.120728 R E S E A R C H A R T I C L Epropensity for spontaneous calcium (Ca 2+ ) release (in the form of Ca 2+ waves) in atrial myocytes of patients with chronic AF (16). Our work indicates that atrial myocytes in the setting of HF have increased susceptibility to the development of Ca 2+ waves during rapid atrial pacing (i.e., triggered Ca 2+ waves; TCWs) (17). Ca 2+ waves are known to create conditions in both the ventricle and atrium for the genesis of afterdepolarizations, which can lead to triggered activity and/or dispersion of repolarization (18,19). Another major mechanism thought to underlie the development of a vulnerable AF substrate in HF is slow and inhomogeneous conduction in the intact atrium, which creates conditions for reentry (20)(21)(22). While several studies suggest that increased fibrosis in the HF atrium is a major cause of this inhomogeneous conduction (21,23), it is also known that the HF atrium undergoes significant electrical remodeling (24), with alterations in the I Na having been implicated in some studies in creation of the AF disease state (25). Our specific hypotheses for this study were, therefore, as follows: (a) OS generation -and downstream oxidation of key signaling proteins -is preferentially increased in the PLA/PVs in the HF atrium; (b) the increased vulnerability of HF atrial myocytes to TCW generation is at least partially mediated by OS, with OS creating substrate for TCWs by increasing CaMKII-p-RyR2 (S2814) in the HF PLA; and (c) OS, via Ox-CaMKII, increases the level of C...

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Section: Discussionmentioning

confidence: 81%

Section: Increased Incidence Of Tcws In Hf Pla Myocytes and Attenuatimentioning

confidence: 93%

Section: Increased Incidence Of Tcws In Hf Pla Myocytes and Attenuatimentioning

confidence: 99%

See 1 more Smart Citation

Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure

Yoo¹,

Aistrup²,

Shiferaw³

et al. 2018

JCI Insight

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“…These results demonstrate that sympathetic stimulation promotes an increased frequency of subcellular Ca 2+ waves that propagate inside the cell interior. These subcellular Ca 2+ waves have been studied extensively by our group (21,22) and have been shown to occur in normal atrial myocytes under rapid pacing conditions. In both cases, these waves originate under conditions of increased sarcoplasmic reticulum (SR) loading, where the interior of the atrial myocyte is sensitized and can support the propagation of Ca 2+ waves.…”

Section: Resultsmentioning

confidence: 99%

Region-specific parasympathetic nerve remodeling in the left atrium contributes to creation of a vulnerable substrate for atrial fibrillation

Gussak¹,

Pfenniger²,

Wren³

et al. 2019

JCI Insight

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“…Increasing SR calcium content is generally pro-arrhythmic as this can lead to an increased frequency of delayed afterdepolarizations, and this is often seen in the atria of those with heart failure (Yeh et al, 2008 ; Hohendanner et al, 2015 , 2016 ; Aistrup et al, 2017 ). While in rodents a decrease in SR calcium content (Saba et al, 2005 ) is associated with reduced SERCA, PLB, and sarcolipin expression (Shanmugam et al, 2011 ), a somewhat different story predominates in large mammals in which atrial SR calcium content increases in heart failure (Yeh et al, 2008 ; Clarke et al, 2015 ; Aistrup et al, 2017 ) despite decreased calcium reuptake by SERCA (Clarke et al, 2015 ; Hohendanner et al, 2016 ). This apparently paradoxical finding has been explained by the decrease in atrial I Ca(L) where inhibiting I Ca(L) in control cells reproduces the increase in SR calcium content.…”

Section: The Interplay Between Heart Failure and Atrial Fibrillationmentioning

confidence: 99%

Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure

et al. 2018

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Atrial fibrillation (AF) is commonly associated with heart failure. A bidirectional relationship exists between the two—AF exacerbates heart failure causing a significant increase in heart failure symptoms, admissions to hospital and cardiovascular death, while pathological remodeling of the atria as a result of heart failure increases the risk of AF. A comprehensive understanding of the pathophysiology of AF is essential if we are to break this vicious circle. In this review, the latest evidence will be presented showing a fundamental role for calcium in both the induction and maintenance of AF. After outlining atrial electrophysiology and calcium handling, the role of calcium-dependent afterdepolarizations and atrial repolarization alternans in triggering AF will be considered. The atrial response to rapid stimulation will be discussed, including the short-term protection from calcium overload in the form of calcium signaling silencing and the eventual progression to diastolic calcium leak causing afterdepolarizations and the development of an electrical substrate that perpetuates AF. The role of calcium in the bidirectional relationship between heart failure and AF will then be covered. The effects of heart failure on atrial calcium handling that promote AF will be reviewed, including effects on both atrial myocytes and the pulmonary veins, before the aspects of AF which exacerbate heart failure are discussed. Finally, the limitations of human and animal studies will be explored allowing contextualization of what are sometimes discordant results.

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Triggered intracellular calcium waves in dog and human left atrial myocytes from normal and failing hearts

Cited by 20 publications

References 28 publications

Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure

Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure

Region-specific parasympathetic nerve remodeling in the left atrium contributes to creation of a vulnerable substrate for atrial fibrillation

Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure

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