Targeting the late component of the cardiac L-type Ca2+ current to suppress early afterdepolarizations

Madhvani, Roshni V.; Angelini, Marina; Xie, Yuanfang; Pantazis, Antonios; Suriany, Silvie; Borgstrom, N P; Garfinkel, Alan; Qu, Zhilin; Weiss, James N.; Olcese, Riccardo

doi:10.1085/jgp.201411288

Cited by 45 publications

(96 citation statements)

References 44 publications

(72 reference statements)

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“…In addition, EADs are promoted by spontaneous Ca 2+ release from the SR that triggers the inward Na + /Ca 2+ -exchange current (Choi et al, 2002). Consistent with these mechanisms, in mammalian ventricular myocytes, EADs can be abolished by reducing the size of the window I CaL (Madhvani et al, 2015) or by blocking the SR Ca 2+ release with ryanodine (Volders et al, 1997). Interestingly, in crucian carp ventricular myocytes, cold acclimation (+4°C) reduces the size of the maximum window I CaL from ca.…”

Section: Avoidance Of Cardiac Arrhythmiamentioning

confidence: 79%

Effects of prolonged anoxia on electrical activity of the heart in Crucian carp (Carassius carassius)

Tikkanen

Haverinen

Egginton

et al. 2016

Journal of Experimental Biology

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The effects of sustained anoxia on cardiac electrical excitability were examined in the anoxia-tolerant crucian carp (Carassius carassius). The electrocardiogram (ECG) and expression of excitationcontraction coupling genes were studied in fish acclimatised to normoxia in summer (+18°C) or winter (+2°C), and in winter fish after 1, 3 and 6 weeks of anoxia. Anoxia induced a sustained bradycardia from a heart rate of 10.3±0.77 beats min −1 to 4.1±0.29 beats min −1 (P<0.05) after 5 weeks, and heart rate slowly recovered to control levels when oxygen was restored. Heart rate variability greatly increased under anoxia, and completely recovered under reoxygenation. The RT interval increased from 2.8±0.34 s in normoxia to 5.8±0.44 s under anoxia (P<0.05), which reflects a doubling of the ventricular action potential (AP) duration. Acclimatisation to winter induced extensive changes in gene expression relative to summer-acclimatised fish, including depression in those genes coding for the sarcoplasmic reticulum calcium pump (Serca2a_q2) and ATP-sensitive K + channels (Kir6.2) (P<0.05). Genes of delayed rectifier K + (kcnh6) and Ca 2+ channels (cacna1c) were up-regulated in winter fish (P<0.05). In contrast, the additional challenge of anoxia caused only minor changes in gene expression, e.g. depressed expression of Kir2.2b K + channel gene (kcnj12b), whereas expression of Ca 2+ (cacna1a, cacna1c and cacna1g) and Na + channel genes (scn4a and scn5a) was not affected. These data suggest that low temperature pre-conditions the crucian carp heart for winter anoxia, whereas sustained anoxic bradycardia and prolongation of AP duration are directly induced by oxygen shortage without major changes in gene expression.

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Section: Avoidance Of Cardiac Arrhythmiamentioning

confidence: 79%

Effects of prolonged anoxia on electrical activity of the heart in Crucian carp (Carassius carassius)

Tikkanen

Haverinen

Egginton

et al. 2016

Journal of Experimental Biology

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“…Activated CaMKII phosphorylates cardiac Na and Ca channels enhancing the highly arrhythmogenic late Na (I Na-L ) [14] and the late L-type Ca (I Ca-L ) [15] currents. Isolated myocytes and dynamic-clamp experiments have shown that an isolated increase of either of these two late inward currents promotes cellular early and delayed afterdepolarizations (EADs and DADs respectively) causing rapid triggered activity [16,17]. Indeed inhibition of the I Na-L with the highly potent (IC 50 =0.143 μM) and selective inhibitor GS-967 [18] suppresses EADs in isolated atrial myocytes [18,19].…”

Section: Introductionmentioning

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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“…L-type calcium channels are modulated by both voltageand calcium-dependent inactivation gating mechanisms. 1 Although the mechanism by which intravenous calcium appeared to suppress EADs in this case is unclear, calcium could lead to a slightly higher plateau of the AP, leaving only a prolonged APD but attenuating EADs. Intravenous calcium might also attenuate EADs by increased calciumdependent inactivation of the late component of L-type calcium channels.…”

Section: Response To Ecg Challengementioning

confidence: 76%

“…The late component of the L-type Ca 2+ current may be especially relevant to EADs. 1 EADs are oscillations of the cell membrane and require inward calcium and outward potassium currents to be properly matched in amplitude and timing. L-type calcium channels are a promising therapeutic target to normalize AP duration (APD) and suppress EADs.…”

Section: Response To Ecg Challengementioning

confidence: 99%

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Electrocardiogram Challenge Syncope in a Woman With Nausea and Diarrhea

Puy¹,

Kay²

2017

Circulation

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A 71-year-old woman was sent referred to the emergency department from a rehabilitation facility after suffering her first episode of syncope. She was recovering from a recent episode of diarrhea and had been receiving intravenous vancomycin, piperacillin-tazobactan, and fluconazole. Her oral medications included 8 mg ondansetron every 8 hours, cholecalciferol, clonazepam, and esomeprazole. A 12-lead ECG was recorded in the emergency department (Figure 1).

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Targeting the late component of the cardiac L-type Ca2+ current to suppress early afterdepolarizations

Abstract: Decreasing the amplitude of the late component of the cardiac L-type Ca2+ channel current suppresses early afterdepolarizations, thereby decreasing the risk of arrhythmias.

Cited by 45 publications

References 44 publications

Effects of prolonged anoxia on electrical activity of the heart in Crucian carp (Carassius carassius)

Effects of prolonged anoxia on electrical activity of the heart in Crucian carp (Carassius carassius)

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

Electrocardiogram Challenge Syncope in a Woman With Nausea and Diarrhea

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