scholarly journals Mechanisms of Ca2+-Triggered Arrhythmias

Tachycardia ◽  
10.5772/25906 ◽  
2012 ◽  
Author(s):  
Simon Sedej ◽  
Burkert Pieske
Keyword(s):  
Triggered Arrhythmias

Abstract 17019: Two Distinct mechanisms by which Na+/Ca2+ dysregulation contributes to Arrhythmogenic Diastolic Ca2+ Release

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Przemyslaw Radwanski ◽  
Rengasayee Veeraraghavan ◽  
Björn Knollmann ◽  
Sándor Györke
Keyword(s):  
Ventricular Myocytes ◽  
Cellular Level ◽  
Polymorphic Ventricular Tachycardia ◽  
Cell Periphery ◽  
Individualized Approach ◽  
Triggered Arrhythmias ◽  
Local Contribution ◽  
Dependent Protein ◽  
Camkii Activation

Na + and Ca 2+ imbalance is associated with triggered arrhythmias resulting from diastolic Ca 2+ release (DCR) from sarcoplasmic reticulum (SR). Recent evidence suggests Na + channel blockade to be a promising therapy for pathologies, including catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the specific mechanism(s) as to how Na + /Ca 2+ dysregulation contribute to arrhythmias is unknown. Confocal microscopy of ventricular myocytes isolated from CPVT mice lacking the cardiac calsequestrin was used to assess Ca 2+ handling response to isoproterenol (Iso) and various pharmacological interventions, while electrocardiograms were acquired during catecholamine challenge to assess the roles of various pools of Na + channels in CPVT. We identify two pools of Na + channels: one composed of cardiac-type Na + channels localized to cell periphery, and a ‘ local pool ’ comprised of neuronal Na + channels colocalizing with RyR2 in the T-tubules. Augmenting function of both Na + channel pools with ATX-II in the presence Iso resulted in SR Ca 2+ overload and activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), which precipitated DCR. These, in turn, translated into frequent arrhythmias in CPVT mice. Selectively augmenting function of ‘local pool’ neuronal Na + channels with β-Pompilidotoxin (β-PMTX) precipitated DCR on the cellular level causing frequent arrhythmias during catecholamine challenge in vivo . However, increasing local Na + fluxes reduced SR Ca 2+ load suggesting that local elevation in cytosolic Ca 2+ rather than global SR Ca 2+ overload underlies DCR and arrhythmias under such conditions. These data suggest two distinct mechanisms for Na + /Ca 2+ dysregulation-mediated arrhythmias. The first relies on SR Ca 2+ overload and CaMKII activation and the other on local contribution of Na + -Ca 2+ exchange to DCR. Consideration of these divergent mechanisms may enhance individualized approach to arrhythmia management.

Electrotonic suppression of early afterdepolarizations in isolated rabbit Purkinje myocytes

2000 ◽  
Vol 279 (1) ◽  
pp. H250-H259 ◽  
Author(s):  
Delilah J. Huelsing ◽  
Kenneth W. Spitzer ◽  
Andrew E. Pollard
Keyword(s):  
Ventricular Myocytes ◽  
Single Cells ◽  
Late Phase ◽  
Input Resistance ◽  
Membrane Resistance ◽  
Early Afterdepolarizations ◽  
Model Cell ◽  
Triggered Arrhythmias ◽  
Electrotonic Interactions ◽  
Coupling Current

Many studies suggest that early afterdepolarizations (EADs) arising from Purkinje fibers initiate triggered arrhythmias under pathological conditions. However, electrotonic interactions between Purkinje and ventricular myocytes may either facilitate or suppress EAD formation at the Purkinje-ventricular interface. To determine conditions that facilitated or suppressed EADs during Purkinje-ventricular interactions, we coupled single Purkinje myocytes and aggregates isolated from rabbit hearts to a passive model cell via an electronic circuit with junctional resistance ( R j). The model cell had input resistance ( R m,v) of 50 MΩ, capacitance of 39 pF, and a variable rest potential ( V rest,v). EADs were induced in Purkinje myocytes during superfusion with 1 μM isoproterenol. Coupling at high R j to normally polarized V rest,v established a repolarizing coupling current during all phases of the Purkinje action potential. This coupling current preferentially suppressed EADs in single cells with mean membrane resistance ( R m,p) of 297 MΩ, whereas EAD suppression in larger aggregates with mean R m,p of 80 MΩ required larger coupling currents. In contrast, coupling to elevated V rest,v established a depolarizing coupling current during late phase 2, phase 3, and phase 4 that facilitated EAD formation and induced spontaneous activity in single Purkinje myocytes and aggregates. These results have important implications for arrhythmogenesis in the infarcted heart when reduction of the ventricular mass due to scarring alters the R m,p-to- R m,v ratio and in the ischemic heart when injury currents are established during coupling between polarized Purkinje myocytes and depolarized ventricular myocytes.

Intracellular calcium activates a chloride current in canine ventricular myocytes

1994 ◽  
Vol 267 (5) ◽  
pp. H1984-H1995 ◽  
Author(s):  
A. C. Zygmunt
Keyword(s):  
Potassium Current ◽  
Ventricular Myocytes ◽  
Single Cells ◽  
Reversal Potential ◽  
Outward Current ◽  
Chloride Current ◽  
Disulfonic Acid ◽  
Transient Outward Current ◽  
Triggered Arrhythmias ◽  
Inward Currents

The contribution of chloride and potassium to the 4-aminopyridine (4-AP)-resistant transient outward current was investigated in dog cardiac myocytes. Whole cell currents were recorded at 37 degrees C in single cells dissociated from epicardial and midmyocardial regions of the canine ventricle. Sodium-calcium exchange current and voltage-dependent transient outward potassium current (IA) were blocked in sodium-free solutions containing 2 mM 4-AP; sodium channels were inactivated by the -50-mV holding potential. When patch pipettes contained 0.4–0.8 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, voltage-clamp steps over the range -20 to +50 mV activated an inward calcium current (ICa) and a Ca(2+)-activated chloride current [ICl(Ca)]. ICl(Ca) was blocked by 200 microM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, 1 mM 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS), or reduction of external chloride. Independent of the presence of potassium, the reversal potential of the SITS-sensitive current varied with extracellular chloride, as predicted for a chloride-selective conductance. The bell-shaped current-voltage relation of ICl(Ca) has a threshold of -20 mV and a peak at +40 mV. No evidence could be found for a Ca(2+)-activated potassium current or a Ca(2+)-activated nonspecific cation current under these conditions. ICl(Ca) contributed to oscillatory inward currents at diastolic potentials in cells superfused by isoproterenol and high Ca2+, suggesting a role for this current in triggered arrhythmias associated with delayed afterdepolarizations. In the normal heart, ICl(Ca) is likely to contribute to rate- and rhythm-dependent repolarization of the cardiac action potential.

Free radicals enhance Na+/Ca2+ exchange in ventricular myocytes

1996 ◽  
Vol 271 (3) ◽  
pp. H823-H833 ◽  
Author(s):  
J. I. Goldhaber
Keyword(s):  
Free Radicals ◽  
Free Radical ◽  
Sarcoplasmic Reticulum ◽  
Ventricular Myocytes ◽  
Similar Response ◽  
Inward Current ◽  
Oxygen Derived Free Radicals ◽  
Triggered Arrhythmias ◽  
Rabbit Ventricular Myocytes ◽  
Generating System

Oxygen-derived free radicals (OFR) have been implicated in the pathogenesis of intracellular Ca2+ overload and the arrhythmias that characterize cardiac reperfusion. These arrhythmias may in large part be due to activation of the pathological transient inward current (ITI). However, the identity of the ITI generated by OFR is uncertain. We previously found that H2O2, an OFR-generating compound, markedly stimulated the ITI elicited by brief caffeine pulses in patch-clamped guinea pig ventricular myocytes. In the present study, using patch-clamped rabbit ventricular myocytes loaded with the Ca(2+)-sensitive indicator fura 2, we have further characterized this ITI and have identified its major component to be Na+/Ca2+ exchange based on its dependence on extracellular Na+ and sarcoplasmic reticulum Ca2+ release, its sensitivity to Ni2+, and the effects of its inhibition on relaxation. The effect on ITI was not unique to H2O2, because another free radical-generating system, xanthine + xanthine oxidase, produced a similar response. We hypothesize that enhancement of Na+/Ca2+ exchange by OFR during reperfusion, when intracellular Na+ is elevated, may promote intracellular Ca2+ overload and triggered arrhythmias.

Dietary fish oil reduces the incidence of triggered arrhythmias in pig ventricular myocytes

Heart Rhythm ◽  
2007 ◽  
Vol 4 (11) ◽  
pp. 1452-1460 ◽  
Author(s):  
Géza Berecki ◽  
Hester M. Den Ruijter ◽  
Arie O. Verkerk ◽  
Cees A. Schumacher ◽  
Antonius Baartscheer ◽  
...  
Keyword(s):  
Fish Oil ◽  
Ventricular Myocytes ◽  
Dietary Fish ◽  
Triggered Arrhythmias

scholarly journals Phospholamban Knockout Breaks Arrhythmogenic Ca 2+ Waves and Suppresses Catecholaminergic Polymorphic Ventricular Tachycardia in Mice

2013 ◽  
Vol 113 (5) ◽  
pp. 517-526 ◽  
Author(s):  
Yunlong Bai ◽  
Peter P. Jones ◽  
Jiqing Guo ◽  
Xiaowei Zhong ◽  
Robert B. Clark ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Mouse Model ◽  
Ventricular Myocytes ◽  
Mutant Mice ◽  
Polymorphic Ventricular Tachycardia ◽  
Patch Clamp Recording ◽  
Plasmic Reticulum ◽  
Paradoxical Effects ◽  
Triggered Arrhythmias ◽  
The Impact

Rationale : Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca 2+ ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum Ca 2+ load and Ca 2+ leak. Conversely, PLN-KO accelerates Ca 2+ sequestration and aborts arrhythmogenic spontaneous Ca 2+ waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca 2+ -triggered arrhythmias. Objective : We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine-receptor (RyR2)-linked catecholaminergic polymorphic VT. Methods and Results : We generated a PLN-deficient, RyR2-mutant mouse model (PLN −/− /RyR2-R4496C +/− ) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT–associated RyR2-R4496C mutant mice. Ca 2+ imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C +/− ventricular myocytes during sarcoplasmic reticulum Ca 2+ overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca 2+ sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca 2+ overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca 2+ ATPase with 2,5-di-tert-butylhydroquinone. However, Bay K, caffeine, or Li + failed to convert mini-waves to cell-wide SCWs in PLN −/− /RyR2-R4496C +/− ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs. Conclusions : Our results demonstrate that despite severe sarcoplasmic reticulum Ca 2+ leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca 2+ sequestration represents an effective approach for suppressing Ca 2+ -triggered arrhythmias.

Wenxin Keli Suppresses Ventricular Triggered Arrhythmias via Selective Inhibition of Late Sodium Current

2013 ◽  
Vol 36 (6) ◽  
pp. 732-740 ◽  
Author(s):  
XIAOLIN XUE ◽  
DONGLIN GUO ◽  
HONGMEI SUN ◽  
DAN WANG ◽  
JIANA LI ◽  
...  
Keyword(s):  
Sodium Current ◽  
Selective Inhibition ◽  
Late Sodium Current ◽  
Triggered Arrhythmias
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