Ischemia-induced arrhythmia: the role of connexins, gap junctions, and attendant changes in impulse propagation

Cascio, Wayne E.; Yang, Hsiao Bai; Muller‐Borer, Barbara J.; Johnson, Timothy A.

doi:10.1016/j.jelectrocard.2005.06.019

Cited by 82 publications

(84 citation statements)

References 35 publications

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“…This early period of acute ischemia is characterized by a maximum rate of incidence of ventricular arrhythmias (13,33), and the phenomenon described in this work can be one of the scenarios for reentry induction in phase 1a arrhythmias. The power of our preparation and analysis lies with our ability to control the severity of the regional heterogeneity and quantify the resulting changes in AP dynamics, conduction, and increases in arrhythmogenicity, which play important roles in the electrophysiological disturbances associated with acute myocardial ischemia.…”

Section: Discussionmentioning

confidence: 90%

Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution

Sidorov¹,

Uzelac

Wikswo

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Sidorov VY, Uzelac I, Wikswo JP. Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution. Am J Physiol Heart Circ Physiol 301: H209 -H220, 2011. First published May 2, 2011; doi:10.1152/ajpheart.01141.2010.-The heterogeneities of electrophysiological properties of cardiac tissue are the main factors that control both arrhythmia induction and maintenance. Although the local increase of extracellular potassium ([K ϩ ]o) due to coronary occlusion is a well-established metabolic response to acute ischemia, the role of local [K ϩ ]o heterogeneity in phase 1a arrhythmias has yet to be determined. In this work, we created local [K ϩ ]o heterogeneity and investigated its role in fast pacing response and arrhythmia induction. The left marginal vein of a Langendorff-perfused rabbit heart was cannulated and perfused separately with solutions containing 4, 6, 8, 10, and 12 mM of K ϩ . The fluorescence dye was utilized to map the voltage distribution. We tested stimulation rates, starting from 400 ms down to 120 ms, with steps of 5-50 ms. We found that local [K ϩ ]o heterogeneity causes action potential (AP) alternans, 2:1 conduction block, and wave breaks. The effect of [K ϩ ]o heterogeneity on electrical stability and vulnerability to arrhythmia induction was largest during regional perfusion with 10 mM of K ϩ . We detected three concurrent dynamics: normally propagating activation when excitation waves spread over tissue perfused with normal K ϩ , alternating 2:2 rhythm near the border of [K ϩ ]o heterogeneity, and 2:1 aperiodicity when propagation was within the high [K ϩ ]o area. [K ϩ ]o elevation changed the AP duration (APD) restitution and shifted the restitution curve toward longer diastolic intervals and shorter APD. We conclude that spatial heterogeneity of the APD restitution, created with regional elevation of [K ϩ ]o, can lead to AP instability, 2:1 block, and reentry induction. restitution heterogeneity; regional perfusion; optical mapping THE STATIONARY AND DYNAMIC heterogeneities of electrophysiological properties of cardiac tissue play a key role in the induction and maintenance of cardiac arrhythmias (1,10,16,59). Cardiac tissue heterogeneities increase drastically when acute regional ischemia occurs. The early stage of acute ischemia is characterized by abrupt metabolic and electrophysiological changes in the affected area (11). Among them, the more prominent are increased extracellular potassium ([K ϩ ] o ) (25, 26), decreased creatine phosphate (43, 63), elevated intracellular inorganic phosphate (63), acidosis (27, 46), catecholamine release (39), and partial depolarization of transmembrane potential (V m ) (28,36).Since an early change in V m closely relates to [K ϩ ] o accumulation (34, 60), the K ϩ imbalance is considered to be the major factor affecting excitability and is responsible for slow impulse propagation and induction of reentry (51) Although numerous studies have been devoted to investigation ...

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Section: Discussionmentioning

confidence: 90%

Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution

Sidorov¹,

Uzelac

Wikswo

2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Notably, multiple cardiac diseases associated with G j remodeling (1,10) are also linked with myocardial edema (7,28). Yet, little is known about the electrophysiological impact of edema.…”

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confidence: 99%

Interstitial volume modulates the conduction velocity-gap junction relationship

Veeraraghavan

Salama

Poelzing

2012

American Journal of Physiology-Heart and Circulatory Physiology

126

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Cardiac conduction through gap junctions is an important determinant of arrhythmia susceptibility. Yet, the relationship between degrees of Gj uncoupling and conduction velocity (θ) remains controversial. Conflicting results in similar experiments are normally attributed to experimental differences. We hypothesized that interstitial volume modulates conduction velocity and its dependence on Gj. Interstitial volume (VIS) was quantified histologically from guinea pig right ventricle. Optical mapping was used to quantify conduction velocity and anisotropy (ARθ). Albumin (4 g/l) decreased histologically assessed VIS, increased transverse θ by 71 ± 10%, and lowered ARθ. Furthermore, albumin did not change isolated cell size. Conversely, mannitol increased VIS, decreased transverse θ by 24 ± 4%, and increased ARθ. Mannitol also decreased cell width by 12%. Furthermore, mannitol was associated with spontaneous ventricular tachycardias in three of eight animals relative to zero of 15 during control. The θ-Gj relationship was assessed using the Gj uncoupler carbenoxolone (CBX). Whereas 13 μM CBX did not significantly affect θ during control, it slowed transverse θ by 38 ± 9% during mannitol (edema). These data suggest changes in VIS modulate θ, ARθ, and the θ-Gj relationship and thereby alter arrhythmia susceptibility. Therefore, VIS may underlie arrhythmia susceptibility, particularly in diseases associated with gap junction remodeling.

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“…Although processes underlying the generation of phase Ib arrhythmias are less well understood than that of the phase Ia, it is proposed that uncoupling of gap junctions play a pivotal role. This is supported by the finding that by this time of ischaemia, the accumulation of catecholamines [11, 20 21] the subsequent intracellular Ca 2+ overload [22] and the drop of intracellular pH [3] create a milieu which facilitates the uncoupling of gap junctions and an increases cellular resistance [23,8] resulting in non-uniform changes in impulse conduction. Coronel et al [24] demonstrated that increased wall stretch due to elevated ventricular filling pressure, as well as a second rise in extracellular K + [18], the latter by further increasing spatial heterogeneity, are also important contributory factors to the development of phase Ib arrhythmias.…”

Section: Temporal Distribution and Mechanisms Of Acute Ischaemia-indumentioning

confidence: 88%

“…In contrast, a more advanced uncoupling attenuates the occurrence of arrhythmias, since the substrate for them disappears [8].…”

Section: Temporal Distribution and Mechanisms Of Acute Ischaemia-indumentioning

confidence: 97%

“…Furthermore, as a consequence of altered function of Na + /Ca 2+ exchanger, intracellular Ca 2+ overload occurs, which is a source of triggered activity [7]. These changes are the most prominent in the central zone of the ischaemic area and lead to dramatic changes in action potential morphology and duration [7] as well as impulse generation and conduction [8]. Within those areas most affected by ischaemia, even conduction block may develop.…”

Section: Temporal Distribution and Mechanisms Of Acute Ischaemia-indumentioning

confidence: 99%

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Functional role of gap junctions in early and delayed cardioprotection induced by nitric oxide donors and rapid cardiac pacing

Gönczi

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Ischemia-induced arrhythmia: the role of connexins, gap junctions, and attendant changes in impulse propagation

Cited by 82 publications

References 35 publications

Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution

Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution

Interstitial volume modulates the conduction velocity-gap junction relationship

Functional role of gap junctions in early and delayed cardioprotection induced by nitric oxide donors and rapid cardiac pacing

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