Regional Ion Channel Gene Expression Heterogeneity and Ventricular Fibrillation Dynamics in Human Hearts

Sivagangabalan, Gopal; Nazzari, Hamed; Bignolais, Olivier; Maguy, Ange; Naud, Patrice; Massé, Stéphane; Gaborit, Nathalie; Varró, András; Nair, Krishnakumar; Backx, Peter H.; Vigmond, Edward J.; Nattel, Stanley; Demolombe, Sophie; Nanthakumar, Kumaraswamy

doi:10.1371/journal.pone.0082179

Cited by 24 publications

(22 citation statements)

References 40 publications

(59 reference statements)

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“…Genetic studies have reported a decreased expression of Ca V ␣2␦ transcripts in patients suffering from atrial (43) and ventricular fibrillation (44). Our current results confirm that mutations in CACNA2D1 could be a contributing factor in cardiac sudden death associated with a short QT interval.…”

Section: Congenital Mutations In the Cardiac L-type Channelsupporting

confidence: 85%

Functional Characterization of CaVα2δ Mutations Associated with Sudden Cardiac Death

Bourdin

Shakeri

Tétreault

et al. 2015

Journal of Biological Chemistry

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Background: Missense mutations in Ca V ␣2␦1, an auxiliary subunit of cardiac L-type Ca V 1.2 channels, are associated with arrhythmias. Results:The reduction in the cell surface density of Ca V ␣2␦1 D550Y/Q917H was sufficient to impair Ca V 1.2 currents. Conclusion: Defects in the cell surface trafficking of Ca V ␣2␦1 mutants down-regulate L-type currents. Significance: CACNA2D1 genetic variants may trigger arrhythmias by reducing L-type Ca 2ϩ currents.

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Section: Congenital Mutations In the Cardiac L-type Channelsupporting

confidence: 85%

Functional Characterization of CaVα2δ Mutations Associated with Sudden Cardiac Death

Bourdin

Shakeri

Tétreault

et al. 2015

Journal of Biological Chemistry

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“…[27][28][29][30] In addition, some studies have observed changes in the gene expression of K ir 6.1/K ir 6.2, underlying the ATP-sensitive K + current (I KATP ), 31,32 NCX1 33 and K ir 2.1/K ir 2.3, molecular components of I K1 . 34,35 Consistent with these molecular data, I K1 density is larger in LV myocytes from guinea pigs, contributing to the stabilisation of the high-frequency rotors in LV. 36,37 However, other studies in different animal models did not find a significant difference between LV and RV I K1 .…”

Section: Differences In Ion Channel Propertiessupporting

confidence: 65%

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis

Molina

Heijman

Dobrev

2016

Arrhythmia &Amp; Electrophysiology Review

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Optimal cardiac function depends on appropriate rate and force of contraction, with specific cardiac regions having developed particular beat-to-beat properties depending on their individual functions. For example, isovolumetric contraction time is shorter in the right ventricle (RV) than in the left ventricle (LV). At the cellular level, cardiac function is regulated by regional cardiomyocyte electrophysiological and Ca 2+ -handling properties (see Figure 1). Differences in these properties between nodal cells and working myocardium, 1,2 atrial and ventricular cardiomyocytes 1,3,4 and different layers of the LV wall (endo-, mid-and epicardium) [5][6][7] have been well established. Although electrophysiological differences between left and right sides of the heart have been less extensively characterised there is evidence for clinically relevant left-toright differences in the atrium 1,[8][9][10] and the ventricle. 1,5,[11][12][13][14] Here, we review the known differences in LV and RV electrophysiology and Ca 2+ handling at baseline and during pathophysiological conditions. Furthermore, we discuss the implications of these differences for arrhythmogenesis. Basic Cardiac Electrophysiology and Arrhythmia MechanismsCardiac excitation-contraction (EC) coupling is a sequence of events occurring in cardiomyocytes upon electrical activation, resulting in the generation of an action potential (AP) and subsequent cardiomyocyte contraction (see Figure 2). This sequence shows many similarities between different cell types, notably between LV and RV cardiomyocytes.In this section we briefly summarise the common features. Figure 2A). Moreover, the Ca 2+ entering the cardiomyocyte through L-type Ca 2+ channels plays a critical role initiating EC coupling by activating type-2 ryanodine receptor (RyR2) channels on the sarcoplasmic reticulum (SR) membrane, producing a much larger SR Ca 2+ release. This process is termed Ca 2+ -induced Ca 2+ release (CICR) and results in an increase in the cytoplasmic Ca 2+ concentration sufficient to activate the contractile apparatus, initiating cardiomyocyte contraction. 15 Subsequently, resequestration of Ca 2+ in the SR by the SR Ca 2+ ATPase type-2a (SERCA2a) and extrusion of Ca 2+ to the extracellular space by the Na + -Ca 2+ exchanger type-1 (NCX1) returns cytosolic Ca 2+ to diastolic levels, promoting cellular relaxation. Finally, ionic homeostasis of intracellular Na + and K + is maintained by the Na + / Abstract A wide range of ion channels, transporters, signaling pathways and tissue structure at a microscopic and macroscopic scale regulate the electrophysiological activity of the heart. Each region of the heart has optimised these properties based on its specific role during the cardiac cycle, leading to well-established differences in electrophysiology, Ca 2+ handling and tissue structure between atria and ventricles and between different layers of the ventricular wall. Similarly, the right ventricle (RV) and left ventricle (LV) have different embryological, structural, metabol...

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“…Additionally, the rescuing effect of exogenous PIP 2 on CO inhibition (Fig. 6) 26 . The elevation expression of Kir2.3 during the myopathic period pronounced the greater effect of CO in APD during the myopathy.…”

Section: Discussionmentioning

confidence: 99%

“…As CO inhibits Kir2.3 current and prolongs APD in myocytes, it may cause slowing down of heart rates [28][29][30] and could be considered as a therapeutic target for AF. Kir2.0 has also previously been identified in mammalian forebrain [31][32][33] , nodes of Ranvier 34 , astrocytes 35 , heart 26,27 and renal epithelial cells 36 , serving important roles in setting membrane potential, modulating AP waveform and buffering extracellular K þ . Increased Hmox1 expression has been found in Alzheimer's disease brains 37,38 and its excessive product CO might cause depolarization and excitement of neuron by inhibition of Kir2.0.…”

Section: Discussionmentioning

confidence: 99%

Carbon monoxide inhibits inward rectifier potassium channels in cardiomyocytes

et al. 2014

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Reperfusion-induced ventricular fibrillation (VF) severely threatens the lives of postmyocardial infarction patients. Carbon monoxide (CO)-produced by haem oxygenase in cardiomyocytes-has been reported to prevent VF through an unknown mechanism of action. Here, we report that CO prolongs action potential duration (APD) by inhibiting a subset of inward-rectifying potassium (Kir) channels. We show that CO blocks Kir2.2 and Kir2.3 but not Kir2.1 channels in both cardiomyocytes and HEK-293 cells transfected with Kir. CO directly inhibits Kir2.3 by interfering with its interaction with the second messenger phosphatidylinositol (4,5)-bisphosphate (PIP 2 ). As the inhibition of Kir2.2 and Kir2.3 by CO prolongs APD in myocytes, cardiac Kir2.2 and Kir2.3 are promising targets for the prevention of reperfusion-induced VF.

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Regional Ion Channel Gene Expression Heterogeneity and Ventricular Fibrillation Dynamics in Human Hearts

Cited by 24 publications

References 40 publications

Functional Characterization of CaVα2δ Mutations Associated with Sudden Cardiac Death

Functional Characterization of CaVα2δ Mutations Associated with Sudden Cardiac Death

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis

Carbon monoxide inhibits inward rectifier potassium channels in cardiomyocytes

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