Left-to-right ventricular differences in IKATP underlie epicardial repolarization gradient during global ischemia

Pandit, Sandeep V.; Kaur, Kuljeet; Zlochiver, Sharon; Noujaim, Sami F.; Furspan, Philip B.; Mironov, Sergey V.; Shibayama, Junco; Anumonwo, Justus M.B.; Jalife, José

doi:10.1016/j.hrthm.2011.06.028

Cited by 32 publications

(26 citation statements)

References 31 publications

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“…5 For example, interventricular differences in I KATP could be an important determinant of LV/RV APD gradients during global ischaemia, 32 and heterogeneous ventricular chamber responses to hypokalaemia and I K1 blockade contributed to bifurcated T-wave patterns in guinea pig. 62 Similarly, differential downregulation of RV and LV delayed rectifier K + currents could contribute to repolarisation abnormalities and arrhythmogenesis in patients with cardiac hypertrophy or failure.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Optical mapping was performed as described in our previous studies [21,22]. Briefly, following sedation (ketamine and xylazine; 10–40 mg/kg, and 3–5 mg/kg respectively, IM), rabbits were treated with heparin and anesthetized with sodium pentobarbital (50–100 mg/kg intravenously via ear vein).…”

Section: Methodsmentioning

confidence: 99%

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

Stables

Musa

Mitra

et al. 2014

Journal of Molecular and Cellular Cardiology

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Diabetes is associated with an increased risk of sudden cardiac death, but the underlying mechanisms remain unclear. Our goal was to investigate changes occurring in the action potential duration (APD) and conduction velocity (CV) in the diabetic rabbit ventricle, and delineate the principal ionic determinants. A rabbit model of alloxan-induced diabetes was utilized. Optical imaging was used to record electrical activity in isolated Langendorff-perfused hearts in normo-, hypo- and hyper-kalemia ([K+]o=4, 2, 12 mM respectively). Patch clamp experiments were conducted to record Na+ current (INa) in isolated ventricular myocytes. The mRNA/protein expression levels for Nav1.5 (the α-subunit of INa) and connexin-43 (Cx43), as well as fibrosis levels were examined. Computer simulations were performed to interpret experimental data. We found that the APD was not different, but that the CV was significantly reduced in diabetic hearts in normo-, hypo-, and, in hyper-kalemic conditions (13%, 17% and 33% reduction in diabetic vs. control, respectively). The cell capacitance (Cm) was increased (by ~14%), and the density of INa was reduced by ~32% in diabetes compared to controls, but the other biophysical properties of INa were unaltered. The mRNA/protein expression levels for Cx43 were unaltered. For Nav1.5, the mRNA expression was not changed, and though the protein level tended to be less in diabetic hearts, this reduction was not statistically significant. Staining showed no difference in fibrosis levels between the control and diabetic ventricles. Computer simulations showed that the reduced magnitude of INa was a key determinant of impaired propagation in the diabetic ventricle, which may have important implications for arrhythmogenesis.

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“…The situation may be aggravated by the regional distribution of K ATP channels. For example, K ATP channels may contribute to the left-right ventricular electrical heterogeneity in guinea pig hearts during global ischemia [but not in the dog heart (797)], mainly due to the higher K ATP channel density in the left ventricle (629). Simulation studies further predict that transmural gradients of K ATP channel density may contribute to activation rate gradients and arrhythmogenicity, with a potential role for the Purkinje system in causing local endocardial spatial heterogeneity, which may serve as an arrhythmogenic trigger (80).…”

Section: Continuedmentioning

confidence: 99%

K_ATPChannels in the Cardiovascular System

Foster

Coetzee

2016

Physiological Reviews

204

237

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KATP channels are integral to the functions of many cells and tissues. The use of electrophysiological methods has allowed for a detailed characterization of KATP channels in terms of their biophysical properties, nucleotide sensitivities, and modification by pharmacological compounds. However, even though they were first described almost 25 years ago (Noma 1983, Trube and Hescheler 1984), the physiological and pathophysiological roles of these channels, and their regulation by complex biological systems, are only now emerging for many tissues. Even in tissues where their roles have been best defined, there are still many unanswered questions. This review aims to summarize the properties, molecular composition, and pharmacology of KATP channels in various cardiovascular components (atria, specialized conduction system, ventricles, smooth muscle, endothelium, and mitochondria). We will summarize the lessons learned from available genetic mouse models and address the known roles of KATP channels in cardiovascular pathologies and how genetic variation in KATP channel genes contribute to human disease.

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Left-to-right ventricular differences in IKATP underlie epicardial repolarization gradient during global ischemia

Cited by 32 publications

References 31 publications

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

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

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

K_ATPChannels in the Cardiovascular System

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Left-to-right ventricular differences in IKATP underlie epicardial repolarization gradient during global ischemia

Cited by 32 publications

References 31 publications

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

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

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

KATPChannels in the Cardiovascular System

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K_ATPChannels in the Cardiovascular System