Small Conductance Calcium-Activated Potassium Current Is Important in Transmural Repolarization of Failing Human Ventricles

Yu, Chih Chieh; Corr, Christopher; Shen, Changyu; Shelton, Richard; Yadava, Mrinal; Rhea, Isaac; Straka, Susan; Fishbein, Michael C.; Chen, Zhenhui; Lin, Shien Fong; Lopshire, John C.; Chen, Peng Sheng

doi:10.1161/circep.114.002296

Cited by 28 publications

(25 citation statements)

References 31 publications

(40 reference statements)

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“…These findings shed light on the underlying mechanisms of cardiac alternans, especially for failing hearts since I SK was shown to be up‐regulated in ventricular myocytes in heart failure (Yu et al . ). In this study, we used a ventricular AP model.…”

Section: Discussionmentioning

confidence: 97%

Dynamical effects of calcium‐sensitive potassium currents on voltage and calcium alternans

Kennedy

Bers

Chiamvimonvat

et al. 2017

The Journal of Physiology

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Cardiac alternans is a precursor to life-threatening arrhythmias. Alternans can be caused by instability of the membrane voltage (V ), instability of the intracellular Ca ( Ca i2+) cycling, or both. V dynamics and Ca i2+ dynamics are coupled via Ca -sensitive currents. In cardiac myocytes, there are several Ca -sensitive potassium (K ) currents such as the slowly activating delayed rectifier current (I ) and the small conductance Ca -activated potassium (SK) current (I ). However, the role of these currents in the development of arrhythmias is not well understood. In this study, we investigated how these currents affect voltage and Ca alternans using a physiologically detailed computational model of the ventricular myocyte and mathematical analysis. We define the coupling between V and Ca i2+ cycling dynamics ( Ca i2+→V coupling) as positive (negative) when a larger Ca transient at a given beat prolongs (shortens) the action potential duration (APD) of that beat. While positive coupling predominates at baseline, increasing I and I promote negative Ca i2+→V coupling at the cellular level. Specifically, when alternans is Ca -driven, electromechanically (APD-Ca ) concordant alternans becomes electromechanically discordant alternans as I or I increase. These cellular level dynamics lead to different types of spatially discordant alternans in tissue. These findings help to shed light on the underlying mechanisms of cardiac alternans especially when the relative strength of these currents becomes larger under pathological conditions or drug administrations.

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Section: Discussionmentioning

confidence: 97%

Dynamical effects of calcium‐sensitive potassium currents on voltage and calcium alternans

Kennedy

Bers

Chiamvimonvat

et al. 2017

The Journal of Physiology

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“…6 With each new study on SK channels, their importance is further demonstrated in arrhythmia vulnerability in both the atria 7 and ventricles. 8 Apamin is a specific blocker of SK currents, and apamin sensitive SK currents ( I KAS ) have been shown to be heterogeneously upregulated within the heart failure substrate in both human studies with transplant hearts, 9, 10 and in animal models of heart failure. 11, 12 This heterogeneity has been observed both transmurally and on the same surface.…”

Section: Introductionmentioning

confidence: 99%

Role of Apamin-Sensitive Calcium-Activated Small-Conductance Potassium Currents on the Mechanisms of Ventricular Fibrillation in Pacing-Induced Failing Rabbit Hearts

Yin

Hsieh

Tsai

et al. 2017

Circ: Arrhythmia and Electrophysiology

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Background Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small conductance calcium activated potassium currents (IKAS) are heterogeneously up-regulated in failing hearts. We hypothesized that IKAS influences the location and stability of rotors during VF. Methods and Results Optical mapping was performed on 9 rabbit hearts with pacing induced heart failure. The epicardial RV and LV were simultaneously mapped in a Langendorff preparation. At baseline and after apamin (100 nmol/L) infusion, the APD80 was determined and VF was induced. Areas with a greater than 50% increase in the maximum APD (ΔAPD) after apamin were considered to have a high IKAS distribution. At baseline, the distribution density of phase singularities (PS) during VF in high IKAS distribution areas was higher than in other areas (0.0035±.0011 vs 0.0014±0.0010 PS/pixel, P=0.004). In addition, high dominant frequencies (DF) also co-localized to high IKAS distribution areas (26.0 vs 17.9 Hz, P=0.003). These correlations were eliminated during VF after apamin infusion, as the number of PS (17.2 versus 11.0, P=0.009), and DFs (22.1 vs 16.2 Hz, P=0.022), were all significantly decreased. In addition, reentrant spiral waves became unstable after apamin infusion and the duration of VF decreased. Conclusions The IKAS current influences the mechanism of VF in failing hearts as PS, high DFs, and reentrant spiral waves all correlated to areas of high IKAS. Apamin eliminated this relationship and reduced VF vulnerability.

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“…Large variations of I KAS densities have also been observed in VMs 8, 15, 35. The mechanisms by which some cells had more I KAS than others remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Small‐Conductance Calcium‐Activated Potassium Current in Normal Rabbit Cardiac Purkinje Cells

Reher

Wang

Hsueh

et al. 2017

JAHA

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BackgroundPurkinje cells (PCs) are important in cardiac arrhythmogenesis. Whether small‐conductance calcium‐activated potassium (SK) channels are present in PCs remains unclear. We tested the hypotheses that subtype 2 SK (SK2) channel proteins and apamin‐sensitive SK currents are abundantly present in PCs.Methods and ResultsWe studied 25 normal rabbit ventricles, including 13 patch‐clamp studies, 4 for Western blotting, and 8 for immunohistochemical staining. Transmembrane action potentials were recorded in current‐clamp mode using the perforated‐patch technique. For PCs, the apamin (100 nmol/L) significantly prolonged action potential duration measured to 80% repolarization by an average of 10.4 ms (95% CI, 0.11–20.72) (n=9, P=0.047). Voltage‐clamp study showed that apamin‐sensitive SK current density was significantly larger in PCs compared with ventricular myocytes at potentials ≥0 mV. Western blotting of SK2 expression showed that the SK2 protein expression in the midmyocardium was 58% (P=0.028) and the epicardium was 50% (P=0.018) of that in the pseudotendons. Immunostaining of SK2 protein showed that PCs stained stronger than ventricular myocytes. Confocal microscope study showed SK2 protein was distributed to the periphery of the PCs.Conclusions SK2 proteins are more abundantly present in the PCs than in the ventricular myocytes of normal rabbit ventricles. Apamin‐sensitive SK current is important in ventricular repolarization of normal PCs.

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Small Conductance Calcium-Activated Potassium Current Is Important in Transmural Repolarization of Failing Human Ventricles

Cited by 28 publications

References 31 publications

Dynamical effects of calcium‐sensitive potassium currents on voltage and calcium alternans

Dynamical effects of calcium‐sensitive potassium currents on voltage and calcium alternans

Role of Apamin-Sensitive Calcium-Activated Small-Conductance Potassium Currents on the Mechanisms of Ventricular Fibrillation in Pacing-Induced Failing Rabbit Hearts

Small‐Conductance Calcium‐Activated Potassium Current in Normal Rabbit Cardiac Purkinje Cells

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