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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Dybkova, N; Ahmad, S; Pabel, S; Tirilomis, P; Hartmann, N; Fischer, TH; Bengel, P; Tirilomis, T; Ljubojevic, S; Renner, A; Gummert, J; Ellenberger, D; Wagner, S; Frey, N; Maier, LS; Streckfuss-Bömeke, K; Hasenfuss, G; Sossalla, S.
Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart.
Cardiovasc Res. 2018; 114(13): 1728-1737. Doi: 10.1093/cvr/cvy152 [OPEN ACCESS]
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Holzer Senka

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In heart failure (HF), enhanced persistent Na+ current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. However, the underlying regulatory mechanisms remain unclear. Our aim was to potentially investigate the regulation and electrophysiological contribution of neuronal sodium channel NaV1.8 in failing human heart and eventually to reveal a novel anti-arrhythmic therapy. By western blot, we found that NaV1.8 protein expression is significantly up-regulated, while of the predominant cardiac isoform NaV1.5 is inversely reduced in human HF. Furthermore, to investigate the relation of NaV1.8 regulation with the cellular proarrhythmic events, we performed comprehensive electrophysiology recordings and explore the effect of NaV1.8 on INaL, action potential duration (APD), Ca2+ spark frequency, and arrhythmia induction in human failing cardiomyocytes. NaV1.8 inhibition with the specific blockers A-803467 and PF-01247324 decreased INaL, abbreviated APD and reduced cellular-spontaneous Ca2+-release and proarrhythmic events in human failing cardiomyocytes. Consistently, in mouse cardiomyocytes stressed with isoproterenol, pharmacologic inhibition and genetically knockout of NaV1.8 (SCN10A-/-), were associated with reduced INaL and abbreviated APD. We provide first evidence of differential regulation of NaV1.8 and NaV1.5 in the failing human myocardium and their contribution to arrhythmogenesis due to generation of INaL. We propose inhibition of NaV1.8 thus constitutes a promising novel approach for selective anti-arrhythmic therapy in HF.

Find related publications in this database (Keywords)
Heart failure
Sodium channels
Late sodium current
SR Ca2+ leak
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