Dybkova, Nataliya and Ahmad, Shakil and Pabel, Steffen and Tirilomis, Petros and Hartmann, Nico and Fischer, Thomas H. and Bengel, Philipp and Tirilomis, Theodoros and Ljubojevic, Senka and Renner, Andre and Gummert, Jan and Ellenberger, David and Wagner, Stefan and Frey, Norbert and Maier, Lars S. and Streckfuss-Boemeke, Katrin and Hasenfuss, Gerd and Sossalla, Samuel (2018) Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart. CARDIOVASCULAR RESEARCH, 114 (13). pp. 1728-1737. ISSN 0008-6363, 1755-3245
Full text not available from this repository. (Request a copy)Abstract
Aims In heart failure (HF), enhanced persistent Na+ current (I-NaL) 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 Na(V)1.8 in failing human heart and eventually to reveal a novel anti-arrhythmic therapy Methods and results By western blot, we found that Na(V)1.8 protein expression is significantly up-regulated, while of the predominant cardiac isoform Na(V)1.5 is inversely reduced in human HF. Furthermore, to investigate the relation of Na(V)1.8 regulation with the cellular proarrhythmic events, we performed comprehensive electrophysiology recordings and explore the effect of Na(V)1.8 on I-NaL, action potential duration (APD), Ca2+ spark frequency, and arrhythmia induction in human failing cardiomyocytes. Na(V)1.8 inhibition with the specific blockers A-803467 and PF-01247324 decreased I-NaL, 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 Na(V)1.8 (SCN10A(-/-)), were associated with reduced I-NaL and abbreviated APD Conclusion We provide first evidence of differential regulation of Na(V)1.8 and Na(V)1.5 in the failing human myocardium and their contribution to arrhythmogenesis due to generation of I-NaL. We propose inhibition of Na(V)1.8 thus constitutes a promising novel approach for selective anti-arrhythmic therapy in HF.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-KINASE-II; VENTRICULAR MYOCYTES; COMMON VARIANTS; FAILURE; DYSFUNCTION; RANOLAZINE; EXPRESSION; NA(V)1.8; BLOCKER; LEAK; Heart failure; Sodium channels; Late sodium current; Arrhythmias; Calcium; SR Ca2+ leak |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 Oct 2019 07:12 |
| Last Modified: | 10 Oct 2019 07:12 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13570 |
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