Nataliya Dybkova1, Shakil Ahmad1,2, Steffen Pabel1,2, Petros Tirilomis1, Nico Hartmann1, Thomas H Fischer1, Philipp Bengel1, Theodoros Tirilomis3, Senka Ljubojevic4, André Renner5, Jan Gummert5, David Ellenberger6, Stefan Wagner2, Norbert Frey7, Lars S Maier2, Katrin Streckfuss-Bömeke1, Gerd Hasenfuss1, Samuel Sossalla1,2. 1. Clinic for Cardiology & Pneumology, Georg-August University Goettingen, DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Germany. 2. Department of Internal Medicine II, University Medical Center Regensburg, Germany. 3. Department of Thoracic, Cardiac and Vascular Surgery, Georg-August University Goettingen, Germany. 4. Department of Cardiology, Medical University of Graz, Austria. 5. Department of Thoracic, Cardiac and Vascular Surgery (Heart and Diabetes Center), North Rhine Westphalia, Bad Oeynhausen, Germany. 6. Department of Medical Statistics, University Medical Center Goettingen, Germany. 7. Department of Internal Medicine III, Molecular Cardiology and Angiology, University Medical Center, Campus Kiel, Schleswig-Holstein, Germany.
Abstract
Aims: 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. Methods and results: 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. Conclusion: 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.
Aims: 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. Methods and results: 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. Conclusion: 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.
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