The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy

2019 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy​
Ahmad, S. ; Tirilomis, P.; Pabel, S. ; Dybkova, N.; Hartmann, N. ; Molina, C. E.   & Tirilomis, T.  et al.​ (2019) 
ESC Heart Failure6(1) pp. 154​-163​.​ DOI: https://doi.org/10.1002/ehf2.12378 

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Authors
Ahmad, Shakil ; Tirilomis, Petros; Pabel, Steffen ; Dybkova, Nataliya; Hartmann, Nico ; Molina, Cristina E. ; Tirilomis, Theodoros ; Kutschka, Ingo ; Frey, Norbert; Maier, Lars S. ; Hasenfuss, Gerd ; Streckfuss-Bömeke, Katrin ; Sossalla, Samuel 
Abstract
Aims In hypertrophy and heart failure, the proarrhythmic persistent Na+ current (INaL) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel NaV1.8 in human hypertrophied myocardium. Methods and results Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload-induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real-time PCR and western blot and detected a significant up-regulation of NaV1.8 mRNA (2.34fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, NaV1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent INaL was significantly reduced after addition of novel NaV1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of NaV1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)-Ca2+ leak and SR-Ca2+ spark frequency after exposure to both NaV1.8 inhibitors.
Issue Date
2019
Journal
ESC Heart Failure 
Project
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur 
Working Group
RG Hasenfuß (Transition zur Herzinsuffizienz) 
RG L. Maier (Experimentelle Kardiologie) 
RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung) 
Language
English

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