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

TY - JOUR

T1 - The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy

AU - Ahmad, Shakil

AU - Tirilomis, Petros

AU - Pabel, Steffen

AU - Dybkova, Nataliya

AU - Hartmann, Nico

AU - Molina, Cristina E.

AU - Tirilomis, Theodoros

AU - Kutschka, Ingo

AU - Frey, Norbert

AU - Maier, Lars S.

AU - Hasenfuss, Gerd

AU - Streckfuss-Bömeke, Katrin

AU - Sossalla, Samuel

N1 - © 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

PY - 2019/2

Y1 - 2019/2

N2 - AIMS: In hypertrophy and heart failure, the proarrhythmic persistent Na + current (I NaL ) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel Na V 1.8 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 Na V 1.8 mRNA (2.34-fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, Na V 1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent I NaL was significantly reduced after addition of novel Na V 1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of Na V 1.8 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)-Ca 2+ leak and SR-Ca 2+ spark frequency after exposure to both Na V 1.8 inhibitors. CONCLUSIONS: We show for the first time that the neuronal sodium channel Na V 1.8 is up-regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of Na V 1.8 reduced augmented I NaL , abbreviated the action potential duration, and decreased the SR-Ca 2+ leak. The findings of our study suggest that Na V 1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.

AB - AIMS: In hypertrophy and heart failure, the proarrhythmic persistent Na + current (I NaL ) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel Na V 1.8 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 Na V 1.8 mRNA (2.34-fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, Na V 1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent I NaL was significantly reduced after addition of novel Na V 1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of Na V 1.8 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)-Ca 2+ leak and SR-Ca 2+ spark frequency after exposure to both Na V 1.8 inhibitors. CONCLUSIONS: We show for the first time that the neuronal sodium channel Na V 1.8 is up-regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of Na V 1.8 reduced augmented I NaL , abbreviated the action potential duration, and decreased the SR-Ca 2+ leak. The findings of our study suggest that Na V 1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.

KW - Left ventricular hypertrophy, Sodium channels, Late sodium current, HFpEF, Arrhythmias, Calcium, SR-Ca2+ leak

KW - Action Potentials

KW - Aged

KW - Blotting, Western

KW - Diastole

KW - Female

KW - Gene Expression Regulation

KW - Heart Ventricles/metabolism

KW - Humans

KW - Hypertrophy, Left Ventricular/diagnosis

KW - Male

KW - Myocytes, Cardiac/metabolism

KW - NAV1.8 Voltage-Gated Sodium Channel/biosynthesis

KW - Patch-Clamp Techniques

KW - RNA/genetics

KW - Real-Time Polymerase Chain Reaction

KW - Sarcoplasmic Reticulum/metabolism

U2 - 10.1002/ehf2.12378

DO - 10.1002/ehf2.12378

M3 - SCORING: Journal article

C2 - 30378291

VL - 6

SP - 154

EP - 163

JO - ESC HEART FAIL

JF - ESC HEART FAIL

SN - 2055-5822

IS - 1

ER -