TY - JOUR
T1 - Enhanced late sodium current underlies pro-arrhythmic intracellular sodium and calcium dysregulation in murine sodium channelopathy
AU - Rivaud, Mathilde R.
AU - Baartscheer, Antonius
AU - Verkerk, Arie O.
AU - Beekman, Leander
AU - Rajamani, Sridharan
AU - Belardinelli, Luiz
AU - Bezzina, Connie R.
AU - Remme, Carol Ann
PY - 2018
Y1 - 2018
N2 - Background: Long QT syndrome mutations in the SCN5A gene are associated with an enhanced late sodium current (INa,L) which may lead to pro-arrhythmic action potential prolongation and intracellular calcium dysregulation. We here investigated the dynamic relation between INa,L, intracellular sodium ([Na+]i) and calcium ([Ca2+]i) homeostasis and pro-arrhythmic events in the setting of a SCN5A mutation. Methods and results: Wild-type (WT) and Scn5a1798insD/+ (MUT) mice (age 3–5 months) carrying the murine homolog of the SCN5A-1795insD mutation on two distinct genetic backgrounds (FVB/N and 129P2) were studied. [Na+]i, [Ca2+]i and Ca2+ transient amplitude were significantly increased in 129P2-MUT myocytes as compared to WT, but not in FVB/N-MUT. Accordingly, INa,L wassignificantly more enhanced in 129P2-MUT than in FVB/N-MUT myocytes, consistent with a dose-dependent correlation. Quantitative RT-PCR analysis revealed intrinsic differences in mRNA expression levels of the sodium/potassium pump, the sodium/hydrogen exchanger, and sodium‑calcium exchanger between the two mouse strains. The rate of increase in [Na+]i, [Ca2+]i and Ca2+ transient amplitude following the application of the Na+/K+-ATPase inhibitor ouabain was significantly greater in 129P2-MUT than in 129P2-WT myocytes and was normalized by the INa,L inhibitor ranolazine. Furthermore, ranolazine decreased the incidence of pro-arrhythmic calcium after-transients elicited in 129P2-MUT myocytes. Conclusions: In this study we established a causal link between the magnitude of INa,L, extent of Na+ and Ca2+ dysregulation, and incidence of pro-arrhythmic events in murine Scn5a1798insD/+ myocytes. Furthermore, our findings provide mechanistic insight into the anti-arrhythmic potential of pharmacological inhibition of INa,L in patients with LQT3 syndrome.
AB - Background: Long QT syndrome mutations in the SCN5A gene are associated with an enhanced late sodium current (INa,L) which may lead to pro-arrhythmic action potential prolongation and intracellular calcium dysregulation. We here investigated the dynamic relation between INa,L, intracellular sodium ([Na+]i) and calcium ([Ca2+]i) homeostasis and pro-arrhythmic events in the setting of a SCN5A mutation. Methods and results: Wild-type (WT) and Scn5a1798insD/+ (MUT) mice (age 3–5 months) carrying the murine homolog of the SCN5A-1795insD mutation on two distinct genetic backgrounds (FVB/N and 129P2) were studied. [Na+]i, [Ca2+]i and Ca2+ transient amplitude were significantly increased in 129P2-MUT myocytes as compared to WT, but not in FVB/N-MUT. Accordingly, INa,L wassignificantly more enhanced in 129P2-MUT than in FVB/N-MUT myocytes, consistent with a dose-dependent correlation. Quantitative RT-PCR analysis revealed intrinsic differences in mRNA expression levels of the sodium/potassium pump, the sodium/hydrogen exchanger, and sodium‑calcium exchanger between the two mouse strains. The rate of increase in [Na+]i, [Ca2+]i and Ca2+ transient amplitude following the application of the Na+/K+-ATPase inhibitor ouabain was significantly greater in 129P2-MUT than in 129P2-WT myocytes and was normalized by the INa,L inhibitor ranolazine. Furthermore, ranolazine decreased the incidence of pro-arrhythmic calcium after-transients elicited in 129P2-MUT myocytes. Conclusions: In this study we established a causal link between the magnitude of INa,L, extent of Na+ and Ca2+ dysregulation, and incidence of pro-arrhythmic events in murine Scn5a1798insD/+ myocytes. Furthermore, our findings provide mechanistic insight into the anti-arrhythmic potential of pharmacological inhibition of INa,L in patients with LQT3 syndrome.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85044620508&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29754923
U2 - https://doi.org/10.1016/j.ijcard.2018.03.044
DO - https://doi.org/10.1016/j.ijcard.2018.03.044
M3 - Article
C2 - 29754923
SN - 0167-5273
VL - 263
SP - 54
EP - 62
JO - International journal of cardiology
JF - International journal of cardiology
ER -