Mathilde R Rivaud1, Antonius Baartscheer1, Arie O Verkerk2, Leander Beekman1, Sridharan Rajamani3, Luiz Belardinelli3, Connie R Bezzina1, Carol Ann Remme4. 1. Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands. 2. Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands; Department of Medical Biology, Academic Medical Center, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands. 3. Gilead Sciences, 333 Lakeside Drive, CA 94404, Foster City, USA. 4. Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands. Electronic address: c.a.remme@amc.uva.nl.
Abstract
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.
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-arrhythmiccalcium 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.
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