Introduction SCN5a + gain-of-function 23 loss-of-function 1 2 31 33 22 24 7 39 38 12 30 2 3 42 20 46 3 13 27 42 3 2 29 21 33 38 39 42 14 17 19 28 40 11 25 43 44 11 26 32 45 34 15 34 36 Scn5a+/Δ 13 Scn5a+/− 29 Materials and methods Experimental animals Scn5a+/Δ Scn5a+/− Solutions 3 2 4 2 2 2 2 9 Preparation 4 10 Electrophysiological measurements 8 Experimental protocol 16 extrasystolic stimulation protocol 37 Scn5a+/Δ Scn5a+/− 13 38 dynamic pacing protocol 17 Data analysis P Results Scn5a+/Δ Scn5a+/− 6 Scn5a+/Δ Scn5a+/− 1 2 1 2 Scn5a+/Δ 1 2 Scn5a+/− 1 2 1 2 Fig. 1 a Scn5a+/Δ b Scn5a+/− c A B C D  Fig. 2 Scn5a+/Δ Scn5a+/− a Scn5a+/Δ b Scn5a+/− c A B C D Hashing dots  2 Scn5a+/Δ 2 Scn5a+/− 2 1 2 2 Scn5a+/Δ 2 Scn5a+/− 2 Graphical analyses of arrhythmogenic tendency 90 17 90 90 90 17 25 28 43 Relationships between epicardial and endocardial action potential durations are not consistently associated with either the presence or absence of arrhythmogenicity 90 Scn5a+/Δ 42 Scn5a+/− 90 90 3 34 3 90 34 y ax 2 bx c a b c χ 2 y mx c χ 2 F N \documentclass[12pt]{minimal}
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\begin{document}$$ F_{\chi }  = N{\left( {\frac{{\chi _{2} ^{2}  - \chi _{3} ^{2} }} {{\chi _{3} ^{2} }}} \right)} $$\end{document} 5 F 34 Fig. 3 90 a Scn5a+/Δ b Scn5a+/− c A B C D Broken lines y ax 2 bx c  3 34 3 in parallel with 2 Scn5a+/Δ 3 in contrast with 2 3 2 3 2 3 Scn5a+/− 3 2 3 2 3 2 Alterations in the slopes of restitution curves correlate with the presence and absence of arrhythmic activity 90 4 5 4 5 Scn5a+/Δ 4 5 Scn5a+/− 4 5 90 Fig. 4 90 circles a Scn5a+/Δ b Scn5a+/− c A B C D 90 solid lines left ordinates broken lines right axes Shaded boxes  Fig. 5 90 squares a Scn5a+/Δ b Scn5a+/− c A B C D 90 solid lines left ordinates broken lines right axes Shaded boxes  Restitution curves yield parameters predictive of arrhythmogenicity 28 1 \documentclass[12pt]{minimal}
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\begin{document}$$y = y_{0}  + A{\left( {1 - e^{{{ - x} \mathord{\left/ {\vphantom {{ - x} \tau }} \right. \kern-\nulldelimiterspace} \tau }} } \right)}$$\end{document} y 90 x y 0 A τ 90 χ 2 1 2 P 3 4 2 \documentclass[12pt]{minimal}
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\begin{document}$$ \frac{{dy}} {{dx}} = \frac{A} {\tau } \cdot e^{{ - x/\tau }}  $$\end{document} Table 1 Fit parameters for epicardial restitution curves Condition y 0 A τ χ 2 WT (6 hearts) 1.6 ± 4.4 56.2 ± 2.4 58.4 ± 9.8 1.4 WT + flecainide (5 hearts) −16.3 ± 9.4 104.7 ± 7.1 82.8 ± 28.0 5.9 WT + 1 μM quinidine (6 hearts) −38.3 ± 17.4 92.4 ± 14.7 45.1 ± 9.4 2.5 WT + 10 μM quinidine (6 hearts) −863.0 ± 1,387.1 981.6 ± 1,369.1 27.1 ± 15.9 113.3 Scn5a+/Δ −19.6 ± 7.2 90.0 ± 4.4 53.1 ± 10.7 14.0 Scn5a+/Δ −16.1 ± 6.5 82.2 ± 12.3 95.3 ± 42.1 3.5 Scn5a+/Δ −677.1 ± 306.1 748.0 ± 304.7 15.2 ± 2.2 10.0 Scn5a+/− −674.8 ± 329.9 729.4 ± 329.1 14.2 ± 2.1 8.4 Scn5a+/− −56,359.8 ± 2,559.7 52,677.3 ± 2.2 7.8 ± 2.5 14.8 Scn5a+/− −118.3 ± 57.4 202.5 ± 49.4 36.4 ± 10.5 16.7 Scn5a+/− −1.7 ± 44.7 131.9 ± 62.3 158.4 ± 262.2 10.8 \documentclass[12pt]{minimal}
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\begin{document}$$y = y_{0}  + A{\left( {1 - e^{{{ - x} \mathord{\left/ {\vphantom {{ - x} \tau }} \right. \kern-\nulldelimiterspace} \tau }} } \right)}$$\end{document} Table 2 Fit parameters for endocardial restitution curves Condition y 0 A τ χ 2 WT (6 hearts) −11.8 ± 3.7 73.8 ± 1.7 65.2 ± 8.4 1.2 WT + flecainide (5 hearts) −769.0 ± 244.1 827.3 ± 243.7 14.5 ± 1.3 1.4 WT + 1 μM quinidine (6 hearts) −65.8 ± 100.4 113.5 ± 98.3 24.9 ± 12.0 11.7 WT + 10 μM quinidine (6 hearts) −41.9 ± 71.5 78.2 ± 68.7 32.8 ± 19.3 13.6 Scn5a+/Δ −31.9 ± 9.0 109.9 ± 5.1 49.6 ± 9.0 10.3 Scn5a+/Δ −561.1 ± 1.2 631.6 ± 15.1 18.7 ± 0.3 6.7 Scn5a+/Δ −499.7 ± 143.8 563.0 ± 142.9 16.3 ± 1.6 56.0 Scn5a+/− −281.7 ± 9.8 43.5 ± 6.4 48.5 ± 19.0 4.3 Scn5a+/− −1,050.6 ± 1,558.5 1,100.1 ± 1,557.8 11.7 ± 4.0 10.0 Scn5a+/− −261.2 ± 117.9 350.5 ± 107.8 34.2 ± 9.3 21.7 Scn5a+/− −220.1 ± 322.0 319.1 ± 316.8 26.2 ± 12.7 45.5 \documentclass[12pt]{minimal}
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\begin{document}$$y = y_{0}  + A{\left( {1 - e^{{{ - x} \mathord{\left/ {\vphantom {{ - x} \tau }} \right. \kern-\nulldelimiterspace} \tau }} } \right)}$$\end{document} Table 3 Fit parameters for endocardial restitution curves separating successive odd- and even-numbered action potentials Condition Odd Even y 0 A τ χ 2 y 0 A τ χ 2 WT (6 hearts) 13.4 ± 7.6 40.5 ± 12.9 50.3 ± 21.4 6.3 8.1 ± 11.2 58.3 ± 25.4 48.2 ± 32.3 4.6 WT + flecainide (5 hearts) −14.7 ± 8.9 105.2 ± 9.0 88.0 ± 31.3 5.8 −44.6 ± 18.5 117.4 ± 14.2 49.0 ± 9.9 1.5 WT + 1 μM quinidine (6 hearts) −20.6 ± 9.9 75.8 ± 6.2 56.4 ± 13.2 3.8 −34.2 ± 11.7 89.2 ± 9.3 45.9 ± 7.8 3.3 WT + 10 μM quinidine (6 hearts) −1,391.7 ± 3,195.9 1,496.0 ± 3,182.0 21.1 ± 14.3 117.9 −393.1 ± 5.3.0 532.8 ± 481.7 41.1 ± 27.6 115.7 Scn5a+/Δ −23.9 ± 8.3 92.0 ± 5.3 47.8 ± 9.0 12.4 −24.4 ± 8.6 92.6 ± 5.6 47.6 ± 8.9 11.8 Scn5a+/Δ 14.6 ± 6.3 77.1 ± 8.4 84.1 ± 32.2 3.4 −33.2 ± 46.4 110.1 ± 41.9 36.4 ± 13.1 2.0 Scn5a+/Δ −250.2 ± 12.8 483.0 ± 24.5 18.8 ± 7.8 12.4 −254.7 ± 321.2 328.1 ± 318.3 20.0 ± 7.7 5.3 Scn5a+/− −850.4 ± 282.7 904.2 ± 282.1 13.5 ± 1.3 4.3 −913.3 ± 283.3 968.6 ± 282.7 13.7 ± 1.2 3.7 Scn5a+/− −1,473.8 ± 3,144.5 1,534.3 ± 2,141.2 14.7 ± 7.6 34.3 −2,108.8 ± 4,489.9 2,171.3 ± 4,486.8 14.0 ± 6.7 35.0 Scn5a+/− −46.8 ± 51.2 146.8 ± 21.3 59.5 ± 43.5 9.4 −46.7 ± 50.6 149.2 ± 20.2 61.0 ± 44.2 9.3 Scn5a+/− 7.3 ± 34.2 167.7 ± 264.8 272.8 ± 78.3 10.8 2.8 ± 44.6 143.1 ± 121.3 192.2 ± 405.8 12.0 \documentclass[12pt]{minimal}
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\begin{document}$$y = y_{0}  + A{\left( {1 - e^{{{ - x} \mathord{\left/ {\vphantom {{ - x} \tau }} \right. \kern-\nulldelimiterspace} \tau }} } \right)}$$\end{document} Table 4 Fit parameters for endocardial restitution curves separating successive odd- and even-numbered action potentials Condition Odd Even y 0 A τ χ 2 y 0 A τ χ 2 WT (6 hearts) −17.4 ± 5.3 73.8 ± 2.8 67.3 ± 13.5 4.7 −38.9 ± 15.4 91.6 ± 13.0 46.5 ± 8.5 1.8 WT + flecainide (5 hearts) −49.2 ± 26.2 113.8 ± 23.0 35.7 ± 8.2 7.6 −367.3 ± 171.3 426.9 ± 170.6 17.7 ± 2.4 1.3 WT + 1 μM quinidine (6 hearts) −393.2 ± 368.6 437.7 ± 368.6 14.9 ± 4.3 18.1 −1,337.3 ± 1,206.4 1,384.5 ± 1,205.7 11.5 ± 2.5 14.7 WT + 10 μM quinidine (6 hearts) −17.7 + −39.0 53.2 ± 35.0 42.6 ± 28.9 11.2 −28.0 ± 62.7 66.6 ± 58.2 39.6 ± 29.7 17.3 Scn5a+/Δ −149.6 ± 131.4 221.0 ± 128.6 26.4 ± 7.6 0.9 −42.3 ± 10.5 115.3 ± 8.2 40.8 ± 5.0 2.6 Scn5a+/Δ −1,133.8 ± 784.2 1,201.4 ± 783.1 15.2 ± 2.6 2.0 −2,164.0 ± 1,195.7 2,233.3 ± 1,195.0 13.6 ± 1.6 1.4 Scn5a+/Δ −2,720.4 ± 3,917.8 2,779.7 ± 3,917.2 10.4 ± 2.8 3.4 −3,527.2 ± 4,674.78 3,603.0 ± 4,674.1 11.1 ± 2.7 3.9 Scn5a+/− −134.6 ± 28.9 195.3 ± 28.0 22.8 ± 2.1 3.3 −149.1 ± 33.5 212.0 ± 32.6 22.9 ± 2.2 3.6 Scn5a+/− −13.8 ± 29.2 66.2 ± 27.1 32.5 ± 11.1 1.8 −55.4 ± 55.5 108.6 ± 54.6 23.6 ± 5.9 1.2 Scn5a+/− −1,979.9 ± 1,709.0 2,051.5 ± 1,704.6 15.9 ± 2.8 13.4 −108.4 ± 15,101.8 10,911.4 ± 15,098.3 11.8 ± 3.0 14.8 Scn5a+/− −332.1 ± 447.2 431.4 ± 439.8 25.2 ± 12.7 116.0 −160.0 ± 289.5 262.2 ± 281.9 20.1 ± 18.1 48.1 \documentclass[12pt]{minimal}
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\begin{document}$$y = y_{0}  + A{\left( {1 - e^{{{ - x} \mathord{\left/ {\vphantom {{ - x} \tau }} \right. \kern-\nulldelimiterspace} \tau }} } \right)}$$\end{document} 4 5 1 1 2 2 25 3 \documentclass[12pt]{minimal}
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\begin{document}$$ {\text{critical}} \,{\text{DI}} =  - \tau  \cdot \ln {\left( {\frac{\tau } {A}} \right)} $$\end{document} 6 A τ 90 in complete agreement Fig. 6 filled bars open bars 4 5 a Scn5a+/Δ b Scn5a+/− c A B C D Asterisks P  6 P 5 2 6 P 2 6 P 2 paralleled Scn5a+/Δ 6 P 2 6 2 23 6 P P 2 6 P 2 33 Scn5a+/Δ Scn5a+/− 6 P 1 2 6 2 Thus, while relationships between epicardial and endocardial action potential durations obtained over a range of cycle lengths are poorly correlated with arrhythmogenicity, restitution curves are, in general, predictive of arrhythmogenicity under the genetic and pharmacological conditions studied. Discussion 3 SCN5a + 1 23 Scn5a+/Δ 13 Scn5a+/− 29 39 38 90 34 at a single Scn5a+/Δ 42 90 34 34 Scn5a+/Δ Scn5a+/− Scn5a+/Δ all Scn5a+/− on increased failed pro did anti 90 14 17 19 28 40 45 any any 32 any Scn5a+/Δ Scn5a+/− Scn5a+/Δ Scn5a+/− Scn5a+/Δ Scn5a+/− 32 Scn5a + 28 40 41