Proarrhythmic changes in human cardiomyocytes during hypothermia by milrinone and isoprenaline, but not levosimendan: an experimental in vitro study

Figures

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  Fig. 1. Average action potentials and contraction recordings from DMSO 0.1% treated wells (top) and levosimendan 1 µM treated wells (bottom) at baseline, normothermia (37 °C) and severe hypothermia (26 °C)

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  Fig. 2. A APD30 (ms) for the lowest concentrations of levosimendan (0.1 µM, n = 9), milrinone (1 µM, n = 9) and isoprenaline (0.01 µM, n = 9) during hypothermia and rewarming. B APD30 (ms) for the different levosimendan concentrations (0.1 µM, 1 µM and 10 µM). C APD30 (ms) for the intermediate concentrations of levosimendan (1 µM, n = 9), milrinone (10 µM, n = 9) and isoprenaline (0.1 µM, n = 9) during hypothermia and rewarming. D APD30 (ms) for the different milrinone concentrations (1 µM, 10 µM and 100 µM). E APD30 (ms) for the highest concentrations of levosimendan (10 µM, n = 9), milrinone (100 µM, n = 9) and isoprenaline (1 µM, n = 9) during hypothermia and rewarming. F APD30 (ms) for the different isoprenaline concentrations (0.01 µM, 0.1 µM and 1 µM). A, C, E *Significant differences between levosimendan and DMSO 0.1% (n = 15), #significant difference between milrinone and DMSO 0.1% (n = 15), $significant difference between isoprenaline and DMSO 0.1% (n = 15). B, D, F *Significant difference between lowest and intermediate concentration, #significant difference between lowest and highest concentration, $significant difference between intermediate and highest concentration

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  Fig. 3. A APD90 (ms) for the lowest concentrations of levosimendan (0.1 µM, n = 9), milrinone (1 µM, n = 9) and isoprenaline (0.01 µM, n = 9) during hypothermia and rewarming. B APD90 (ms) for the different levosimendan concentrations (0.1 µM, 1 µM and 10 µM). C APD90 (ms) for the intermediate concentrations of levosimendan (1 µM, n = 9), milrinone (10 µM, n = 9) and isoprenaline (0.1 µM, n = 9) during hypothermia and rewarming. D APD90 (ms) for the different milrinone concentrations (1 µM, 10 µM and 100 µM). E APD90 (ms) for the highest concentrations of levosimendan (10 µM, n = 9), milrinone (100 µM, n = 9) and isoprenaline (1 µM, n = 9) during hypothermia and rewarming. F APD90 (ms) for the different isoprenaline concentrations (0.01 µM, 0.1 µM and 1 µM). A, C, E *Significant differences between levosimendan and DMSO 0.1% (n = 15), #significant difference between milrinone and DMSO 0.1% (n = 15), $significant difference between isoprenaline and DMSO 0.1% (n = 15). B, D, F *Significant difference between lowest and intermediate concentration, #significant difference between lowest and highest concentration, $significant difference between intermediate and highest concentration

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  Fig. 4. A Triangulation ((APD90-APD30)/APD90) for the lowest concentrations of levosimendan (0.1 µM, n = 9), milrinone (1 µM, n = 9) and isoprenaline (0.01 µM, n = 9) during hypothermia and rewarming. B Triangulation ((APD90-APD30)/APD90) for the different levosimendan concentrations (0.1 µM, 1 µM and 10 µM). C Triangulation ((APD90-APD30)/APD90) for the intermediate concentrations of levosimendan (1 µM, n = 9), milrinone (10 µM, n = 9) and isoprenaline (0.1 µM, n = 9) during hypothermia and rewarming. D Triangulation ((APD90-APD30)/APD90) for the different milrinone concentrations (1 µM, 10 µM and 100 µM). E Triangulation ((APD90-APD30)/APD90) for the highest concentrations of levosimendan (10 µM, n = 9), milrinone (100 µM, n = 9) and isoprenaline (1 µM, n = 9) during hypothermia and rewarming. F Triangulation ((APD90-APD30)/APD90) for the different isoprenaline concentrations (0.01 µM, 0.1 µM and 1 µM). A, C, E *Significant differences between levosimendan and DMSO 0.1% (n = 15), #significant difference between milrinone and DMSO 0.1% (n = 15), $significant difference between isoprenaline and DMSO 0.1% (n = 15). B, D, F *Significant difference between lowest and intermediate…

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  Fig. 5. A Upstroke of action potential, Trise (ms), for the lowest concentrations of levosimendan (0.1 µM, n = 9), milrinone (1 µM, n = 9) and isoprenaline (0.01 µM, n = 9) during hypothermia and rewarming. B Upstroke of action potential, Trise (ms), for the different levosimendan concentrations (0.1 µM, 1 µM and 10 µM). C Upstroke of action potential, Trise (ms), for the intermediate concentrations of levosimendan (1 µM, n = 9), milrinone (10 µM, n = 9) and isoprenaline (0.1 µM, n = 9) during hypothermia and rewarming. D Upstroke of action potential, Trise (ms), for the different milrinone concentrations (1 µM, 10 µM and 100 µM). E Upstroke of action potential, Trise (ms), for the highest concentrations of levosimendan (10 µM, n = 9), milrinone (100 µM, n = 9) and isoprenaline (1 µM, n = 9) during hypothermia and rewarming. F Upstroke of action potential, Trise (ms), for the different isoprenaline concentrations (0.01 µM, 0.1 µM and 1 µM). A, C, E *Significant differences between levosimendan and DMSO 0.1% (n = 15), #significant difference between milrinone and DMSO 0.1% (n = 15), $significant difference between isoprenaline and DMSO 0.1% (n = 15). B, D, F *Significant difference…

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  Fig. 6. A Contraction duration, CtD50 (ms), for the lowest concentrations of levosimendan (0.1 µM, n = 9), milrinone (1 µM, n = 9) and isoprenaline (0.01 µM, n = 9) during hypothermia and rewarming. B Contraction duration, CtD50 (ms), for the different levosimendan concentrations (0.1 µM, 1 µM and 10 µM). C Contraction duration, CtD50 (ms), for the intermediate concentrations of levosimendan (1 µM, n = 9), milrinone (10 µM, n = 9) and isoprenaline (0.1 µM, n = 9) during hypothermia and rewarming. D Contraction duration, CtD50 (ms), for the different milrinone concentrations (1 µM, 10 µM and 100 µM). E Contraction duration, CtD50 (ms), for the highest concentrations of levosimendan (10 µM, n = 9), milrinone (100 µM, n = 9) and isoprenaline (1 µM, n = 9) during hypothermia and rewarming. F Contraction duration, CtD50 (ms), for the different isoprenaline concentrations (0.01 µM, 0.1 µM and 1 µM). A, C, E *Significant differences between levosimendan and DMSO 0.1% (n = 15), #significant difference between milrinone and DMSO 0.1% (n = 15), $significant difference between isoprenaline and DMSO 0.1% (n = 15). B, D, F *Significant difference between lowest and intermediate concentration,…

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  Fig. 7. A Contraction rise time, CtTrise (ms), for the lowest concentrations of levosimendan (0.1 µM, n = 9), milrinone (1 µM, n = 9) and isoprenaline (0.01 µM, n = 9) during hypothermia and rewarming. B Contraction rise time, CtTrise (ms), for the different levosimendan concentrations (0.1 µM, 1 µM and 10 µM). C Contraction rise time, CtTrise (ms), for the intermediate concentrations of levosimendan (1 µM, n = 9), milrinone (10 µM, n = 9) and isoprenaline (0.1 µM, n = 9) during hypothermia and rewarming. D Contraction rise time, CtTrise (ms), for the different milrinone concentrations (1 µM, 10 µM and 100 µM). E Contraction rise time, CtTrise (ms), for the highest concentrations of levosimendan (10 µM, n = 9), milrinone (100 µM, n = 9) and isoprenaline (1 µM, n = 9) during hypothermia and rewarming. F Contraction rise time, CtTrise (ms), for the different isoprenaline concentrations (0.01 µM, 0.1 µM and 1 µM). A, C, E *Significant differences between levosimendan and DMSO 0.1% (n = 15), #significant difference between milrinone and DMSO 0.1% (n = 15), $significant difference between isoprenaline and DMSO 0.1% (n = 15). B, D, F *Significant difference between lowest and intermediate…