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. 2023 Jul 17;16(7):dmm049962. doi: 10.1242/dmm.049962

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© 2023. Published by The Company of Biologists Ltd

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Fig. 6. — Multiple perturbations are required to generate arrhythmicity across platforms. (A) Schematic describing the logistic regression analysis approach to identify the mechanisms underlying the generation of DADs in HAMs. Red asterisks indicate the occurrence of DAD. G_Ca, maximal conductance of L-type Ca²⁺ current; G_Kur, maximal conductance of ultra-rapid delayed rectifier K⁺ current; G_Na, maximal conductance of fast Na⁺ current; G_to, maximal conductance of transient outward K⁺ current. (B) Logistic regression analysis of DAD incidence in the context of moderate PLN KD (Kmf 50%) revealed the influence of model parameters on the genesis of DADs in the population of HAMs in response to the pacing–pause protocol. Positive coefficients indicate that increasing the associated parameters promotes DAD production, and vice versa. G_CaB, maximal conductance of background Ca²⁺ current; G_CaP, maximal rate of plasma membrane Ca²⁺ ATPase current; G_ClB, maximal conductance of background Cl⁻ current; G_ClCa, maximal conductance of Ca²⁺-activated Cl⁻ current; G_Kp, maximal conductance of plateau K⁺ current; G_Kr, maximal conductance of rapid delayed rectifier K⁺ current; G_Ks, maximal conductance of slow delayed rectifier K⁺ current; G_K1, maximal conductance of inward rectifier K⁺ current; G_NaB, maximal conductance of background Na⁺ current; V_NaK, maximal pump rate of Na⁺/K⁺ pump current; V_NCX, maximal exchange rate of Na⁺/Ca²⁺ exchange current; V_RyRLeak, maximal rate of ryanodine receptor Ca²⁺ leak; V_RyRRel, maximal rate of ryanodine receptor Ca²⁺ release; V_SERCA, maximal rate of sarcoplasmic reticulum Ca²⁺ ATPase flux. (C) The percentage of irregularly beating (AI>20) ACMs co-cultured with fibroblasts and treated with Isop is increased when transfected with siPLN and siNCX compared to siPLN alone. (D) Representative AP peak trains for siControl, PLN siPLN+siNCX conditions in ACMs co-cultured with fibroblasts and treated with Isop. Arrowheads show examples of irregular beat-to-beat intervals in arrhythmically beating ACMs. (E) Mean SI in response to cardiac KD of the plasma membrane Na⁺/Ca²⁺ exchanger NCX, SclA, and combined SclA+NCX KD. Co-KD caused a greater decrease in SI than did single KD alone (Wilcoxon ranked sum test). (F) Representative M-modes showing the effects of KD on SI. (G) The percentage of irregularly beating (AI>20) ACMs co-cultured with fibroblasts and treated with Isop is decreased with verapamil (30 nM) treatment in comparison to that with DMSO treatment. (H) Representative AP peak trains and AI values for siPLN; siPLN+verapamil (30 nM); siControl conditions in ACMs co-cultured with fibroblasts and treated with Isop. Arrowheads show examples of irregular beat-to-beat intervals in arrhythmically beating ACMs. ****P<0.0001 (KS-D).