Using Nanosecond Shocks for Cardiac Defibrillation

Neuber, J.; Varghese, Frency; Pakhomov, Andrei G.; Zemlin, Christian W.

doi:10.1089/bioe.2019.0030

Cited by 15 publications

(9 citation statements)

References 61 publications

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“…Observing the non-steady-state transient kinetic regimes is beyond the time resolution of most experiments. As such, our model has the advantage of characterizing the transient initial kinetic regime, which should be important when exposing cells to increasingly used pulses with duration in the (sub)nanosecond range ( Pakhomov and Pakhomova, 2020 ; Neuber et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of electroporation sites in the complex lipid organization of the plasma membrane

Rems

Tang

Zhao

et al. 2022

eLife

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The plasma membrane of a biological cell is a complex assembly of lipids and membrane proteins, which tightly regulate transmembrane transport. When a cell is exposed to strong electric field, the membrane integrity becomes transiently disrupted by formation of transmembrane pores. This phenomenon termed electroporation is already utilized in many rapidly developing applications in medicine including gene therapy, cancer treatment, and treatment of cardiac arrythmias. However, the molecular mechanisms of electroporation are not yet sufficiently well understood; in particular, it is unclear where exactly pores form in the complex organization of the plasma membrane. In this study we combine coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis to identify how formation of pores depends on the local lipid organization. We show that pores do not form homogeneously across the membrane, but colocalize with domains that have specific features, the most important being high density of polyunsaturated lipids. We further show that knowing the lipid organization is sufficient to reliably predict poration sites with machine learning. Additionally, by analysing poration kinetics with Bayesian survival analysis we show that poration does not depend solely on local lipid arrangement, but also on membrane mechanical properties and the polarity of the electric field. Finally, we discuss how the combination of atomistic and coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis can guide the design of future experiments and help us to develop an accurate description of plasma membrane electroporation on the whole-cell level. Achieving this will allow us to shift the optimization of electroporation applications from blind trial-and-error approaches to mechanistic-driven design.

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Section: Discussionmentioning

confidence: 99%

Identification of electroporation sites in the complex lipid organization of the plasma membrane

Rems

Tang

Zhao

et al. 2022

eLife

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“…However, even for 200 ns shocks, there was still significant PI uptake, and repeat excitation of cardiomyocytes at the stimulation threshold using nanosecond shocks is not possible without electroporative damage. It should be noted that in whole hearts, the defibrillation threshold is almost 6 times higher than the stimulation threshold for 300 ns [9,28]. Thus, for whole heart experiments, there must be other factors at play that cause the safety factors of 300 ns and 10 ms to be similar and much greater than one.…”

Section: Comparison To Earlier Results On Electroporation With Millisecond Pulsesmentioning

confidence: 98%

Electroporation safety factor of 300 nanosecond and 10 millisecond defibrillation in Langendorff-perfused rabbit hearts

2021

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Aims Recently, a new defibrillation modality using nanosecond pulses was shown to be effective at much lower energies than conventional 10 millisecond monophasic shocks in ex vivo experiments. Here we compare the safety factors of 300 nanosecond and 10 millisecond shocks to assess the safety of nanosecond defibrillation. Methods and results The safety factor, i.e. the ratio of median effective doses (ED50) for electroporative damage and defibrillation, was assessed for nanosecond and conventional (millisecond) defibrillation shocks in Langendorff-perfused New Zealand white rabbit hearts. In order to allow for multiple shock applications in a single heart, a pair of needle electrodes was used to apply shocks of varying voltage. Propidium iodide (PI) staining at the surface of the heart showed that nanosecond shocks had a slightly lower safety factor (6.50) than millisecond shocks (8.69), p = 0.02; while PI staining cross-sections in the electrode plane showed no significant difference (5.38 for 300 ns shocks and 6.29 for 10 ms shocks, p = 0.22). Conclusions In Langendorff-perfused rabbit hearts, nanosecond defibrillation has a similar safety factor as millisecond defibrillation, between 5 and 9, suggesting that nanosecond defibrillation can be performed safely.

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“…Observing the non-steady state transient kinetic regimes is beyond the time resolution of most experiments. As such, our model has the advantage of characterizing the transient initial kinetic regime, which should be important when exposing cells to increasingly-used pulses with duration in the (sub)nanosecond range (63, 64).…”

Section: Discussionmentioning

confidence: 99%

“…As such, our model has the advantage of characterizing the transient initial kinetic regime, which should be important when exposing cells to increasingly-used pulses with duration in the (sub)nanosecond range (63,64).…”

Section: Electroporation Kineticsmentioning

confidence: 99%

Identification of electroporation sites in the complex lipid organization of the plasma membrane

Rems

Tang

Zhao

et al. 2021

Preprint

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The plasma membrane of a biological cell is a complex assembly of lipids and membrane proteins, which tightly regulate transmembrane transport. When a cell is exposed to a strong electric field, the membrane integrity becomes transiently disrupted by formation of transmembrane pores. This phenomenon, termed electroporation, is already utilized in many rapidly developing applications in medicine including gene therapy, cancer treatment, and treatment of cardiac arrythmias. However, the molecular mechanisms of electroporation are not yet sufficiently well understood; in particular, it is unclear where exactly pores form in the complex organization of the plasma membrane. In this study we combine coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis to identify how formation of pores depends on the local lipid organization. We show that pores do not form homogeneously across the membrane, but colocalize with domains that have specific features, the most important being high density of polyunsaturated lipids. We further show that knowing the lipid organization is sufficient to reliably predict poration sites with machine learning. However, by analysing poration kinetics with Bayesian survival analysis we then show that poration does not depend solely on local lipid arrangement, but also on membrane mechanical properties and the polarity of the electric field. Finally, we discuss how the combination of atomistic and coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis can guide the design of future experiments and help us to develop an accurate description of plasma membrane electroporation on the whole-cell level. Achieving this will allow us to shift the optimization of electroporation applications from blind trial-and-error approaches to mechanistic-driven design.

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Using Nanosecond Shocks for Cardiac Defibrillation

Cited by 15 publications

References 61 publications

Identification of electroporation sites in the complex lipid organization of the plasma membrane

Identification of electroporation sites in the complex lipid organization of the plasma membrane

Electroporation safety factor of 300 nanosecond and 10 millisecond defibrillation in Langendorff-perfused rabbit hearts

Identification of electroporation sites in the complex lipid organization of the plasma membrane

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