Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models

Fassina, Damiano; Costa, Caroline Mendonça; Bishop, Martin J.; Plank, Gernot; Whitaker, John; Harding, Siân E.; Niederer, Steven

doi:10.1016/j.compbiomed.2023.106550

Cited by 5 publications

(6 citation statements)

References 48 publications

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“…According to Gibbs et al slow-conducting passive scars may reduce the occurrence of spontaneous beats compared to non-conducting scars (Gibbs et al, 2023). Results by Fassina et al, suggest that cells with a CV 20 % or less that of healthy myocardium, like chosen here, may promote arrhythmic events (Fassina et al, 2022, 2023).…”

Section: Discussionmentioning

confidence: 70%

“…Results by Fassina et al, suggest that cells with a CV 20 % or less that of healthy myocardium, like chosen here, may promote arrhythmic events (Fassina et al, 2022(Fassina et al, , 2023.…”

Section: Discussionmentioning

confidence: 71%

“…Human modelling and simulation of cardiac electrophysiology is a mature and well-established technology enabling multiscale investigations into disease mechanisms (Arevalo et al, 2013;Martinez-Navarro et al, 2019;Wang et al, 2021), therapeutic interventions such as ablation (Roney et al, 2020), diagnostics (O'Hara et al, 2022) and pharmacological treatment (Dasí et al, 2022). While several studies have provided insights into specific pro-arrhythmic mechanisms following cell delivery (Fassina et al, 2022(Fassina et al, , 2023Gibbs et al, 2023;Yu et al, 2019Yu et al, , 2021, they so far did not include thorough multi-scale validation from ionic to ECG level, nor did they address crucial factors such as disease progression, scar size and cell heterogeneity caused by differences in differentiation and purification protocols (Ban et al, 2017;Jiang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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In SilicoEvaluation of Cell Therapy in Acute versus Chronic Infarction: Role of Automaticity, Heterogeneity and Purkinje in Human

Riebel,

Wang,

Martinez-Navarro

et al. 2023

Preprint

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Human-based modelling and simulation offer an ideal testbed for novel medical therapies to guide experimental and clinical studies. Myocardial infarction (MI) is a common cause of heart failure and mortality, for which novel therapies are urgently needed. Although cell therapy offers promise, electrophysiological heterogeneity raises pro-arrhythmic safety concerns, where underlying complex spatio-temporal dynamics cannot be investigated experimentally. After demonstrating credibility of the modelling and simulation framework, we investigate cell therapy in acute versus chronic MI, and the role of cell heterogeneity, scar size and the Purkinje system.Simulations agreed with experimental and clinical recordings from ionic to ECG dynamics in acute and chronic infarction. Following cell delivery, spontaneous beats were facilitated by heterogeneity in cell populations, chronic MI due to tissue depolarisation, and slow sinus rhythm. Subsequent re-entrant arrhythmias occurred, in some instances with Purkinje involvement, and their susceptibility was enhanced by impaired Purkinje-myocardium coupling, large scars, and acute infarction.We conclude that homogeneity in injected cell populations minimises their spontaneous beating, which is enhanced by chronic MI, whereas a healthy Purkinje-myocardium coupling is key to prevent subsequent re-entrant arrhythmias, particularly for large scars.

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Section: Discussionmentioning

confidence: 70%

“…Results by Fassina et al, suggest that cells with a CV 20 % or less that of healthy myocardium, like chosen here, may promote arrhythmic events (Fassina et al, 2022(Fassina et al, , 2023.…”

Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In SilicoEvaluation of Cell Therapy in Acute versus Chronic Infarction: Role of Automaticity, Heterogeneity and Purkinje in Human

Riebel,

Wang,

Martinez-Navarro

et al. 2023

Preprint

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“…Emerging practical applications of cardiac models both in drug-safety studies and patient-specific simulations (Dutta et al, 2017a;Boyle et al, 2019;Tomek et al, 2019;Fassina et al, 2023) require an accurate description of ionic channel dynamics. The fast kinetics and high amplitude of sodium current may result in uncontrollable membrane potential during patch-clamp recordings, a challenge that has been a persistent issue for the electrophysiology community for decades.…”

Section: Discussionmentioning

confidence: 99%

Human sodium current voltage-dependence at physiological temperature measured by coupling patch-clamp experiment to a mathematical model

Abrasheva,

Kovalenko,

Slotvitsky

et al. 2023

Preprint

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Voltage-gated sodium channels are crucial to action potential propagation in excitable tissues. Voltage-clamp measurements of sodium current are very challenging and are usually performed at room temperature due to the high amplitude and fast activation of the current. In this study, we measured sodium current's voltage dependence in stem-cell-derived cardiomyocytes at physiological temperature. Although apparent activation and inactivation curves measured as the sodium current amplitude dependence on voltage step is within the range reported in previous studies, we demonstrate a systematic error in our measurements that is due to deviation of membrane potential from the command potential of the amplifier. We show how this artifact can be accounted for by the computer simulation of the patch-clamp experiment. This patch-clamp model optimization technique yields a surprising result: -11.5 mV half-activation and -87 mV half-inactivation of the sodium current. Although the half-activation is strikingly different from what was previously believed to be typical for the cardiac sodium current, we show that this estimate explains conduction velocity dependence on extracellular potassium in hyperkalemic conditions.

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“…Fibroblasts have been shown to exert a negative influence on hiPSC-CMs maturation through both Cx43-mediated cell–cell contacts [ 57 ] and paracrine signalling [ 64 , 65 ]. Electrophysiological heterogeneity at the site of hiPSC-CMs grafts may create a substrate for arrhythmogenic activity [ 10 , 66 ] which can be further exacerbated by the MyoFB induced changes to APD or Ca 2+ decay reported here. Our study identifies druggable pathways that could reduce the risks of cell therapy mediated arrhythmia.…”

Section: Discussionmentioning

confidence: 99%

Human myofibroblasts increase the arrhythmogenic potential of human induced pluripotent stem cell-derived cardiomyocytes

Johnson,

Lei,

McVey

et al. 2023

Cell. Mol. Life Sci.

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Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have the potential to remuscularize infarcted hearts but their arrhythmogenicity remains an obstacle to safe transplantation. Myofibroblasts are the predominant cell-type in the infarcted myocardium but their impact on transplanted hiPSC-CMs remains poorly defined. Here, we investigate the effect of myofibroblasts on hiPSC-CMs electrophysiology and Ca2+ handling using optical mapping of advanced human cell coculture systems mimicking cell–cell interaction modalities. Human myofibroblasts altered the electrophysiology and Ca2+ handling of hiPSC-CMs and downregulated mRNAs encoding voltage channels (KV4.3, KV11.1 and Kir6.2) and SERCA2a calcium pump. Interleukin-6 was elevated in the presence of myofibroblasts and direct stimulation of hiPSC-CMs with exogenous interleukin-6 recapitulated the paracrine effects of myofibroblasts. Blocking interleukin-6 reduced the effects of myofibroblasts only in the absence of physical contact between cell-types. Myofibroblast-specific connexin43 knockdown reduced functional changes in contact cocultures only when combined with interleukin-6 blockade. This provides the first in-depth investigation into how human myofibroblasts modulate hiPSC-CMs function, identifying interleukin-6 and connexin43 as paracrine- and contact-mediators respectively, and highlighting their potential as targets for reducing arrhythmic risk in cardiac cell therapy.

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Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models

Cited by 5 publications

References 48 publications

In SilicoEvaluation of Cell Therapy in Acute versus Chronic Infarction: Role of Automaticity, Heterogeneity and Purkinje in Human

In SilicoEvaluation of Cell Therapy in Acute versus Chronic Infarction: Role of Automaticity, Heterogeneity and Purkinje in Human

Human sodium current voltage-dependence at physiological temperature measured by coupling patch-clamp experiment to a mathematical model

Human myofibroblasts increase the arrhythmogenic potential of human induced pluripotent stem cell-derived cardiomyocytes

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