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

Damiano Fassina; Caroline M. Costa; Martin Bishop; Gernot Plank; John Whitaker; Sian E. Harding; Steven A. Niederer

doi:10.1016/j.compbiomed.2023.106550

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

Damiano Fassina^*, Caroline M. Costa, Martin Bishop, Gernot Plank, John Whitaker, Sian E. Harding, Steven A. Niederer

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Background: Post myocardial infarction (MI) ventricles contain fibrotic tissue and may have disrupted electrical properties, both of which predispose to an increased risk of life-threatening arrhythmias. Application of epicardial patches obtained from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a potential long-term therapy to treat heart failure resulting from post MI remodelling. However, whether the introduction of these patches is anti- or pro-arrhythmic has not been studied. Methods: We studied arrhythmic risk using in silico engineered heart tissue (EHT) patch engraftment on human post-MI ventricular models. Two patient models were studied, including one with a large dense scar and one with an apparent channel of preserved viability bordered on both sides by scar. In each heart model a virtual EHT patch was introduced as a layer of viable tissue overlying the scarred area, with hiPSC-CMs electrophysiological properties. The incidence of re-entrant and sustained activation in simulations with and without EHT patches was assessed and the arrhythmia inducibility compared in the context of different EHT patch properties (conduction velocity (CV) and action potential duration (APD)). The impact of the EHT patch on the likelihood of focal ectopic impulse propagation was estimated by assessing the minimum stimulus strength and duration required to generate a propagating impulse in the scar border zone (BZ) with and without patch. Results: We uncovered two main mechanisms by which ventricular tachycardia (VT) risk could be either augmented or attenuated by the interaction of the patch with the tissue. In the case of isthmus-related VT, our simulations predict that EHT patches can prevent the induction of VT when the, generally longer, hiPSC-CMs APD is reduced towards more physiological values. In the case of large dense scar, we found that, an EHT patch with CV similar to the host myocardium does not promote VT, while EHT patches with lower CV increase the risk of VT, by promoting both non-sustained and sustained re-entry. Finally, our simulations indicate that electrically coupled EHT patches reduce the likelihood of propagation of focal ectopic impulses. Conclusions: The introduction of EHT patches as a treatment for heart failure has the potential to augment or attenuate the risk of ventricular arrhythmias, and variations in the anatomic configuration of the substrate, the functional properties of the BZ and the electrophysiologic properties of the patch itself will determine the overall impact. Planning for delivery of this therapy will need to consider the possible impact on arrhythmia.

Original language	English
Article number	106550
Journal	Computers in Biology and Medicine
Volume	154
DOIs	https://doi.org/10.1016/j.compbiomed.2023.106550
Publication status	Published - Mar 2023

Keywords

Cardiac arrhythmias
Cardiac electrophysiology
Cardiac modelling
Engineered heart tissue
Stem cell derived cardiomyocytes

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10.1016/j.compbiomed.2023.106550

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Fassina, D., M. Costa, C., Bishop, M., Plank, G., Whitaker, J., Harding, S. E., & Niederer, S. A. (2023). Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models: In silico engraftment of engineered heart tissue patches. Computers in Biology and Medicine, 154, Article 106550. https://doi.org/10.1016/j.compbiomed.2023.106550

@article{59867a0aa00f40bda3911708598b56be,

title = "Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models: In silico engraftment of engineered heart tissue patches",

abstract = "Background: Post myocardial infarction (MI) ventricles contain fibrotic tissue and may have disrupted electrical properties, both of which predispose to an increased risk of life-threatening arrhythmias. Application of epicardial patches obtained from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a potential long-term therapy to treat heart failure resulting from post MI remodelling. However, whether the introduction of these patches is anti- or pro-arrhythmic has not been studied. Methods: We studied arrhythmic risk using in silico engineered heart tissue (EHT) patch engraftment on human post-MI ventricular models. Two patient models were studied, including one with a large dense scar and one with an apparent channel of preserved viability bordered on both sides by scar. In each heart model a virtual EHT patch was introduced as a layer of viable tissue overlying the scarred area, with hiPSC-CMs electrophysiological properties. The incidence of re-entrant and sustained activation in simulations with and without EHT patches was assessed and the arrhythmia inducibility compared in the context of different EHT patch properties (conduction velocity (CV) and action potential duration (APD)). The impact of the EHT patch on the likelihood of focal ectopic impulse propagation was estimated by assessing the minimum stimulus strength and duration required to generate a propagating impulse in the scar border zone (BZ) with and without patch. Results: We uncovered two main mechanisms by which ventricular tachycardia (VT) risk could be either augmented or attenuated by the interaction of the patch with the tissue. In the case of isthmus-related VT, our simulations predict that EHT patches can prevent the induction of VT when the, generally longer, hiPSC-CMs APD is reduced towards more physiological values. In the case of large dense scar, we found that, an EHT patch with CV similar to the host myocardium does not promote VT, while EHT patches with lower CV increase the risk of VT, by promoting both non-sustained and sustained re-entry. Finally, our simulations indicate that electrically coupled EHT patches reduce the likelihood of propagation of focal ectopic impulses. Conclusions: The introduction of EHT patches as a treatment for heart failure has the potential to augment or attenuate the risk of ventricular arrhythmias, and variations in the anatomic configuration of the substrate, the functional properties of the BZ and the electrophysiologic properties of the patch itself will determine the overall impact. Planning for delivery of this therapy will need to consider the possible impact on arrhythmia.",

keywords = "Cardiac arrhythmias, Cardiac electrophysiology, Cardiac modelling, Engineered heart tissue, Stem cell derived cardiomyocytes",

author = "Damiano Fassina and {M. Costa}, Caroline and Martin Bishop and Gernot Plank and John Whitaker and Harding, {Sian E.} and Niederer, {Steven A.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = mar,

doi = "10.1016/j.compbiomed.2023.106550",

language = "English",

volume = "154",

journal = "Computers in Biology and Medicine",

issn = "0010-4825",

publisher = "Elsevier Limited",

}

Fassina, D, M. Costa, C, Bishop, M, Plank, G, Whitaker, J, Harding, SE & Niederer, SA 2023, 'Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models: In silico engraftment of engineered heart tissue patches', Computers in Biology and Medicine, vol. 154, 106550. https://doi.org/10.1016/j.compbiomed.2023.106550

Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models: In silico engraftment of engineered heart tissue patches. / Fassina, Damiano; M. Costa, Caroline; Bishop, Martin et al.
In: Computers in Biology and Medicine, Vol. 154, 106550, 03.2023.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models

T2 - In silico engraftment of engineered heart tissue patches

AU - Fassina, Damiano

AU - M. Costa, Caroline

AU - Bishop, Martin

AU - Plank, Gernot

AU - Whitaker, John

AU - Harding, Sian E.

AU - Niederer, Steven A.

PY - 2023/3

Y1 - 2023/3

N2 - Background: Post myocardial infarction (MI) ventricles contain fibrotic tissue and may have disrupted electrical properties, both of which predispose to an increased risk of life-threatening arrhythmias. Application of epicardial patches obtained from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a potential long-term therapy to treat heart failure resulting from post MI remodelling. However, whether the introduction of these patches is anti- or pro-arrhythmic has not been studied. Methods: We studied arrhythmic risk using in silico engineered heart tissue (EHT) patch engraftment on human post-MI ventricular models. Two patient models were studied, including one with a large dense scar and one with an apparent channel of preserved viability bordered on both sides by scar. In each heart model a virtual EHT patch was introduced as a layer of viable tissue overlying the scarred area, with hiPSC-CMs electrophysiological properties. The incidence of re-entrant and sustained activation in simulations with and without EHT patches was assessed and the arrhythmia inducibility compared in the context of different EHT patch properties (conduction velocity (CV) and action potential duration (APD)). The impact of the EHT patch on the likelihood of focal ectopic impulse propagation was estimated by assessing the minimum stimulus strength and duration required to generate a propagating impulse in the scar border zone (BZ) with and without patch. Results: We uncovered two main mechanisms by which ventricular tachycardia (VT) risk could be either augmented or attenuated by the interaction of the patch with the tissue. In the case of isthmus-related VT, our simulations predict that EHT patches can prevent the induction of VT when the, generally longer, hiPSC-CMs APD is reduced towards more physiological values. In the case of large dense scar, we found that, an EHT patch with CV similar to the host myocardium does not promote VT, while EHT patches with lower CV increase the risk of VT, by promoting both non-sustained and sustained re-entry. Finally, our simulations indicate that electrically coupled EHT patches reduce the likelihood of propagation of focal ectopic impulses. Conclusions: The introduction of EHT patches as a treatment for heart failure has the potential to augment or attenuate the risk of ventricular arrhythmias, and variations in the anatomic configuration of the substrate, the functional properties of the BZ and the electrophysiologic properties of the patch itself will determine the overall impact. Planning for delivery of this therapy will need to consider the possible impact on arrhythmia.

AB - Background: Post myocardial infarction (MI) ventricles contain fibrotic tissue and may have disrupted electrical properties, both of which predispose to an increased risk of life-threatening arrhythmias. Application of epicardial patches obtained from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a potential long-term therapy to treat heart failure resulting from post MI remodelling. However, whether the introduction of these patches is anti- or pro-arrhythmic has not been studied. Methods: We studied arrhythmic risk using in silico engineered heart tissue (EHT) patch engraftment on human post-MI ventricular models. Two patient models were studied, including one with a large dense scar and one with an apparent channel of preserved viability bordered on both sides by scar. In each heart model a virtual EHT patch was introduced as a layer of viable tissue overlying the scarred area, with hiPSC-CMs electrophysiological properties. The incidence of re-entrant and sustained activation in simulations with and without EHT patches was assessed and the arrhythmia inducibility compared in the context of different EHT patch properties (conduction velocity (CV) and action potential duration (APD)). The impact of the EHT patch on the likelihood of focal ectopic impulse propagation was estimated by assessing the minimum stimulus strength and duration required to generate a propagating impulse in the scar border zone (BZ) with and without patch. Results: We uncovered two main mechanisms by which ventricular tachycardia (VT) risk could be either augmented or attenuated by the interaction of the patch with the tissue. In the case of isthmus-related VT, our simulations predict that EHT patches can prevent the induction of VT when the, generally longer, hiPSC-CMs APD is reduced towards more physiological values. In the case of large dense scar, we found that, an EHT patch with CV similar to the host myocardium does not promote VT, while EHT patches with lower CV increase the risk of VT, by promoting both non-sustained and sustained re-entry. Finally, our simulations indicate that electrically coupled EHT patches reduce the likelihood of propagation of focal ectopic impulses. Conclusions: The introduction of EHT patches as a treatment for heart failure has the potential to augment or attenuate the risk of ventricular arrhythmias, and variations in the anatomic configuration of the substrate, the functional properties of the BZ and the electrophysiologic properties of the patch itself will determine the overall impact. Planning for delivery of this therapy will need to consider the possible impact on arrhythmia.

KW - Cardiac arrhythmias

KW - Cardiac electrophysiology

KW - Cardiac modelling

KW - Engineered heart tissue

KW - Stem cell derived cardiomyocytes

UR - http://www.scopus.com/inward/record.url?scp=85146692921&partnerID=8YFLogxK

U2 - 10.1016/j.compbiomed.2023.106550

DO - 10.1016/j.compbiomed.2023.106550

M3 - Article

C2 - 36701966

AN - SCOPUS:85146692921

SN - 0010-4825

VL - 154

JO - Computers in Biology and Medicine

JF - Computers in Biology and Medicine

M1 - 106550

ER -

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

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