PMID- 33881518 OWN - NLM STAT- MEDLINE DCOM- 20220425 LR - 20221019 IS - 1755-3245 (Electronic) IS - 0008-6363 (Print) IS - 0008-6363 (Linking) VI - 118 IP - 5 DP - 2022 Mar 25 TI - Assessment of arrhythmia mechanism and burden of the infarcted ventricles following remuscularization with pluripotent stem cell-derived cardiomyocyte patches using patient-derived models. PG - 1247-1261 LID - 10.1093/cvr/cvab140 [doi] AB - AIMS: Direct remuscularization with pluripotent stem cell-derived cardiomyocytes (PSC-CMs) seeks to address the onset of heart failure post-myocardial infarction (MI) by treating the persistent muscle deficiency that underlies it. However, direct remuscularization with PSC-CMs could potentially be arrhythmogenic. We investigated two possible mechanisms of arrhythmogenesis-focal vs. re-entrant-arising from direct remuscularization with PSC-CM patches in two personalized, human ventricular computer models of post-MI. Moreover, we developed a principled approach for evaluating arrhythmogenicity of direct remuscularization that factors in the VT propensity of the patient-specific post-MI fibrotic substrate and use it to investigate different conditions of patch remuscularization. METHODS AND RESULTS: Two personalized, human ventricular models of post-MI (P1 and P2) were constructed from late gadolinium enhanced (LGE)-magnetic resonance images (MRIs). In each model, remuscularization with PSC-CM patches was simulated under different treatment conditions that included patch engraftment, patch myofibril orientation, remuscularization site, patch size (thickness and diameter), and patch maturation. To determine arrhythmogenicity of treatment conditions, VT burden of heart models was quantified prior to and after simulated remuscularization and compared. VT burden was quantified based on inducibility (i.e. weighted sum of pacing sites that induced) and severity (i.e. the number of distinct VT morphologies induced). Prior to remuscularization, VT burden was significant in P1 (0.275) and not in P2 (0.0, not VT inducible). We highlight that re-entrant VT mechanisms would dominate over focal mechanisms; spontaneous beats emerging from PSC-CM grafts were always a fraction of resting sinus rate. Moreover, incomplete patch engraftment can be particularly arrhythmogenic, giving rise to particularly aberrant electrical activation and conduction slowing across the PSC-CM patches along with elevated VT burden when compared with complete engraftment. Under conditions of complete patch engraftment, remuscularization was almost always arrhythmogenic in P2 but certain treatment conditions could be anti-arrhythmogenic in P1. Moreover, the remuscularization site was the most important factor affecting VT burden in both P1 and P2. Complete maturation of PSC-CM patches, both ionically and electrotonically, at the appropriate site could completely alleviate VT burden. CONCLUSION: We identified that re-entrant VT would be the primary VT mechanism in patch remuscularization. To evaluate the arrhythmogenicity of remuscularization, we developed a principled approach that factors in the propensity of the patient-specific fibrotic substrate for VT. We showed that arrhythmogenicity is sensitive to the patient-specific fibrotic substrate and remuscularization site. We demonstrate that targeted remuscularization can be safe in the appropriate individual and holds the potential to non-destructively eliminate VT post-MI in addition to addressing muscle deficiency underlying heart failure progression. CI - Published on behalf of the European Society of Cardiology. All rights reserved. (c) The Author(s) 2021. For permissions, please email: journals.permissions@oup.com. FAU - Yu, Joseph K AU - Yu JK AUID- ORCID: 0000-0002-8282-7399 AD - Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. AD - Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. AD - Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. AD - Alliance for Cardiovascular Diagnostic and Treatment Innovation (ADVANCE), Johns Hopkins University, 3400 N Charles Street, 216 Hackerman, Baltimore, MD, USA. FAU - Liang, Jialiu A AU - Liang JA AUID- ORCID: 0000-0003-1475-2353 AD - Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. AD - Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. FAU - Franceschi, William H AU - Franceschi WH AUID- ORCID: 0000-0002-3042-5128 AD - Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. AD - Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. FAU - Huang, Qinwen AU - Huang Q AD - Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. AD - Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. FAU - Pashakhanloo, Farhad AU - Pashakhanloo F AUID- ORCID: 0000-0002-6616-2948 AD - Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. FAU - Sung, Eric AU - Sung E AUID- ORCID: 0000-0001-9918-0133 AD - Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. AD - Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. AD - Alliance for Cardiovascular Diagnostic and Treatment Innovation (ADVANCE), Johns Hopkins University, 3400 N Charles Street, 216 Hackerman, Baltimore, MD, USA. FAU - Boyle, Patrick M AU - Boyle PM AUID- ORCID: 0000-0001-9048-1239 AD - Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. AD - Department of Bioengineering, University of Washington, Seattle, WA, USA. AD - Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA. AD - Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA. FAU - Trayanova, Natalia A AU - Trayanova NA AUID- ORCID: 0000-0002-8661-063X AD - Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA. AD - Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. AD - Alliance for Cardiovascular Diagnostic and Treatment Innovation (ADVANCE), Johns Hopkins University, 3400 N Charles Street, 216 Hackerman, Baltimore, MD, USA. LA - eng GR - T32 GM007057/GM/NIGMS NIH HHS/United States GR - F31 HL152525/HL/NHLBI NIH HHS/United States GR - DP1-HL123271/NH/NIH HHS/United States GR - R01 HL142893/HL/NHLBI NIH HHS/United States GR - R01 HL142496/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Cardiovasc Res JT - Cardiovascular research JID - 0077427 SB - IM MH - Arrhythmias, Cardiac/etiology/therapy MH - *Heart Failure/therapy MH - Heart Ventricles MH - Humans MH - *Myocardial Infarction/pathology MH - Myocytes, Cardiac/pathology MH - *Pluripotent Stem Cells MH - *Tachycardia, Ventricular PMC - PMC8953447 OTO - NOTNLM OT - Cardiac regeneration OT - Cell therapy OT - Heart failure OT - Ischaemic cardiomyopathy OT - Ventricular tachycardia EDAT- 2021/04/22 06:00 MHDA- 2022/04/26 06:00 PMCR- 2022/04/21 CRDT- 2021/04/21 12:18 PHST- 2020/07/06 00:00 [received] PHST- 2021/01/14 00:00 [revised] PHST- 2021/04/19 00:00 [accepted] PHST- 2021/04/22 06:00 [pubmed] PHST- 2022/04/26 06:00 [medline] PHST- 2021/04/21 12:18 [entrez] PHST- 2022/04/21 00:00 [pmc-release] AID - 6243725 [pii] AID - cvab140 [pii] AID - 10.1093/cvr/cvab140 [doi] PST - ppublish SO - Cardiovasc Res. 2022 Mar 25;118(5):1247-1261. doi: 10.1093/cvr/cvab140.