Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue
BACKGROUND: Modeling of human arrhythmias with induced pluripotent stem cell-derived cardiomyocytes has focused on single-cell phenotypes. However, arrhythmias are the emergent properties of cells assembled into tissues, and the impact of inherited arrhythmia mutations on tissue-level properties of human heart tissue has not been reported.
METHODS: Here, we report an optogenetically based, human engineered tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia caused by mutation of the cardiac ryanodine channel and triggered by exercise. We developed a human induced pluripotent stem cell-derived cardiomyocyte-based platform to study the tissue-level properties of engineered human myocardium. We investigated pathogenic mechanisms in CPVT by combining this novel platform with genome editing.
RESULTS: In our model, CPVT tissues were vulnerable to developing reentrant rhythms when stimulated by rapid pacing and catecholamine, recapitulating hallmark features of the disease. These conditions elevated diastolic Ca2+ levels and increased temporal and spatial dispersion of Ca2+ wave speed, creating a vulnerable arrhythmia substrate. Using Cas9 genome editing, we pinpointed a single catecholamine-driven phosphorylation event, ryanodine receptor-serine 2814 phosphorylation by Ca2+/calmodulin-dependent protein kinase II, that is required to unmask the arrhythmic potential of CPVT tissues.
CONCLUSIONS: Our study illuminates the molecular and cellular pathogenesis of CPVT and reveals a critical role of calmodulin-dependent protein kinase II-dependent reentry in the tissue-scale mechanism of this disease. We anticipate that this approach will be useful for modeling other inherited and acquired cardiac arrhythmias.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:140 |
|---|---|
| Enthalten in: |
Circulation - 140(2019), 5 vom: 30. Juli, Seite 390-404 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Park, Sung-Jin [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 24.04.2020 Date Revised 01.08.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1161/CIRCULATIONAHA.119.039711 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM299241971 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM299241971 | ||
| 003 | DE-627 | ||
| 005 | 20231225095919.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1161/CIRCULATIONAHA.119.039711 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0997.xml |
| 035 | |a (DE-627)NLM299241971 | ||
| 035 | |a (NLM)31311300 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Park, Sung-Jin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 24.04.2020 | ||
| 500 | |a Date Revised 01.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: Modeling of human arrhythmias with induced pluripotent stem cell-derived cardiomyocytes has focused on single-cell phenotypes. However, arrhythmias are the emergent properties of cells assembled into tissues, and the impact of inherited arrhythmia mutations on tissue-level properties of human heart tissue has not been reported | ||
| 520 | |a METHODS: Here, we report an optogenetically based, human engineered tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia caused by mutation of the cardiac ryanodine channel and triggered by exercise. We developed a human induced pluripotent stem cell-derived cardiomyocyte-based platform to study the tissue-level properties of engineered human myocardium. We investigated pathogenic mechanisms in CPVT by combining this novel platform with genome editing | ||
| 520 | |a RESULTS: In our model, CPVT tissues were vulnerable to developing reentrant rhythms when stimulated by rapid pacing and catecholamine, recapitulating hallmark features of the disease. These conditions elevated diastolic Ca2+ levels and increased temporal and spatial dispersion of Ca2+ wave speed, creating a vulnerable arrhythmia substrate. Using Cas9 genome editing, we pinpointed a single catecholamine-driven phosphorylation event, ryanodine receptor-serine 2814 phosphorylation by Ca2+/calmodulin-dependent protein kinase II, that is required to unmask the arrhythmic potential of CPVT tissues | ||
| 520 | |a CONCLUSIONS: Our study illuminates the molecular and cellular pathogenesis of CPVT and reveals a critical role of calmodulin-dependent protein kinase II-dependent reentry in the tissue-scale mechanism of this disease. We anticipate that this approach will be useful for modeling other inherited and acquired cardiac arrhythmias | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a CaMKII | |
| 650 | 4 | |a arrhythmias, cardiac | |
| 650 | 4 | |a biological engineering | |
| 650 | 4 | |a catecholaminergic polymorphic ventricular tachycardia disease models | |
| 650 | 4 | |a gene editing | |
| 650 | 4 | |a stem cells | |
| 700 | 1 | |a Zhang, Donghui |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yifei |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Keel Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Bezzerides, Vassilios J |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Pengcheng |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Shutao |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Sean L |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xujie |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Fujian |e verfasserin |4 aut | |
| 700 | 1 | |a Pasqualini, Francesco S |e verfasserin |4 aut | |
| 700 | 1 | |a Campbell, Patrick H |e verfasserin |4 aut | |
| 700 | 1 | |a Geva, Judith |e verfasserin |4 aut | |
| 700 | 1 | |a Roberts, Amy E |e verfasserin |4 aut | |
| 700 | 1 | |a Kleber, Andre G |e verfasserin |4 aut | |
| 700 | 1 | |a Abrams, Dominic J |e verfasserin |4 aut | |
| 700 | 1 | |a Pu, William T |e verfasserin |4 aut | |
| 700 | 1 | |a Parker, Kevin Kit |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Circulation |d 1950 |g 140(2019), 5 vom: 30. Juli, Seite 390-404 |w (DE-627)NLM000039020 |x 1524-4539 |7 nnns |
| 773 | 1 | 8 | |g volume:140 |g year:2019 |g number:5 |g day:30 |g month:07 |g pages:390-404 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1161/CIRCULATIONAHA.119.039711 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 140 |j 2019 |e 5 |b 30 |c 07 |h 390-404 | ||