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Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue.
Park, Sung-Jin; Zhang, Donghui; Qi, Yan; Li, Yifei; Lee, Keel Yong; Bezzerides, Vassilios J; Yang, Pengcheng; Xia, Shutao; Kim, Sean L; Liu, Xujie; Lu, Fujian; Pasqualini, Francesco S; Campbell, Patrick H; Geva, Judith; Roberts, Amy E; Kleber, Andre G; Abrams, Dominic J; Pu, William T; Parker, Kevin Kit.
Afiliación
  • Park SJ; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA.
  • Zhang D; State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, China (D.Z., Y.Q., P.Y., S.X.).
  • Qi Y; Department of Cardiology, Boston Children's Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.).
  • Li Y; State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, China (D.Z., Y.Q., P.Y., S.X.).
  • Lee KY; Department of Cardiology, Boston Children's Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.).
  • Bezzerides VJ; Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu (Y.L.).
  • Yang P; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA.
  • Xia S; Department of Cardiology, Boston Children's Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.).
  • Kim SL; State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, China (D.Z., Y.Q., P.Y., S.X.).
  • Liu X; State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, China (D.Z., Y.Q., P.Y., S.X.).
  • Lu F; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA.
  • Pasqualini FS; Department of Cardiology, Boston Children's Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.).
  • Campbell PH; Department of Cardiology, Boston Children's Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.).
  • Geva J; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA.
  • Roberts AE; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA.
  • Kleber AG; Department of Cardiology, Boston Children's Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.).
  • Abrams DJ; Department of Cardiology, Boston Children's Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.).
  • Pu WT; Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (A.G.K.).
  • Parker KK; Department of Cardiology, Boston Children's Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.).
Circulation ; 140(5): 390-404, 2019 07 30.
Article en En | MEDLINE | ID: mdl-31311300
ABSTRACT

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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Taquicardia Ventricular / Ingeniería de Tejidos / Miocitos Cardíacos / Células Madre Pluripotentes Inducidas Tipo de estudio: Etiology_studies Límite: Humans Idioma: En Revista: Circulation Año: 2019 Tipo del documento: Article País de afiliación: Marruecos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Taquicardia Ventricular / Ingeniería de Tejidos / Miocitos Cardíacos / Células Madre Pluripotentes Inducidas Tipo de estudio: Etiology_studies Límite: Humans Idioma: En Revista: Circulation Año: 2019 Tipo del documento: Article País de afiliación: Marruecos