Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity

Jessica M. Miller; Moustafa H. Meki; Qinghui Ou; Sharon A. George; Anna Gams; Riham R.E. Abouleisa; Xian Liang Tang; Brooke M. Ahern; Guruprasad A. Giridharan; Ayman El-Baz; Bradford G. Hill; Jonathan Satin; Daniel J. Conklin; Javid Moslehi; Roberto Bolli; Alexandre J.S. Ribeiro; Igor R. Efimov; Tamer M.A. Mohamed

doi:10.1016/j.taap.2020.115213

Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity

Jessica M. Miller, Moustafa H. Meki, Qinghui Ou, Sharon A. George, Anna Gams, Riham R.E. Abouleisa, Xian Liang Tang, Brooke M. Ahern, Guruprasad A. Giridharan, Ayman El-Baz, Bradford G. Hill, Jonathan Satin, Daniel J. Conklin, Javid Moslehi, Roberto Bolli, Alexandre J.S. Ribeiro, Igor R. Efimov, Tamer M.A. Mohamed^*

^*Corresponding author for this work

Biomedical Engineering

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

22 Scopus citations

Abstract

The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 μm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, heart slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1–1 μM. These results indicate that heart slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.

Original language	English (US)
Article number	115213
Journal	Toxicology and Applied Pharmacology
Volume	406
DOIs	https://doi.org/10.1016/j.taap.2020.115213
State	Published - Nov 1 2020

Funding

TMAM is supported by NIH grants R01HL147921 and P30GM127607 and American Heart Association grant 16SDG29950012. The authors also acknowledge NIH grants P30GM127607 (BGH), R01HL130174 (BGH), R01HL147844 (BGH), R01ES028268 (BGH), GM127607 (DJC), P01HL78825 (RB, BGH) and UM1HL113530 (RB), Leducq Foundation RHYTHM grant (IRE), R01HL126802 (IRE), R44HL139248 (IRE) and an American Heart Association Postdoctoral fellowship (19POST34370122) to SAG. We also acknowledge the USA Department of Defense for the grant W81XWH-20-1-0419 (JS, TMAM). We acknowledge the guidance of Ruslan Deviatiiarov from the Institute of Fundamental Medicine and Biology. Kazan Federal University, Russia in the Cap Analysis of Gene expression data analysis. TMAM is supported by NIH grants R01HL147921 and P30GM127607 and American Heart Association grant 16SDG29950012 . The authors also acknowledge NIH grants P30GM127607 (BGH), R01HL130174 (BGH), R01HL147844 (BGH), R01ES028268 (BGH), GM127607 (DJC), P01HL78825 (RB, BGH) and UM1HL113530 (RB), Leducq Foundation RHYTHM grant (IRE), R01HL126802 (IRE), R44HL139248 (IRE) and an American Heart Association Postdoctoral fellowship ( 19POST34370122 ) to SAG. We also acknowledge the USA Department of Defense for the grant W81XWH-20-1-0419 (JS, TMAM). We acknowledge the guidance of Ruslan Deviatiiarov from the Institute of Fundamental Medicine and Biology. Kazan Federal University, Russia in the Cap Analysis of Gene expression data analysis.

ASJC Scopus subject areas

Toxicology
Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.taap.2020.115213

Cite this

Miller, J. M., Meki, M. H., Ou, Q., George, S. A., Gams, A., Abouleisa, R. R. E., Tang, X. L., Ahern, B. M., Giridharan, G. A., El-Baz, A., Hill, B. G., Satin, J., Conklin, D. J., Moslehi, J., Bolli, R., Ribeiro, A. J. S., Efimov, I. R., & Mohamed, T. M. A. (2020). Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity. Toxicology and Applied Pharmacology, 406, Article 115213. https://doi.org/10.1016/j.taap.2020.115213

@article{456efab55ffa4260a69af3e343ce85c2,

title = "Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity",

abstract = "The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 μm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, heart slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1–1 μM. These results indicate that heart slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.",

author = "Miller, {Jessica M.} and Meki, {Moustafa H.} and Qinghui Ou and George, {Sharon A.} and Anna Gams and Abouleisa, {Riham R.E.} and Tang, {Xian Liang} and Ahern, {Brooke M.} and Giridharan, {Guruprasad A.} and Ayman El-Baz and Hill, {Bradford G.} and Jonathan Satin and Conklin, {Daniel J.} and Javid Moslehi and Roberto Bolli and Ribeiro, {Alexandre J.S.} and Efimov, {Igor R.} and Mohamed, {Tamer M.A.}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = nov,

day = "1",

doi = "10.1016/j.taap.2020.115213",

language = "English (US)",

volume = "406",

journal = "Toxicology and Applied Pharmacology",

issn = "0041-008X",

publisher = "Academic Press Inc.",

}

Miller, JM, Meki, MH, Ou, Q, George, SA, Gams, A, Abouleisa, RRE, Tang, XL, Ahern, BM, Giridharan, GA, El-Baz, A, Hill, BG, Satin, J, Conklin, DJ, Moslehi, J, Bolli, R, Ribeiro, AJS, Efimov, IR & Mohamed, TMA 2020, 'Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity', Toxicology and Applied Pharmacology, vol. 406, 115213. https://doi.org/10.1016/j.taap.2020.115213

TY - JOUR

T1 - Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity

AU - Miller, Jessica M.

AU - Meki, Moustafa H.

AU - Ou, Qinghui

AU - George, Sharon A.

AU - Gams, Anna

AU - Abouleisa, Riham R.E.

AU - Tang, Xian Liang

AU - Ahern, Brooke M.

AU - Giridharan, Guruprasad A.

AU - El-Baz, Ayman

AU - Hill, Bradford G.

AU - Satin, Jonathan

AU - Conklin, Daniel J.

AU - Moslehi, Javid

AU - Bolli, Roberto

AU - Ribeiro, Alexandre J.S.

AU - Efimov, Igor R.

AU - Mohamed, Tamer M.A.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 μm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, heart slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1–1 μM. These results indicate that heart slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.

AB - The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 μm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, heart slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1–1 μM. These results indicate that heart slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.

UR - http://www.scopus.com/inward/record.url?scp=85090122053&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85090122053&partnerID=8YFLogxK

U2 - 10.1016/j.taap.2020.115213

DO - 10.1016/j.taap.2020.115213

M3 - Article

C2 - 32877659

AN - SCOPUS:85090122053

SN - 0041-008X

VL - 406

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

M1 - 115213

ER -

Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this