Abstract 15537: Poor Recovery From Receptor Tyrosine Kinase Inhibitor Cardiotoxicity is Linked to Toxic Effects on Cardiac Stem Cells

IntroductionReceptor tyrosine kinase inhibitors (RTKIs) improve cancer survival but have cardiotoxic side effects, the mechanisms for which warrant further investigation. Endogenous cardiac stem cells (CSCs) support cardiac function and recovery from injury through paracrine action and tissue format...

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Published in:Circulation (New York, N.Y.) N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A15537-A15537
Main Authors: Smith, Andrew J, Ruchaya, Prashant, Walmsley, Robert, Wright, Kathleen E, Nadal-Ginard, Bernardo, Ellison-Hughes, Georgina M
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container_title Circulation (New York, N.Y.)
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creator Smith, Andrew J
Ruchaya, Prashant
Walmsley, Robert
Wright, Kathleen E
Nadal-Ginard, Bernardo
Ellison-Hughes, Georgina M
description IntroductionReceptor tyrosine kinase inhibitors (RTKIs) improve cancer survival but have cardiotoxic side effects, the mechanisms for which warrant further investigation. Endogenous cardiac stem cells (CSCs) support cardiac function and recovery from injury through paracrine action and tissue formation.HypothesisRTKI effects on CSCs directly impact on their ability to aid cardiac recovery from RTKI toxicity.MethodsWe applied RTKIs (imatinib, sunitinib or sorafenib) to human CSCs in vitro, assessingcell viability (fluorescein diacetate), proliferation (cell cycle flow cytometry), differentiation (quantified immunostaining) and growth factor generation (real-time qPCR). To determine in vivo impacts of the most CSC-toxic RTKI, adult male Wistar rats were injected with sunitinib (40mg.kg (i.p.), 9 days), before 7 days’ sunitinib withdrawal, with echocardiographic assessment throughout and end-point histology (in vivo work compliant with UK regulations). StatisticsANOVA plus Tukey’s test, significancep
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Endogenous cardiac stem cells (CSCs) support cardiac function and recovery from injury through paracrine action and tissue formation.HypothesisRTKI effects on CSCs directly impact on their ability to aid cardiac recovery from RTKI toxicity.MethodsWe applied RTKIs (imatinib, sunitinib or sorafenib) to human CSCs in vitro, assessingcell viability (fluorescein diacetate), proliferation (cell cycle flow cytometry), differentiation (quantified immunostaining) and growth factor generation (real-time qPCR). To determine in vivo impacts of the most CSC-toxic RTKI, adult male Wistar rats were injected with sunitinib (40mg.kg (i.p.), 9 days), before 7 days’ sunitinib withdrawal, with echocardiographic assessment throughout and end-point histology (in vivo work compliant with UK regulations). StatisticsANOVA plus Tukey’s test, significancep&lt;0.05; data are mean±SEM.ResultsAll 3 RTKIs reduced CSC survival (imatinib 91.5±0.9%; sunitinib 83.9±1.8%; sorafenib 75.0±1.6%, vs. 100% viability in control, n=4) and proliferation by cell cycling (imatinib29.3±4.3% cells in S/G2/M-phases, vs. 50.3±5.1% in control, n=3). RTKIs also reduced CSC regenerative potentialexpression of genes linked to secretome (HGF, PDGF-A), or endothelial (PECAM1) and cardiomyocyte (Nkx2.5, Wnt2) differentiation were respectively decreased 3, 2, 2, 3 and 6-fold (n=3). Sunitinib also repressed CSC ability to form endothelial (32.3±3.2% vs. 44.3±3.5%, n=4) or smooth muscle (39.9±3.1% vs. 63.1±2.3%, n=4) cells. In vivo, sunitinib reduced cardiac ejection fraction to 67.9±1.9% (82.9±1.9% in control, n=12). CSC numbers in situ were reduced in hearts which failed to recover functionally after sunitinib withdrawal221.8±92.1 per 10 myocytes (non-recovery) vs. 427.0±56.4 (recovery) (n=6).ConclusionsWe have found RTKIs reduce both CSC population maintenance and pro-regenerative abilities, and that CSC loss in vivo corresponds to cardiac inability to recover from RTKI-induced cardiotoxicity. This identifies an important mechanism for detecting long-term heart failure risk.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><language>eng</language><publisher>by the American College of Cardiology Foundation and the American Heart Association, Inc</publisher><ispartof>Circulation (New York, N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A15537-A15537</ispartof><rights>2018 by the American College of Cardiology Foundation and the American Heart Association, Inc.</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids></links><search><creatorcontrib>Smith, Andrew J</creatorcontrib><creatorcontrib>Ruchaya, Prashant</creatorcontrib><creatorcontrib>Walmsley, Robert</creatorcontrib><creatorcontrib>Wright, Kathleen E</creatorcontrib><creatorcontrib>Nadal-Ginard, Bernardo</creatorcontrib><creatorcontrib>Ellison-Hughes, Georgina M</creatorcontrib><title>Abstract 15537: Poor Recovery From Receptor Tyrosine Kinase Inhibitor Cardiotoxicity is Linked to Toxic Effects on Cardiac Stem Cells</title><title>Circulation (New York, N.Y.)</title><description>IntroductionReceptor tyrosine kinase inhibitors (RTKIs) improve cancer survival but have cardiotoxic side effects, the mechanisms for which warrant further investigation. Endogenous cardiac stem cells (CSCs) support cardiac function and recovery from injury through paracrine action and tissue formation.HypothesisRTKI effects on CSCs directly impact on their ability to aid cardiac recovery from RTKI toxicity.MethodsWe applied RTKIs (imatinib, sunitinib or sorafenib) to human CSCs in vitro, assessingcell viability (fluorescein diacetate), proliferation (cell cycle flow cytometry), differentiation (quantified immunostaining) and growth factor generation (real-time qPCR). To determine in vivo impacts of the most CSC-toxic RTKI, adult male Wistar rats were injected with sunitinib (40mg.kg (i.p.), 9 days), before 7 days’ sunitinib withdrawal, with echocardiographic assessment throughout and end-point histology (in vivo work compliant with UK regulations). StatisticsANOVA plus Tukey’s test, significancep&lt;0.05; data are mean±SEM.ResultsAll 3 RTKIs reduced CSC survival (imatinib 91.5±0.9%; sunitinib 83.9±1.8%; sorafenib 75.0±1.6%, vs. 100% viability in control, n=4) and proliferation by cell cycling (imatinib29.3±4.3% cells in S/G2/M-phases, vs. 50.3±5.1% in control, n=3). RTKIs also reduced CSC regenerative potentialexpression of genes linked to secretome (HGF, PDGF-A), or endothelial (PECAM1) and cardiomyocyte (Nkx2.5, Wnt2) differentiation were respectively decreased 3, 2, 2, 3 and 6-fold (n=3). Sunitinib also repressed CSC ability to form endothelial (32.3±3.2% vs. 44.3±3.5%, n=4) or smooth muscle (39.9±3.1% vs. 63.1±2.3%, n=4) cells. In vivo, sunitinib reduced cardiac ejection fraction to 67.9±1.9% (82.9±1.9% in control, n=12). CSC numbers in situ were reduced in hearts which failed to recover functionally after sunitinib withdrawal221.8±92.1 per 10 myocytes (non-recovery) vs. 427.0±56.4 (recovery) (n=6).ConclusionsWe have found RTKIs reduce both CSC population maintenance and pro-regenerative abilities, and that CSC loss in vivo corresponds to cardiac inability to recover from RTKI-induced cardiotoxicity. This identifies an important mechanism for detecting long-term heart failure risk.</description><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNqdjltKxDAUhoMoWC97OBso5NK01jcpMyj6INr3IZM5pXEyieRExy7AfduiK_Dp5_sv8J-wQmhZlZVW7SkrOOdt2Sgpz9kF0duMtWp0wb7vtpSTsRmE1qq5hecYE7ygjZ-YJlineFgI3_Ns91OK5ALCowuGEB7C6LZuSTqTdi7m-OWsyxM4gicX9riDHKFfXFgNA9pMEMNv2Vh4zXiADr2nK3Y2GE94_aeXrFqv-u6-PEafMdHefxwxbUY0Po-b-TxXXDSl5OJGCF6Lksu6atU_Zz9Ub1n5</recordid><startdate>20181106</startdate><enddate>20181106</enddate><creator>Smith, Andrew J</creator><creator>Ruchaya, Prashant</creator><creator>Walmsley, Robert</creator><creator>Wright, Kathleen E</creator><creator>Nadal-Ginard, Bernardo</creator><creator>Ellison-Hughes, Georgina M</creator><general>by the American College of Cardiology Foundation and the American Heart Association, Inc</general><scope/></search><sort><creationdate>20181106</creationdate><title>Abstract 15537: Poor Recovery From Receptor Tyrosine Kinase Inhibitor Cardiotoxicity is Linked to Toxic Effects on Cardiac Stem Cells</title><author>Smith, Andrew J ; Ruchaya, Prashant ; Walmsley, Robert ; Wright, Kathleen E ; Nadal-Ginard, Bernardo ; Ellison-Hughes, Georgina M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-wolterskluwer_health_00003017-201811061-026493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><toplevel>online_resources</toplevel><creatorcontrib>Smith, Andrew J</creatorcontrib><creatorcontrib>Ruchaya, Prashant</creatorcontrib><creatorcontrib>Walmsley, Robert</creatorcontrib><creatorcontrib>Wright, Kathleen E</creatorcontrib><creatorcontrib>Nadal-Ginard, Bernardo</creatorcontrib><creatorcontrib>Ellison-Hughes, Georgina M</creatorcontrib><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smith, Andrew J</au><au>Ruchaya, Prashant</au><au>Walmsley, Robert</au><au>Wright, Kathleen E</au><au>Nadal-Ginard, Bernardo</au><au>Ellison-Hughes, Georgina M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Abstract 15537: Poor Recovery From Receptor Tyrosine Kinase Inhibitor Cardiotoxicity is Linked to Toxic Effects on Cardiac Stem Cells</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><date>2018-11-06</date><risdate>2018</risdate><volume>138</volume><issue>Suppl_1 Suppl 1</issue><spage>A15537</spage><epage>A15537</epage><pages>A15537-A15537</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><abstract>IntroductionReceptor tyrosine kinase inhibitors (RTKIs) improve cancer survival but have cardiotoxic side effects, the mechanisms for which warrant further investigation. Endogenous cardiac stem cells (CSCs) support cardiac function and recovery from injury through paracrine action and tissue formation.HypothesisRTKI effects on CSCs directly impact on their ability to aid cardiac recovery from RTKI toxicity.MethodsWe applied RTKIs (imatinib, sunitinib or sorafenib) to human CSCs in vitro, assessingcell viability (fluorescein diacetate), proliferation (cell cycle flow cytometry), differentiation (quantified immunostaining) and growth factor generation (real-time qPCR). To determine in vivo impacts of the most CSC-toxic RTKI, adult male Wistar rats were injected with sunitinib (40mg.kg (i.p.), 9 days), before 7 days’ sunitinib withdrawal, with echocardiographic assessment throughout and end-point histology (in vivo work compliant with UK regulations). StatisticsANOVA plus Tukey’s test, significancep&lt;0.05; data are mean±SEM.ResultsAll 3 RTKIs reduced CSC survival (imatinib 91.5±0.9%; sunitinib 83.9±1.8%; sorafenib 75.0±1.6%, vs. 100% viability in control, n=4) and proliferation by cell cycling (imatinib29.3±4.3% cells in S/G2/M-phases, vs. 50.3±5.1% in control, n=3). RTKIs also reduced CSC regenerative potentialexpression of genes linked to secretome (HGF, PDGF-A), or endothelial (PECAM1) and cardiomyocyte (Nkx2.5, Wnt2) differentiation were respectively decreased 3, 2, 2, 3 and 6-fold (n=3). Sunitinib also repressed CSC ability to form endothelial (32.3±3.2% vs. 44.3±3.5%, n=4) or smooth muscle (39.9±3.1% vs. 63.1±2.3%, n=4) cells. In vivo, sunitinib reduced cardiac ejection fraction to 67.9±1.9% (82.9±1.9% in control, n=12). CSC numbers in situ were reduced in hearts which failed to recover functionally after sunitinib withdrawal221.8±92.1 per 10 myocytes (non-recovery) vs. 427.0±56.4 (recovery) (n=6).ConclusionsWe have found RTKIs reduce both CSC population maintenance and pro-regenerative abilities, and that CSC loss in vivo corresponds to cardiac inability to recover from RTKI-induced cardiotoxicity. This identifies an important mechanism for detecting long-term heart failure risk.</abstract><pub>by the American College of Cardiology Foundation and the American Heart Association, Inc</pub></addata></record>
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title Abstract 15537: Poor Recovery From Receptor Tyrosine Kinase Inhibitor Cardiotoxicity is Linked to Toxic Effects on Cardiac Stem Cells
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