Phenomapping for classification of doxorubicin-induced cardiomyopathy in rats
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Pajović, VladislavKovacshazi, Csenger
Kosić, Marija
Vasić, Marko
Dukić, Ljiljana
Brenner, Gabor B.
Giricz, Zoltan
Bajić, Dragana
Ferdinandy, Peter
Japundžić-Žigon, Nina
Article (Published version)
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Cardiomyopathy resistant to treatment is the most serious adverse effect of doxorubicin (dox). The mechanisms of dox-induced cardiomyopathy (DCM) have been extensively studied in dilated forms of DCM. However, efficient treatment did not emerge. The aim of the present work was to revisit the experimental model of DCM in rats, to define phenotype/s and associate them to the changes in cardiac transcriptome. Male Wistar rats equipped with radiotelemetry device, were randomized in DOX group (5 mg/0,5 mL/kg, IV dox; n = 18) and CONT group (0,5 mL/kg IV saline; n = 6). Echocardiography, autonomic spectral markers and baroreceptor reflex evaluation was performed prior to, and after treatment. Blood samples were collected at the end of experimentation. Cardiac, renal and hepatic tissues were analysed post-mortem by histology. Changes in expression of key cardiac genes affected by dox were assessed by RT-qPCR. Phenotypes were identified by clustering non-redundant features using four different... algorithms averaged by evidence accumulation cluster technique. The results emphasize the existence of two major phenotypes of DCM with comparably high mortality rates: phenotype 1 characterized by, left ventricular (LV) dilatation, thinning of LV posterior wall, reduced LV ejection fraction (LVEF) and fractional shortening (LVFS), decreased HR variability (HRV), decreased baroreceptor effectiveness index (BEI) and increased NT-proBNP; and phenotype 2 with LV hypertrophy - increased LV mass, preserved LVEF, LVFS, no changes in HRV and BEI and moderate NT-proBNP increase. Both phenotypes exhibited a genetic shift to a new-born program.
Keywords:
Phenotype / Myh7 / Myh6 / Doxorubicin / Cardiovascular Variability / CardiomyopathySource:
Toxicology and Applied Pharmacology, 2021, 423Publisher:
- Academic Press Inc Elsevier Science, San Diego
Funding / projects:
- National Research, Development and Innovation Office of Hungary (NKFIH) [VEKOP-2.3.2-16-2016-00002, TET_16-1-2016-0057]
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200110 (University of Belgrade, Faculty of Medicine) (RS-MESTD-inst-2020-200110)
- 451-03-02294/2015-09/1
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200156 (University of Novi Sad, Faculty of Technical Science) (RS-MESTD-inst-2020-200156)
DOI: 10.1016/j.taap.2021.115579
ISSN: 0041-008X
PubMed: 34015281
WoS: 000662666000001
Scopus: 2-s2.0-85106367851
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Pajović, Vladislav AU - Kovacshazi, Csenger AU - Kosić, Marija AU - Vasić, Marko AU - Dukić, Ljiljana AU - Brenner, Gabor B. AU - Giricz, Zoltan AU - Bajić, Dragana AU - Ferdinandy, Peter AU - Japundžić-Žigon, Nina PY - 2021 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1447 AB - Cardiomyopathy resistant to treatment is the most serious adverse effect of doxorubicin (dox). The mechanisms of dox-induced cardiomyopathy (DCM) have been extensively studied in dilated forms of DCM. However, efficient treatment did not emerge. The aim of the present work was to revisit the experimental model of DCM in rats, to define phenotype/s and associate them to the changes in cardiac transcriptome. Male Wistar rats equipped with radiotelemetry device, were randomized in DOX group (5 mg/0,5 mL/kg, IV dox; n = 18) and CONT group (0,5 mL/kg IV saline; n = 6). Echocardiography, autonomic spectral markers and baroreceptor reflex evaluation was performed prior to, and after treatment. Blood samples were collected at the end of experimentation. Cardiac, renal and hepatic tissues were analysed post-mortem by histology. Changes in expression of key cardiac genes affected by dox were assessed by RT-qPCR. Phenotypes were identified by clustering non-redundant features using four different algorithms averaged by evidence accumulation cluster technique. The results emphasize the existence of two major phenotypes of DCM with comparably high mortality rates: phenotype 1 characterized by, left ventricular (LV) dilatation, thinning of LV posterior wall, reduced LV ejection fraction (LVEF) and fractional shortening (LVFS), decreased HR variability (HRV), decreased baroreceptor effectiveness index (BEI) and increased NT-proBNP; and phenotype 2 with LV hypertrophy - increased LV mass, preserved LVEF, LVFS, no changes in HRV and BEI and moderate NT-proBNP increase. Both phenotypes exhibited a genetic shift to a new-born program. PB - Academic Press Inc Elsevier Science, San Diego T2 - Toxicology and Applied Pharmacology T1 - Phenomapping for classification of doxorubicin-induced cardiomyopathy in rats VL - 423 DO - 10.1016/j.taap.2021.115579 ER -
@article{ author = "Pajović, Vladislav and Kovacshazi, Csenger and Kosić, Marija and Vasić, Marko and Dukić, Ljiljana and Brenner, Gabor B. and Giricz, Zoltan and Bajić, Dragana and Ferdinandy, Peter and Japundžić-Žigon, Nina", year = "2021", abstract = "Cardiomyopathy resistant to treatment is the most serious adverse effect of doxorubicin (dox). The mechanisms of dox-induced cardiomyopathy (DCM) have been extensively studied in dilated forms of DCM. However, efficient treatment did not emerge. The aim of the present work was to revisit the experimental model of DCM in rats, to define phenotype/s and associate them to the changes in cardiac transcriptome. Male Wistar rats equipped with radiotelemetry device, were randomized in DOX group (5 mg/0,5 mL/kg, IV dox; n = 18) and CONT group (0,5 mL/kg IV saline; n = 6). Echocardiography, autonomic spectral markers and baroreceptor reflex evaluation was performed prior to, and after treatment. Blood samples were collected at the end of experimentation. Cardiac, renal and hepatic tissues were analysed post-mortem by histology. Changes in expression of key cardiac genes affected by dox were assessed by RT-qPCR. Phenotypes were identified by clustering non-redundant features using four different algorithms averaged by evidence accumulation cluster technique. The results emphasize the existence of two major phenotypes of DCM with comparably high mortality rates: phenotype 1 characterized by, left ventricular (LV) dilatation, thinning of LV posterior wall, reduced LV ejection fraction (LVEF) and fractional shortening (LVFS), decreased HR variability (HRV), decreased baroreceptor effectiveness index (BEI) and increased NT-proBNP; and phenotype 2 with LV hypertrophy - increased LV mass, preserved LVEF, LVFS, no changes in HRV and BEI and moderate NT-proBNP increase. Both phenotypes exhibited a genetic shift to a new-born program.", publisher = "Academic Press Inc Elsevier Science, San Diego", journal = "Toxicology and Applied Pharmacology", title = "Phenomapping for classification of doxorubicin-induced cardiomyopathy in rats", volume = "423", doi = "10.1016/j.taap.2021.115579" }
Pajović, V., Kovacshazi, C., Kosić, M., Vasić, M., Dukić, L., Brenner, G. B., Giricz, Z., Bajić, D., Ferdinandy, P.,& Japundžić-Žigon, N.. (2021). Phenomapping for classification of doxorubicin-induced cardiomyopathy in rats. in Toxicology and Applied Pharmacology Academic Press Inc Elsevier Science, San Diego., 423. https://doi.org/10.1016/j.taap.2021.115579
Pajović V, Kovacshazi C, Kosić M, Vasić M, Dukić L, Brenner GB, Giricz Z, Bajić D, Ferdinandy P, Japundžić-Žigon N. Phenomapping for classification of doxorubicin-induced cardiomyopathy in rats. in Toxicology and Applied Pharmacology. 2021;423. doi:10.1016/j.taap.2021.115579 .
Pajović, Vladislav, Kovacshazi, Csenger, Kosić, Marija, Vasić, Marko, Dukić, Ljiljana, Brenner, Gabor B., Giricz, Zoltan, Bajić, Dragana, Ferdinandy, Peter, Japundžić-Žigon, Nina, "Phenomapping for classification of doxorubicin-induced cardiomyopathy in rats" in Toxicology and Applied Pharmacology, 423 (2021), https://doi.org/10.1016/j.taap.2021.115579 . .