Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy

Mária Lódi, Dániel Priksz, Gábor Áron Fülöp, Beáta Bódi, Alexandra Gyöngyösi, Lilla Nagy, Árpád Kovács, Attila Béla Kertész, Judit Kocsis, I. Édes, Zoltán Csanádi, I. Czuriga, Z. Kisvárday, B. Juhász, I. Lekli, P. Bai, Attila Tóth, Z. Papp, Dániel Czuriga

Research output: Contribution to journalArticle

Abstract

Background: Chemotherapy-induced left ventricular dysfunction represents a major clinical problem, which is often only recognised at an advanced stage, when supportive therapy is ineffective. Although an early heart failure treatment could positively influence the health status and clinical outcome, there is still no evidence of routine prophylactic cardioprotection for the majority of patients without previous cardiovascular history awaiting potentially cardiotoxic chemotherapy. In this study, we set out to investigate whether a prophylactic cardioprotective therapy relative to a conventionally scheduled heart failure treatment is more effective in preventing cardiotoxicity in a rodent model of doxorubicin (DOX)-induced cardiomyopathy. Methods: Male Wistar rats (n = 7-11 per group) were divided into 4 subgroups, namely negative controls receiving intravenous saline (CON), positive controls receiving intravenous DOX (6 cycles; D-CON), and DOX-treated animals receiving either prophylactic (PRE, started 1 week before DOX) or conventionally applied (POST, started 1 month after DOX) combined heart failure therapy of oral bisoprolol, perindopril and eplerenone. Blood pressure, heart rate, body weight and echocardiographic parameters were monitored in vivo, whereas myocardial fibrosis, capillarisation, ultrastructure, myofilament function, apoptosis, oxidative stress and mitochondrial biogenesis were studied in vitro. Results: The survival rate in the PRE group was significantly improved compared to D-CON (p = 0.0207). DOX increased the heart rate of the animals (p = 0.0193), while the blood pressure (p ≤ 0.0105) and heart rate (p = 0.0029) were significantly reduced in the PRE group compared to D-CON and POST. The ejection fraction remained preserved in the PRE group compared to D-CON or POST (p ≤ 0.0237), while none of the treatments could prevent the DOX-induced increase in the isovolumetric relaxation time. DOX decreased the rate of the actin-myosin cross-bridge cycle, irrespective of any treatment applied (p ≤ 0.0433). The myocardium of the D-CON and POST animals displayed pronounced ultrastructural damage, which was not apparent in the PRE group (p ≤ 0.033). While the DOX-induced apoptotic activity could be reduced in both the PRE and POST groups (p ≤ 0.0433), no treatment was able to prevent fibrotic remodelling or the disturbed mitochondrial biogenesis. Conclusion: For attenuating DOX-induced adverse myocardial effects, prophylactic cardioprotection has many advantages compared to a late-applied treatment.

Original languageEnglish
Article number229
JournalJournal of Translational Medicine
Volume17
Issue number1
DOIs
Publication statusPublished - Jul 19 2019

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Cardiomyopathies
Doxorubicin
Theoretical Models
Heart Failure
Therapeutics
Animals
Chemotherapy
Heart Rate
Blood pressure
Organelle Biogenesis
Bisoprolol
Perindopril
Blood Pressure
Drug Therapy
Oxidative stress
Myofibrils
Left Ventricular Dysfunction
Myosins
Relaxation time
Health Status

Keywords

  • Animal model
  • Apoptosis
  • Cardio-oncology
  • Cardioprotection
  • Cardiotoxicity
  • Doxorubicin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy. / Lódi, Mária; Priksz, Dániel; Fülöp, Gábor Áron; Bódi, Beáta; Gyöngyösi, Alexandra; Nagy, Lilla; Kovács, Árpád; Kertész, Attila Béla; Kocsis, Judit; Édes, I.; Csanádi, Zoltán; Czuriga, I.; Kisvárday, Z.; Juhász, B.; Lekli, I.; Bai, P.; Tóth, Attila; Papp, Z.; Czuriga, Dániel.

In: Journal of Translational Medicine, Vol. 17, No. 1, 229, 19.07.2019.

Research output: Contribution to journalArticle

Lódi, Mária ; Priksz, Dániel ; Fülöp, Gábor Áron ; Bódi, Beáta ; Gyöngyösi, Alexandra ; Nagy, Lilla ; Kovács, Árpád ; Kertész, Attila Béla ; Kocsis, Judit ; Édes, I. ; Csanádi, Zoltán ; Czuriga, I. ; Kisvárday, Z. ; Juhász, B. ; Lekli, I. ; Bai, P. ; Tóth, Attila ; Papp, Z. ; Czuriga, Dániel. / Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy. In: Journal of Translational Medicine. 2019 ; Vol. 17, No. 1.
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T1 - Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy

AU - Lódi, Mária

AU - Priksz, Dániel

AU - Fülöp, Gábor Áron

AU - Bódi, Beáta

AU - Gyöngyösi, Alexandra

AU - Nagy, Lilla

AU - Kovács, Árpád

AU - Kertész, Attila Béla

AU - Kocsis, Judit

AU - Édes, I.

AU - Csanádi, Zoltán

AU - Czuriga, I.

AU - Kisvárday, Z.

AU - Juhász, B.

AU - Lekli, I.

AU - Bai, P.

AU - Tóth, Attila

AU - Papp, Z.

AU - Czuriga, Dániel

PY - 2019/7/19

Y1 - 2019/7/19

N2 - Background: Chemotherapy-induced left ventricular dysfunction represents a major clinical problem, which is often only recognised at an advanced stage, when supportive therapy is ineffective. Although an early heart failure treatment could positively influence the health status and clinical outcome, there is still no evidence of routine prophylactic cardioprotection for the majority of patients without previous cardiovascular history awaiting potentially cardiotoxic chemotherapy. In this study, we set out to investigate whether a prophylactic cardioprotective therapy relative to a conventionally scheduled heart failure treatment is more effective in preventing cardiotoxicity in a rodent model of doxorubicin (DOX)-induced cardiomyopathy. Methods: Male Wistar rats (n = 7-11 per group) were divided into 4 subgroups, namely negative controls receiving intravenous saline (CON), positive controls receiving intravenous DOX (6 cycles; D-CON), and DOX-treated animals receiving either prophylactic (PRE, started 1 week before DOX) or conventionally applied (POST, started 1 month after DOX) combined heart failure therapy of oral bisoprolol, perindopril and eplerenone. Blood pressure, heart rate, body weight and echocardiographic parameters were monitored in vivo, whereas myocardial fibrosis, capillarisation, ultrastructure, myofilament function, apoptosis, oxidative stress and mitochondrial biogenesis were studied in vitro. Results: The survival rate in the PRE group was significantly improved compared to D-CON (p = 0.0207). DOX increased the heart rate of the animals (p = 0.0193), while the blood pressure (p ≤ 0.0105) and heart rate (p = 0.0029) were significantly reduced in the PRE group compared to D-CON and POST. The ejection fraction remained preserved in the PRE group compared to D-CON or POST (p ≤ 0.0237), while none of the treatments could prevent the DOX-induced increase in the isovolumetric relaxation time. DOX decreased the rate of the actin-myosin cross-bridge cycle, irrespective of any treatment applied (p ≤ 0.0433). The myocardium of the D-CON and POST animals displayed pronounced ultrastructural damage, which was not apparent in the PRE group (p ≤ 0.033). While the DOX-induced apoptotic activity could be reduced in both the PRE and POST groups (p ≤ 0.0433), no treatment was able to prevent fibrotic remodelling or the disturbed mitochondrial biogenesis. Conclusion: For attenuating DOX-induced adverse myocardial effects, prophylactic cardioprotection has many advantages compared to a late-applied treatment.

AB - Background: Chemotherapy-induced left ventricular dysfunction represents a major clinical problem, which is often only recognised at an advanced stage, when supportive therapy is ineffective. Although an early heart failure treatment could positively influence the health status and clinical outcome, there is still no evidence of routine prophylactic cardioprotection for the majority of patients without previous cardiovascular history awaiting potentially cardiotoxic chemotherapy. In this study, we set out to investigate whether a prophylactic cardioprotective therapy relative to a conventionally scheduled heart failure treatment is more effective in preventing cardiotoxicity in a rodent model of doxorubicin (DOX)-induced cardiomyopathy. Methods: Male Wistar rats (n = 7-11 per group) were divided into 4 subgroups, namely negative controls receiving intravenous saline (CON), positive controls receiving intravenous DOX (6 cycles; D-CON), and DOX-treated animals receiving either prophylactic (PRE, started 1 week before DOX) or conventionally applied (POST, started 1 month after DOX) combined heart failure therapy of oral bisoprolol, perindopril and eplerenone. Blood pressure, heart rate, body weight and echocardiographic parameters were monitored in vivo, whereas myocardial fibrosis, capillarisation, ultrastructure, myofilament function, apoptosis, oxidative stress and mitochondrial biogenesis were studied in vitro. Results: The survival rate in the PRE group was significantly improved compared to D-CON (p = 0.0207). DOX increased the heart rate of the animals (p = 0.0193), while the blood pressure (p ≤ 0.0105) and heart rate (p = 0.0029) were significantly reduced in the PRE group compared to D-CON and POST. The ejection fraction remained preserved in the PRE group compared to D-CON or POST (p ≤ 0.0237), while none of the treatments could prevent the DOX-induced increase in the isovolumetric relaxation time. DOX decreased the rate of the actin-myosin cross-bridge cycle, irrespective of any treatment applied (p ≤ 0.0433). The myocardium of the D-CON and POST animals displayed pronounced ultrastructural damage, which was not apparent in the PRE group (p ≤ 0.033). While the DOX-induced apoptotic activity could be reduced in both the PRE and POST groups (p ≤ 0.0433), no treatment was able to prevent fibrotic remodelling or the disturbed mitochondrial biogenesis. Conclusion: For attenuating DOX-induced adverse myocardial effects, prophylactic cardioprotection has many advantages compared to a late-applied treatment.

KW - Animal model

KW - Apoptosis

KW - Cardio-oncology

KW - Cardioprotection

KW - Cardiotoxicity

KW - Doxorubicin

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