Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12967-019-1978-0 |
| _version_ | 1818151121230757888 |
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| author | Mária Lódi Dániel Priksz Gábor Áron Fülöp Beáta Bódi Alexandra Gyöngyösi Lilla Nagy Árpád Kovács Attila Béla Kertész Judit Kocsis István Édes Zoltán Csanádi István Czuriga Zoltán Kisvárday Béla Juhász István Lekli Péter Bai Attila Tóth Zoltán Papp Dániel Czuriga |
| author_facet | Mária Lódi Dániel Priksz Gábor Áron Fülöp Beáta Bódi Alexandra Gyöngyösi Lilla Nagy Árpád Kovács Attila Béla Kertész Judit Kocsis István Édes Zoltán Csanádi István Czuriga Zoltán Kisvárday Béla Juhász István Lekli Péter Bai Attila Tóth Zoltán Papp Dániel Czuriga |
| author_sort | Mária Lódi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T13:33:47Z |
| format | Article |
| id | doaj.art-8267468ab3be437ba254b9563f758148 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-11T13:33:47Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-8267468ab3be437ba254b9563f7581482022-12-22T01:05:09ZengBMCJournal of Translational Medicine1479-58762019-07-0117111610.1186/s12967-019-1978-0Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathyMária Lódi0Dániel Priksz1Gábor Áron Fülöp2Beáta Bódi3Alexandra Gyöngyösi4Lilla Nagy5Árpád Kovács6Attila Béla Kertész7Judit Kocsis8István Édes9Zoltán Csanádi10István Czuriga11Zoltán Kisvárday12Béla Juhász13István Lekli14Péter Bai15Attila Tóth16Zoltán Papp17Dániel Czuriga18Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of DebrecenDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of DebrecenDivision of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of DebrecenDivision of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of DebrecenDepartment of Pharmacology, Faculty of Pharmacy, University of DebrecenMTA-DE Lendület Laboratory of Cellular MetabolismDivision of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of DebrecenDivision of Cardiology, Department of Cardiology, Faculty of Medicine, University of DebrecenDepartment of 3rd Internal Medicine, Semmelweis UniversityDivision of Cardiology, Department of Cardiology, Faculty of Medicine, University of DebrecenDivision of Cardiology, Department of Cardiology, Faculty of Medicine, University of DebrecenDivision of Cardiology, Department of Cardiology, Faculty of Medicine, University of DebrecenDepartment of Anatomy, Histology and Embryology, Faculty of Medicine, University of DebrecenDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of DebrecenDepartment of Pharmacology, Faculty of Pharmacy, University of DebrecenMTA-DE Lendület Laboratory of Cellular MetabolismDivision of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of DebrecenDivision of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of DebrecenDivision of Cardiology, Department of Cardiology, Faculty of Medicine, University of DebrecenAbstract 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.http://link.springer.com/article/10.1186/s12967-019-1978-0Animal modelApoptosisCardio-oncologyCardioprotectionCardiotoxicityDoxorubicin |
| spellingShingle | Mária Lódi Dániel Priksz Gábor Áron Fülöp Beáta Bódi Alexandra Gyöngyösi Lilla Nagy Árpád Kovács Attila Béla Kertész Judit Kocsis István Édes Zoltán Csanádi István Czuriga Zoltán Kisvárday Béla Juhász István Lekli Péter Bai Attila Tóth Zoltán Papp Dániel Czuriga Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy Journal of Translational Medicine Animal model Apoptosis Cardio-oncology Cardioprotection Cardiotoxicity Doxorubicin |
| title | Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy |
| title_full | Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy |
| title_fullStr | Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy |
| title_full_unstemmed | Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy |
| title_short | Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy |
| title_sort | advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin induced cardiomyopathy |
| topic | Animal model Apoptosis Cardio-oncology Cardioprotection Cardiotoxicity Doxorubicin |
| url | http://link.springer.com/article/10.1186/s12967-019-1978-0 |
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