Doxorubicin's (DOX) cardiotoxicity contributes to the development of chemotherapy-induced heart failure (HF) and new treatment strategies are in high demand. The aim of the present study was to characterize a DOX-induced model of HF in Ren-2 transgenic rats (TGR), those characterized by hypertension and hyperactivity of the renin-angiotensin-aldosterone system, and to compare the results with normotensive transgene-negative, Hannover Sprague-Dawley (HanSD) rats. DOX was administered for two weeks in a cumulative dose of 15 mg/kg. In HanSD rats DOX administration resulted in the development of an early phase of HF with the dominant symptom of bilateral cardiac atrophy demonstrable two weeks after the last DOX injection. In TGR, DOX caused substantial impairment of systolic function already at the end of the treatment, with further progression observed throughout the experiment. Additionally, two weeks after the termination of DOX treatment, TGR exhibited signs of HF characteristic for the transition stage between the compensated and decompensated phases of HF. In conclusion, we suggest that DOX-induced HF in TGR is a suitable model to study the pathophysiological aspects of chemotherapy-induced HF and to evaluate novel therapeutic strategies to combat this form of HF, which are urgently needed.

Center for Experimental Medicine Institute for Clinical and Experimental Medicine 140 21 Prague Czech Republic

Department of Cardiology Institute for Clinical and Experimental Medicine 140 21 Prague Czech Republic

Department of Cardiology University Hospital Motol and 2nd Faculty of Medicine Charles University 150 06 Prague Czech Republic

Department of Pathophysiology 2nd Faculty of Medicine Charles University 110 00 Prague Czech Republic

Department of Renal and Body Fluid Physiology Mossakowski Medical Research Centre Polish Academy of Sciences 01 224 Warsaw Poland

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Bluethmann S.M., Mariotto A.B., Rowland J.H. Anticipating the “Silver Tsunami”: Prevalence trajectories and co-morbidity burden among older cancer survivors in the United States. Cancer Epidemiol. Biomark. Prev. 2016;25:1029–1036. doi: 10.1158/1055-9965.EPI-16-0133. PubMed DOI PMC

Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2016. CA Cancer J. Clin. 2016;66:7–30. doi: 10.3322/caac.21332. PubMed DOI

Trachtenberg B.H. Future Directions in Cardio-Oncology. Methodist Debakey Cardiovasc. J. 2019;15:300–302. PubMed PMC

Lenneman C.G., Sawyer D.B. Cardio-Oncology. An updated on cardiotoxicity of cancer-related treatment. Circ. Res. 2016;118:1008–1020. doi: 10.1161/CIRCRESAHA.115.303633. PubMed DOI

Bansal N., Blanco J.G., Sharma U.C., Pokharel S., Shisler S., Lipshult S.E. Cardiovascular diseases in survivors of childhood cancer. Cancer Metastasis Rev. 2020;39:55–68. doi: 10.1007/s10555-020-09859-w. PubMed DOI PMC

Corremans R., Adao R., De Keulenaer G.W., Leite-Moreira A.F., Brás-Silva C. Update on pathophysiology of anthacycline-induced cardiotoxicity. Clin. Exp. Pharmacol. Physiol. 2019;46:204–215. doi: 10.1111/1440-1681.13036. PubMed DOI

Mancilla T.R., Iskra B., Aune G.J. Doxorubicin-induced cardiomyopathy in children. Compr. Physiol. 2019;9:905–931. PubMed PMC

Henriksen P.A. Anthracycline cardiotoxicity: And update on mechanisms, monitoring and prevention. Heart. 2018;104:971–977. doi: 10.1136/heartjnl-2017-312103. PubMed DOI

Cai F., Luis M.A.F., Lin X., Wang M., Cai L., Cen C., Biskup E. Anthracycline-induced cardiotoxicity in the chemotherapy treatment of breast cancer: Preventive strategies and treatment. Mol. Clin. Oncol. 2019;11:15–23. doi: 10.3892/mco.2019.1854. PubMed DOI PMC

Cardinala D., Colombo A., Bacchiani G., Tedeschi I., Meroni C.A., Veglia F., Civelli M., Lamantia G., Colombo N., Curigliano G., et al. Early detection of anthracyclines cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131:1981–1988. doi: 10.1161/CIRCULATIONAHA.114.013777. PubMed DOI

Szmit S., Jurczak W., Zaucha J.M., Drozd-Sokolowska J., Spychalowicz W., Joks M., Dlugosz-Danecka M., Torbicky A. Pre-existing arterial hypertension as a risk factor for early left ventricular systolic dysfunction following (R)-CHOP chemotherapy in patients with lymphoma. J. Am. Soc. Hypertens. 2014;8:791–799. doi: 10.1016/j.jash.2014.08.009. PubMed DOI

Von Hoff D.D., Layard M.W., Basa P., Davis H.L., Jr., Von Hoff A.L., Rozencweig M., Muggia F.M. Risk factors for doxorubicin-induced congestive heart failure. Ann. Intern. Med. 1979;91:710–717. doi: 10.7326/0003-4819-91-5-710. PubMed DOI

Zamorano J.L., Lancellotti P., Munoz R.D., Aboyans V., Asteggiano R., Galderisi M., Habib G., Lenihan D.J., Lip G.Y.H., Lyon A.R., et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under auspices of the ESC Committee for Practice Guildelines. Eur. Heart J. 2016;37:2768–2801. doi: 10.1093/eurheartj/ehw211. PubMed DOI

Hassen L.J., Lenihan D.J., Baliga R.R. Hypertension in the cardio-oncology clinic. Heart Fail. Clin. 2019;15:487–495. doi: 10.1016/j.hfc.2019.06.010. PubMed DOI

Kalyanaraman B. Teaching the basic of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree? Redox Biol. 2020;29:101394. doi: 10.1016/j.redox.2019.101394. PubMed DOI PMC

Feijen E.A., Leisenring W.M., Stratton K.L., Ness K.K., van der Pal H.J.H., van Dalen E.C., Armstrong G.T., Aune G.J., Green D.M., Hudson M.M., et al. Derivation of anthracyclines and anthraquinone equivalence ratios to doxorubicin for late-onset cardiotoxicity. JAMA Oncol. 2019;5:864–871. doi: 10.1001/jamaoncol.2018.6634. PubMed DOI PMC

Agunbiade T., Zaghlol R.Y., Barac A. Heat failure in relation to anthracyclines and other chemotherapies. Methodist Debakey Cardiovasc. J. 2019;15:243–249. PubMed PMC

Lefrak E.A., Pit’ha J., Rosenheim S., Gottlieb J.A. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973;32:302–314. doi: 10.1002/1097-0142(197308)32:2<302::AID-CNCR2820320205>3.0.CO;2-2. PubMed DOI

Ponikowski P., Voors A.A., Anker S.D., Bueno H., Cleland J.G., Coats A.J., Falk V., González-Juanaatey J.R., Harjola V.-P., Jankowska E.A., et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 2016;37:2129–2200. PubMed

Seferovic P.M., Ponikowski P., Anker S.D., Bauersachs J., Chioncel O., Cleland J.G.F., de Boer R.A., Drexel H., Gal T.B., Hill L., et al. Clinical practice update on heart failure 2019, pharmacotherapy, procedures, devices and patients management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail. 2019;21:1169–1186. doi: 10.1002/ejhf.1531. PubMed DOI

Xi J., Li M., An M., Yu C., Pinnock C.B., Zhu Y., Lam T.A., Li H. Long-circulating amphilic doxorubicin for tumor mitochondria-specific targeting. ACS Appl. Mater. Interfaces. 2018;50:43482–43492. doi: 10.1021/acsami.8b17399. PubMed DOI PMC

Houser S.R., Margulies K.B., Murphy A.M., Spinale F.G., Francis G.S., Prabhu S.D. Animal models of heart failure: A scientific statement from the American Heart Association. Circ. Res. 2012;111:131–150. doi: 10.1161/RES.0b013e3182582523. PubMed DOI

Riehle C., Bauersachs J. Small animals models of heart failure. Cardiovasc. Res. 2019;115:1838–1849. doi: 10.1093/cvr/cvz161. PubMed DOI PMC

Nakahara T., Tanimoto T., Petrov A.D., Ishikawa K., Strauss H.W., Narula J. Rat model of cardiotoxic drug-induced cardiomyopathy. In: Ishikawa K., editor. Experimental Models of Cardiovascular Diseases: Methods and Protocols. Volume 1816. Springer + Business Media, Part of Springer Nature; Berlin/Heidelberg, Germany: 2018. pp. 221–232. PubMed

Singal P.K., Siveski-Iliskovic N., Hill M., Thomas T.P., Li T. Combination therapy with probucol prevents adriamycin-induced cardiomyopathy. J. Mol. Cell Cardiol. 1995;27:1055–1063. doi: 10.1016/0022-2828(95)90074-8. PubMed DOI

Olson H.M., Capen C.C. Subacute cardiotoxicity of Adriamycin in the rat. Biochemical and ultrastructural investigation. Lab Investig. 1977;37:386–394. PubMed

Baris V.O., Gedikli E., Yersal N., Muftuoglu S., Erdem A. Protective effect of taurine against doxorubicin-induced cardiotoxicity in rats: Echocardiographical and histological findings. Amino Acids. 2019;51:1649–1655. doi: 10.1007/s00726-019-02801-7. PubMed DOI

Lódi M., Priksz D., Fulop G., Bodi B., Gyongyoi A., Nagy L., Kovács A., Kertész A.B., Kocsis J., Édes I., et al. Advantages of prophylactic versus conventionally scheduled heart failure therapy in and experimental model of doxorubicin-induced cardiomyopathy. J. Transl. Med. 2019;17:229–245. doi: 10.1186/s12967-019-1978-0. PubMed DOI PMC

Zhu W., Reuter S., Field J. Targeted expression of cyclin D2 ameliorates late stage anthracyclines cardiotoxicity. Cardiovasc. Res. 2019;115:960–965. doi: 10.1093/cvr/cvy273. PubMed DOI PMC

Arnolda L., McGrath B., Cocks M., Sumithran E., Johnston C. Adriamycin cardiomyopathy in the rabbit: An animal model of low output cardiac failure with activation of vasoconstrictor mechanisms. Cardiovasc. Res. 1985;19:378–382. doi: 10.1093/cvr/19.6.378. PubMed DOI

Hayward R., Hydock D.S. Doxorubicin cardiotoxicity in the rat: An in vivo characterization. J. Am. Assoc. Lab. Anim. Sci. 2007;46:20–32. PubMed

Medeiros-Lima D.J.M., Carvalho J.J., Tibirica E., Borges J.P., Matsuura C. Time course of cardiomyopathy induced by doxorubicin in rats. Pharmacol. Rep. 2019;71:583–590. doi: 10.1016/j.pharep.2019.02.013. PubMed DOI

Razmari B.H., Assanassab N., Nayebi M.G., Azarmi A., Mohammadnejad Y., Azami D. Ultrastructural and echocardiographic assessment of chronic doxorubicin-induced cardiotoxicity in rats. Arch. Razi Inst. 2020;75:55–62. PubMed PMC

Pfeffer M.A., Pfeffer J.M., Fishbein M.C., Fletcher P.J., Spadaro J., Kloner R.A., Braunwald E. Myocardial infarction size and ventricular function in rats. Circ. Res. 1979;44:503–512. doi: 10.1161/01.RES.44.4.503. PubMed DOI

Garcia R., Diebold S. Simple, rapid, and effective method of producing aorto-caval shunts in the rat. Cardiovasc. Res. 1990;24:430–432. doi: 10.1093/cvr/24.5.430. PubMed DOI

Husková Z., Kramer H.J., Vaňourková Z., Červenka L. Effects of changes in sodium balance on plasma and kidney angiotensin II levels in anesthetized and conscious Ren-2 transgenic rats. J. Hypertens. 2006;24:517–527. doi: 10.1097/01.hjh.0000209988.51606.c7. PubMed DOI

Elased K.M., Cunha T.S., Marcondes F.K., Morris M. Brain angiotensin-converting enzyme 2 in processing angiotensin II in mice. Exp. Physiol. 2008;93:665–675. doi: 10.1113/expphysiol.2007.040311. PubMed DOI PMC

Husková Z., Kopkan L., Červenková L., Doleželová Š., Vaňourková Z., Škaroupková P., Nishiyama A., Kompanowska-Jezierska E., Sadowski J., Kramer H.J., et al. Intrarenal alterations of the angiotensin-converting enzyme type 2/angiotensin 1-7 complex of the renin-angiotensin system do no alter the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats. Clin. Exp. Pharmacol. Physiol. 2016;43:438–449. doi: 10.1111/1440-1681.12553. PubMed DOI

Bertero E., Ameri P., Maack C. Bidirectional relationship between cancer and heart failure: Old and new issues in cardio-oncology. Card. Fail. Rev. 2019;5:106–111. doi: 10.15420/cfr.2019.1.2. PubMed DOI PMC

Jordan J.H., Castellino S.M., Meléndez G.C., Klepin H.D., Ellis L.R., Lamar Z., Vasu S., Kitzman D.W., Ntim W.O., Brubaker P.H., et al. Left ventricular mass change after anthracyclines chemotherapy. Circ. Heart Fail. 2018;11:e004560. doi: 10.1161/CIRCHEARTFAILURE.117.004560. PubMed DOI PMC

Plana J.C., Galderisi M., Barac A., Ewer M.S., Ky B., Scherrer-Crosbie M., Ganame J., Sebag I.A., Agler D.A., Badano L.P., et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: A report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J. Am. Soc. Echocardiogr. 2014;27:911–939. doi: 10.1016/j.echo.2014.07.012. PubMed DOI

Russell R.R., Alexander J., Jain D., Poornima I.G., Srivastava A.V., Storozynsky E., Schwartz R.G. The role and clinical effectiveness of multimodality imaging in the management of cardiac complications of cancer and cancer therapy. J. Nucl. Cardiol. 2016;23:856–884. doi: 10.1007/s12350-016-0538-8. PubMed DOI

Wang K., Basu R., Poglitsch M., Bakal J.A., Stat P., Oudit G.Y. Elevated angiotensin 1-7/angiotensin II ratio predicts favorable outcomes in patients with heart failure. Circ. Heart Fail. 2020;13:e006939. doi: 10.1161/CIRCHEARTFAILURE.120.006939. PubMed DOI

Dube P., Weber K.T. Congestive heart failure: Pathophysiological consequences of neurohormonal activation and the potential for recovery: Part I. Am. J. Med. Sci. 2011;342:348–351. doi: 10.1097/MAJ.0b013e318232750d. PubMed DOI

Hartupee J., Mann D.L. Neurohormonal activation in heart failure with reduced ejection fraction. Nat. Rev. Cardiol. 2017;14:30–38. doi: 10.1038/nrcardio.2016.163. PubMed DOI PMC

Packer M., McMurray J.J. Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure. Lancet. 2017;389:1831–1840. doi: 10.1016/S0140-6736(16)30969-2. PubMed DOI

Díaz H.S., Toledo C., Andrade D.C., Marcus N.J., Del Rio R. Neuroinflammation in heart failure: New insights for an old disease. J. Physiol. 2020;598:33–59. doi: 10.1113/JP278864. PubMed DOI

Sharkey L.C., Radin M.J., Heller L., Rogers L.K., Tobias A., Matise I., Wang Q., Apple F.S., McCune S.A. Differential cardiotoxicity in response to chronic doxorubicin treatment in male spontaneous hypertension-heart failure (SHHF), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats. Toxicol. Appl. Pharmacol. 2013;273:47–57. doi: 10.1016/j.taap.2013.08.012. PubMed DOI

Meijers W.C., de Boer R.A. Common risk factors for heart failure and cancer. Cardiovasc. Res. 2019;115:844–853. doi: 10.1093/cvr/cvz035. PubMed DOI PMC

Moslehi J., Zhang Q., Moore K.J. Crosstalk between the heart and cancer. Beyond drug toxicity. Circulation. 2020;142:684–687. doi: 10.1161/CIRCULATIONAHA.120.048655. PubMed DOI PMC

Avraham S., Abu-Sharki S., Shofti R., Haas T., Korin B., Kalfon R., Firiedman T., Shiran A., Saliba W., Shaked Y., et al. Early cardiac remodeling promotes tumor growth and metastasis. Circulation. 2020;142:670–683. doi: 10.1161/CIRCULATIONAHA.120.046471. PubMed DOI

Červenka L., Melenovský V., Husková Z., Škaroupková P., Nishiyama A., Sadowski J. Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren-2 transgenic hypertensive rats with aorto-caval fistula. Clin. Exp. Pharmacol. Physiol. 2015;42:795–807. doi: 10.1111/1440-1681.12419. PubMed DOI

Vacková Š., Kikerlová S., Melenovský V., Kolář F., Imig J.D., Kompanowska-Jezierska E., Sadowski J., Červenka L. Altered renal vascular responsiveness to vasoactive agents in rats with angiotensin II-dependent hypertension and congestive heart failure. Kidney Blood Press Res. 2019;44:792–809. doi: 10.1159/000501688. PubMed DOI PMC

Honetschlagerová Z., Gawrys O., Jíchová Š., Škaroupková P., Kikerlová S., Vaňourková Z., Husková Z., Melenovský V., Kompanowska-Jezierska E., Sadowski J., et al. Renal sympathetic denervation attenuates congestive heart failure in angiotensin II-dependent hypertension: Studies with Ren-2 transgenic hypertensive rats with aorto-caval fistula. Kidney Blood Press Res. 2020 in press. PubMed

Doggrell S.A., Brown L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc. Res. 1998;39:89–105. doi: 10.1016/S0008-6363(98)00076-5. PubMed DOI

Melenovsky V., Skaroupkova P., Benes J., Torresova V., Kopkan L., Cervenka L. The course of heart failure development and mortality in rats with volume overload due aorto-caval fistula. Kidney Blood Press Res. 2012;35:167–173. doi: 10.1159/000331562. PubMed DOI

Červenka L., Škaroupková P., Kompanowska-Jezierska E., Sadowski J. Sex-linked differences in the course of chronic kidney disease and congestive heart failure: A study in 5/6 nephrectomized Ren-2 transgenic hypertensive rats with volume overload induced using aorto-caval fistula. Clin. Exp. Pharmacol. Physiol. 2016;43:883–895. doi: 10.1111/1440-1681.12619. PubMed DOI

Kala P., Sedláková L., Škaroupková P., Kopkan L., Vaňourková Z., Táborský M., Nishiyama A., Hwang S.H., Hammock B.D., Sadowski J., et al. Effect of angiotensin-converting enzyme blockade, alone of combined with blockade with blockade of soluble epoxide hydrolase, on the course of congestive heart failure and occurrence of renal dysfunction in Ren-2 transgenic hypertensive rats with aorto-caval fistula. Physiol. Res. 2018;67:401–415. PubMed PMC

Weinberg L.E., Singal P.K. Refractory heart failure and age-related differences in adriamyicn-induced myocardial changes in rats. Can. J. Physiol. Pharmacol. 1987;65:1957–1965. doi: 10.1139/y87-305. PubMed DOI

Volkova M., Russell R. Anthracyline cardiotoxicity: Prevalence, pathogenesis and treatment. Curr. Cardiol. Rev. 2011;7:214–220. doi: 10.2174/157340311799960645. PubMed DOI PMC

Pokorný M., Mrázová I., Kubátová H., Piťha J., Malý J., Pirk J., Maxová H., Melenovský V., Šochman J., Sadowski J., et al. Intraventricular placement of a spring expander does not attenuate cardiac atrophy of the healthy heart induced by unloading via heterotopic heart transplantation. Physiol. Res. 2019;68:567–580. doi: 10.33549/physiolres.933936. PubMed DOI

Červenka L., Melenovský V., Husková Z., Sporková A., Burgelová M., Škaroupková P., Hwang S.H., Hammock B.D., Imig J.D., Sadowski J. Inhibition of soluble epoxide hydrolase does not improve the course of congestive heart failure and the development of renal dysfunction in rats with volume overload induced by aorto-caval fistula. Physiol. Res. 2015;64:857–873. doi: 10.33549/physiolres.932977. PubMed DOI PMC

Čertíková Chábová V., Kujal P., Škaroupková P., Vaňourková Z., Vacková Š., Husková Z., Kikerlová S., Sadowski J., Kompanowska-Jezierska E., Baranowska I., et al. Combined inhibition of soluble epoxide hydrolase and renin-angiotensin system exhibit superior renoprotection to renin-angiotensin system blockade in 5/6 nephrectomized Ren-2 transgenic hypertensive rats with established chronic kidney disease. Kidney Blood Press Res. 2018;43:329–349. doi: 10.1159/000487902. PubMed DOI PMC

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