Abstract
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.
Highlights
The past two decades have brought a remarkable improvement in the treatment of diverse cancer forms
The first important finding of the present study is that, two weeks after the end of DOX treatment, normotensive Hannover Sprague-Dawley (HanSD) rats showed an impairment of cardiac function
The finding of marked cardiac atrophy agrees well with the recent report by Jordan et al [40] who clearly demonstrated that the recipients of anthracycline-based chemotherapy showed a 5% decline in myocardial mass as early as six months post treatment, even under conditions of increased afterload The study by Jordan et al [40] was a milestone in the field because, up to this point, most of the surveillance strategies for the detection of early signs of chemotherapy-induced heart failure (HF) with HF with reduced ejection fraction (HFrEF) were focused on a serial assessment of left ventricle (LV) ejection fraction to identify LV systolic dysfunction but did not include LV mass evaluation [41,42]
Summary
The past two decades have brought a remarkable improvement in the treatment of diverse cancer forms. The success of cancer treatment was achieved at a considerable cost [3,4,5]. This was connected with the properties of anthracyclines, discovered 60 years ago but still listed among the World Health Organization (WHO) recommended drugs for the treatment of childhood and adult cancer [4,6,7,8,9]. In young patients, pre-existing cardiovascular diseases (hypertension, hyperlipidemia), the recognized risk factors, are uncommon [10,11,12,13,14,15]
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