Construction of a mouse model of adriamycin-induced cardiomyopathy

doi:10.19401/j.cnki.1007-3639.2022.10.003

Abstract

Abstract:

Background and purpose: Adriamycin also named as doxorubicin, is one of the most widely used cytotoxic chemotherapeutic agents for clinical practice for the treatment of various tumors, and belongs to anthracycline antitumor drugs. Unfortunately, this drug will cause serious side effects, especially dose-dependent cardiotoxicity, which has become a concern in the field of onco-cardiology. At present, there is no universally recognized, unified and robust method to construct Doxorubicin-induced cardiomyopathy model. This experiment was designed to explore the optimal dose and frequency of doxorubicin-induced cardiomyopathy in a mouse model.Methods: Forty 8-10-week-old male C57BL/6J mice were randomly divided into 4 groups (control group and 3 model groups). The model group was divided into model 1 (M1) group (15 mg/kg, single dose) and M2 group (5 mg/ kg, once a day for 3 days continuously) and M3 group (7.5 mg/kg, twice on alternate days). General vital signs (body weight change and survival rate), echocardiography, body surface electrocardiogram (ECG), N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin I (cTnI) and myocardial tissue morphological changes were evaluated comprehensively.Results: Compared with the control group, the body weight of mice in M1, M2 and M3 groups decreased significantly (P<0.001); M3 group had higher survival rate than M1 and M2 group (80% vs 40% and 50%, P<0.05). Compared with the control group, M1 group and M2 group, the body surface ECG showed that the PR interval of M3 group [(0.064 2±0.003 8)s vs (0.042 3±0.000 9)s, (0.052 7±0.007 9) s and (0.062 0±0.001 2)s, P<0.05] and QT interval [(0.047 5±0.000 2)s vs (0.022 0±0.000 9)s, (0.038 6±0.004 4)s and (0.044 4±0.003 0)s, P<0.05] were significantly prolonged. Cardiac ultrasound showed that M3 ejection fraction decreased significantly (40.40%±2.24% vs 54.72%±1.64%, 46.00%±4.41% and 54.68%±3.38%, P<0.05). M3 short-axis shortening rate decreased significantly (19.40%±1.20% vs 27.88%±1.05%, 22.57%±2.50% and 27.86%±2.20%, P<0.05). Cardiac markers showed that compared with CON, the serum NT-proBNP levels of M1, M2 and M3 in adriamycin group were significantly increased [(638.13±12.69) pg/mL vs (1 271.36±11.76) pg/mL, (1 270.85±36.19) pg/mL and (1 225.26±24.19) pg/ mL, P<0.05]. Histomorphology showed that the vacuoles in cardiomyocyte of M3 group was significantly increased compared with CON, M1 and M2 group (81/field vs 3/field, 65/field and 34/field, P<0.05).Conclusion: Intraperitoneal injection of adriamycin in acute heart failure model is simple and reliable. The model in which adriamycin is administered by intraperitoneal injection at a dose of 7.5 mg/ kg, twice on alternate days, with cumulative dose of 15 mg/kg is optimal.

Key words: Adriamycin-induced cardiotoxicity, Cardiomyopathy, Onco-cardiology, Model

CLC Number:

R542.2

ZHANG Qingling, ZHANG Yunpeng, ZHOU Zandong, ZHANG Yue, LIU Tong. Construction of a mouse model of adriamycin-induced cardiomyopathy[J]. China Oncology, 2022, 32(10): 948-959.

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Reference	Cumulative dose	Mode of administration
^[17]	7 mg	1 mg/kg, once a day for continued 7 days
^[15,18]	15 mg	15 mg/kg, once
^[19]		2.5 mg/kg, every other day, six times in a row
^[15]		5 mg /kg, once a week for 3 weeks
^[16]		7.5 mg/kg, twice on alternate days
^[20]	16 mg	4 mg/kg, once a week for 4 weeks
^[21]	18 mg	6 mg/kg, via tail vein at day 0, 2, and 4
^[22-23]	20 mg	5 mg/kg, once a week for 4 weeks
^[24]		20 mg/kg, once
^[25]	24 mg	6 mg/kg, once a week for 4 weeks
^[26-27]	25 mg	5 mg/kg, once a week for 5 weeks

Item	CON	M1	M2	M3
LVID^d/mm	3.752 4±0.133 9	3.738 9±0.152 0	3.427 8±0.157 4	3.247 3±0.229 8
LVID^s/mm	2.706 6±0.104 7	2.707 0±0.142 0	2.470 1±0.124 2	2.486 2±0.180 3
LVPW^d/mm	0. 715 0±0.045 7	0.639 3±0.056 6	0.710 2±0.013 1	0.717 2±0.048 3
LVPW^s/mm	0.990 9±0.027 5	0.686 3±0.019 6	0.916 1±0.030 3	0.927 0±0.071 7
IVS^d/mm	0.787 2±0.075 6	0.822 8±0.100 7	0.778 2±0.049 9	0.727 3±0.053 9
IVS^s/mm	1.200 4±0.039 3	1.130 3±0.182 4	0.951 7±0.027 9	0.940 5±0.046 2
LVEF/%	54.722 9±1.635 1	46.009 3±4.413 7	54.684 3±3.375 4	40.396 6±2.240 7^*
LVFS/%	27.880 8±1.050 3	22.568 3±2.503 1	27.857 9±2.202 7	19.395 5±1.207 5^*
P wave duration/s	0.014 0±0.001 3	0.012 0±0.000 7	0.012 1±0.000 3	0.015 3±0.001 2
PR interval/s	0.042 3±0.000 9	0.052 7±0.007 9	0.062 0±0.001 2	0.064 2±0.003 8^**
QRS duration/s	0.011 2±0.001 0	0.010 5±0.000 8	0.010 5±0.000 1	0.010 3±0.000 6
QT interval/s	0.022 0±0.000 9	0.038 6±0.004 4^*	0.044 4±0.003 0^**	0.047 5±0.000 2^**
QTc interval/s	0.041 9±0.002 0	0.072 1±0.007 5^*	0.848 1±0.003 4^**	0.637 7±0.004 2^*
RR interval^s/s	0.148 5±0.008 6	0.152 2±0.007 6	0.143 3±0.011 7	0.164 8±0.017 5