Objective To observe the effects of four different modeling method on the hypothalamuspituitary-adrenal (HPA) axis, blood rheology, platelet aggregation rate, and myocardial ischemia in rats, and to provide new ideas for the establishment of a rat model of “double heart” disease in line with clinical diagnosis and treatment characteristics. Methods Sixty-nine male Sprague-Dawley rats were divided randomly into a Control group (unstimulated), chronic unpredictable mild stimulation (CUMS) group, isoproterenol (ISO) group (intraperitoneal injection of ISO), high-fat diet (HFD) group (fed high-fat chow), and composite model (CUMS+ISO+HFD) group ( n= 12 rats in the Control and HFD groups; n = 15 rats in the other three groups, respectively). Modeling procedures were carried out for a total of 8 weeks, with ISO injection started from week 6 of the experiment for a total of 3 weeks. At the end of modeling, rats in each group were subjected to absent-field and sugar-water preference behavioral tests. Electrocardiography ( ECG) was performed to observe changes in ECG lead II in each group. Serum levels of adrenocorticotropic hormone (ACTH), cortisol (Cor), corticosterone (CORT), endothelin-1 (ET-1), and soluble intercellular adhesion molecule-1 ( sICAM-1) were detected by enzyme-linked immunosorbent assay. Myocardial histopathological changes were detected by hematoxylin / eosin ( HE ) staining. Serum total cholesterol ( TC ), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured using an enzyme labeling instrument. Whole-blood high-cut viscosity (200 V/ S), whole-blood low-cut viscosity (10 I/ S), plasma viscosity, and fibrinogen were assessed using an automatic blood rheology analyzer. The maximum platelet aggregation rate (MAR) and average platelet aggregation rate (AAR) induced by arachidonic acid and adenosine diphosphate were detected using a whole-blood platelet aggregometer. Results Compared with the Control group, all four model groups had significantly lower absenteeism distance and number of entries into the central region in the absent-field test, and a lower sugar-water preference ratio (P<0. 01). ECG revealed ST-segment elevation in the ISO and CUMS+ISO+HFD groups, tachycardia in the CUMS group, and mild ST-segment elevation in the HFD. Serum ACTH, Cor, CORT, ET-1, and sICAM-1 were all significantly elevated in the four model groups (P<0. 01). HE staining showed that myocardial tissue was severely damaged in rats in the ISO and CUMS+ISO+HFD groups, with pathological changes such as localized fibrosis and inflammatory infiltration of the myocardium, while mild cardiomyocyte disarrangement and fracture was seen in the CUMS and HFD groups. Rats in the HFD group had increased serum TC and LDL (P<0. 01) and decreased HDL contents (P<0. 01). Compared with the Control group, vwhole-blood high-cut viscosity (200 V/ S), whole-blood low-cut viscosity (10 I/ S), plasma viscosity, and fibrinogen were all increased in the CUMS, HFD, and CUMS+ISO+HFD groups (P<0. 01, P<0. 05), while whole blood highcut viscosity (200 V/ S), whole blood low-cut viscosity ( 10 I/ S), plasma viscosity, and fibrinogen levels were decreased in rats in the ISO group (P< 0. 01, P<0. 05). MAR and AAR were significantly higher in rats in the CUMS, HFD, and CUMS+ISO+HFD groups (P<0. 01), while the platelet aggregation rate was decreased in the ISO group compared with the Control group (P<0. 01, P<0. 05). Conclusions These result showed that the rat CUMS+ISO+HFD model better reflected the complexity of clinical double heart disease than the other three models.