Novel "Dual Hit" Rat Model of Diabetic Cardiomyopathy

Abstract

The pathogenesis of diabetic cardiomyopathy (DC) is poorly understood and new drugs targeting the myocardium are absent. This may be ascribed to the failure of available pre-clinical models to recapitulate essential clinical features of DC and heart failure. We hypothesized that the combination of experimental diabetes and pharmacologically induced cardiac stress might provide a novel rat model displaying a distinct profile of DC. Non-insulin dependent type 1 like diabetes mellitus was induced by partial (90%) pancreatectomy (Px). Pronounced hyperglycemia was established within two weeks (blood glucose levels of 23.3 ± 3.7 mM). Five weeks post Px or sham surgery, vehicle or the sympathomimetic agent, isoproterenol (Iso, 1 mg/kg, SC) was administered for 10 days. Ten weeks after surgery, the heart was isolated for detailed histological and molecular characterization. The relative weight of the left ventricle (LV) was significantly increased in Px-Iso rats compared to sham-vehicle treated control rats (0.22 ± 0.03 vs. 0.25 ± 0.02 mg/g BW, p<0.05), indicating Px-Iso-induced cardiac hypertrophy. Compared to sham-vehicle rats, cardiac muscle fibers of Px-vehicle rats had attenuated respiratory function and increased reliance upon oxidation of fatty acid substrates, measured by high-resolution respirometry. Interestingly, this aggravation was reversed in Px-Iso rats. Moreover, Iso induced cardiac fibrosis demonstrated by quantitative histology (area fraction; Px-vehicle vs. Px-Iso: 3.1 ± 0.2% vs. 6.3 ± 0.5%; Sham-vehicle vs. Sham-Iso: 3.7 ± 0.4% vs. 7.6 ± 0.5%, p<0.001). Echo- and electrocardiography as well as transcriptome analyses were applied to further assess LV remodeling and cardiac function. In conclusion, the Px-Iso rat model may provide a state-of-the-art model of DC displaying key features of the clinical condition. Hereby, this model may be useful in the evaluation of cardiovascular effects of novel compounds in the pre-clinical phase of drug development. Disclosure L. Thisted: Employee; Self; Gubra. R.T. Lindsay: None. K. Fosgerau: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S. M.B. Thomsen: None. T. Jespersen: None. A.J. Murray: None. P.J. Pedersen: None. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. T.X. Pedersen: Employee; Self; Gubra. N.E. Zois: Employee; Self; Gubra.