Clinically Relevant Models of Diabetic Cardiac Complications
To the Editor:
We read with great interest the article by Hsueh et al in a recent edition of Circulation Research.1 We concur with the efforts of the Animal Models of Diabetic Complications Consortium (AMDCC) to attempt to create clinically relevant models of diabetes induced cardiovascular disease. Like the AMDCC, our own group has studied extensively diabetic complications in the retina,2 kidney,3 and heart in the diabetic Ren-2 rat, a model of enhanced tissue based renin–angiotensin system. After induction of diabetes with streptozotocin, the diabetic Ren-2 rat develops many of the criteria suggested by Hsueh et al for the validation of diabetic cardiomyopathy, such as invasive evidence of systolic and diastolic dysfunction, altered gene expression, and evidence of oxidative stress, activation of profibrotic signaling pathways, and changes in myocardial calcium handling.4 Furthermore, the clinical relevance of any rodent model must be based on the predictive power for both negative and positive clinical trials. The diabetic Ren-2 rat, to date, has confirmed faithfully both positive5,6 and negative7 results that are remarkably similar to those findings in human clinical studies, validating the relevance of this model. We, therefore, encourage the AMDCC to continue its development of new models, and we suggest that amplification of the renin–angiotensin system may offer valuable insights into the pathophysiology of this complex disease.
Sources of Funding
Supported by the Canadian Institutes of Health Research and the National Health and Medical Research Council of Australia. D.K. is the recipient of a Career Development Award from the Juvenile Diabetes Research Foundation. K.C. was supported by a Postgraduate research award from the National Heart Foundation of Australia (PC 02M 0875), a TACTICS scholarship (Canada), and a National Health and Medical Research Council Neil Hamilton Fairley scholarship (no. 440712).
Hsueh W, Abel ED, Breslow JL, Maeda N, Davis RC, Fisher EA, Dansky H, McClain DA, McIndoe R, Wassef MK, Rabadan-Diehl C, Goldberg IJ. Recipes for creating animal models of diabetic cardiovascular disease. Circ Res. 2007; 100: 1415–1427.
Moravski CJ, Kelly DJ, Cooper ME, Gilbert RE, Bertram JF, Shahinfar S, Skinner SL, Wilkinson-Berka JL. Retinal neovascularization is prevented by blockade of the renin-angiotensin system. Hypertension. 2000; 36: 1099–1104.
Connelly KA, Zhang Y, Prior DL, Martin J, Cox AJ, Thai K, Feneley MP, Tsoporis J, White KE, Krum H, Gilbert RE. Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat. Cardiovasc Res. In Press.
Kelly DJ, Zhang Y, Hepper C, Gow RM, Jaworski K, Kemp BE, Wilkinson-Berka JL, Gilbert RE. Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes. 2003; 52: 512–518.
Cao Z, Cooper ME, Wu LL, Cox AJ, Jandeleit-Dahm K, Kelly DJ, Gilbert RE. Blockade of the renin-angiotensin and endothelin systems on progressive renal injury. Hypertension. 2000; 36: 561–568.