Animal Models in Heart Failure: A First Step in Avoiding a Translation Failure
Disclosure: Dr. Ardehali and Ms. Rines have nothing to disclose.
Pub Date: Thursday, May 17, 2012
Author: Amy Rines, BA, and Hossein Ardehali, MD, PhD
Affiliation: Feinberg Cardiovascular Research Institute, Northwestern University
Citation: Houser SR, Margulies KB, Murphy AM, Spinale F, Francis GS, Prabhu SD, Rockman HA, Kass DA, Molkentin JD, Sussman MA, Koch W; on behalf of the American Heart Association Council on Basic Cardiovascular Sciences, Council on Clinical Cardiology, and Council on Functional Genomics and Translational Biology. Animal models of heart failure: a scientific statement from the American Heart Association. Circulation Research. 2012: published online before print May 17, 2012, 10.1161/RES.0b013e3182582523.
Heart failure remains a leading cause of death in the developed world. Progress toward developing novel therapeutic approaches to treating heart failure requires research utilizing appropriate animal models that sufficiently reproduce characteristics of heart failure found in humans. Finding animal models for this purpose can be particularly challenging for a multifactorial disorder such as heart failure, which can stem from a number of causes and present a diverse set of symptoms. Thus, established guidelines for selecting appropriate animal models to study particular manifestations of heart failure are warranted.
Margulies et al. describe the major clinical characteristics of heart failure in humans, as well as the small and large animal models currently available for heart failure, and the challenges associated with using these models. The authors stress that not all heart failure cases in the clinic present with the same complications, and thus a “one size fits all” mentality is not appropriate in selecting an animal model for studying heart failure. Instead, one should select an animal model based on the characteristics present in the particular clinical form of heart failure of interest, depending on whether it is related to valvular lesions, dilated cardiomyopathies, hypertension, or restrictive cardiomyopathies. While others have provided summaries of available animal models for heart failure research 1, 2, specific guidelines for selecting animal models that best recapitulate specific clinical forms of heart failure have not been described.
A set of guidelines such as this shines a central focus on the limitations associated with the use of animal models. These limitations should remain at the forethought of any researcher who strives to translate their basic research into a clinically relevant finding. Indeed, review of the literature has revealed that at most one third of highly cited animal research translates to clinical results3. This translational competency is reduced if the animal studies are not designed and implemented carefully, and if they lack proper randomization and blinding4. Beyond the need for careful experimental design and execution, a major concern involving many animal models is that they do not exhibit the same characteristics as chronic heart disease in humans. Thus, as Margulies et al. emphasize, the use of animal models that most closely mimics the clinical manifestation of the disease can increase the potential for animal model research to translate into successful clinical therapies.
However, even with sound experimental practice and a careful choice of animal model, there are still unavoidable discrepancies between animal and clinical research5. This is revealed by an examination of clinical trials of reperfusion treatments, in which several reperfusion injury treatments found to be effective in animal models have not translated to clinical efficacy6, 7. Although occlusion modeling did not accurately reflect the more heterogeneous clinical situation in several of these trials, there were also additional variables that differed among the animal research and clinical studies. These variables included, among others, comorbidities in the clinical population, the typically older and more diverse population of patients in the clinic compared to the young animals frequently used in animal research, and the inability to detect infarction endpoints as extensively as in animal models. For the researcher who would like to maximize the likelihood of discovering novel clinical treatments with animal research, one should carefully consider these discrepancies and take strides to better match the conditions of animal research to clinical trials. These steps can include using multiple animal models with different comorbidities if possible, verifying treatment efficacy in animal models at multiple sites, and working first with a small population of clinical subjects that best resembles the animal models before expanding to large population trials.
Despite the limitations, the use of animal models has been crucial in the progression of developing new clinical therapeutics. One of the greatest successes in translated therapies of heart failure has been β–adrenergic receptor antagonists8. The translation of this therapy occurred only after extensive animal modeling work at several institutions. Additionally, basic science and clinical research findings were integrated both from bench-to-bedside and bedside-to-bench to help develop effective clinical therapies. Thus, the success of this therapy highlights the importance of carefully designed and diffuse animal research that remains informed from clinical data.
Overall, there is no doubt that animal models of cardiac disease have been and will continue to be essential in developing new clinical therapies. However, the road to successful translation is complex and requires many careful considerations, including an appropriate choice of animal models, systematic experimental design, involvement of multiple institutions, and integration of information from both the bench and the bedside. The guidelines proposed by Margulies et al. should give the researcher who is interested in translating therapies for heart failure a solid foundation on which to choose suitable animal models, which is an essential first step in discovering novel and promising treatments.
- Dixon JA, Spinale FG. Large animal models of heart failure: a critical link in the translation of basic science to clinical practice. Circ Heart Fail. 2009;2(3):262-71.
- Patten RD, Hall-Porter MR. Small animal models of heart failure: development of novel therapies, past and present. Circ Heart Fail. 2009;2(2):138-44.
- Hackam DG, Redelmeier DA. Translation of research evidence from animals to humans. JAMA. 2006;296(14):1731-2.
- Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I, Group RATSR. Where is the evidence that animal research benefits humans? BMJ. 2004;328(7438):514-7.
- van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O'Collins V, et al. Can animal models of disease reliably inform human studies? PLoS Med. 2010;7(3):e1000245.
- Dirksen MT, Laarman GJ, Simoons ML, Duncker DJ. Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies. Cardiovasc Res. 2007;74(3):343-55.
- Bolli R, Becker L, Gross G, Mentzer R, Balshaw D, Lathrop DA, et al. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res. 2004;95(2):125-34.
- Feldman AM. The development of β-adrenergic receptor antagonists for the treatment of heart failure: a paradigm for translational science. Circ Res. 2011;109(10):1173-5.