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Figure 2. Translational failures are often due to the contrasting characteristics of animal model investigations and of interventional therapeutic studies in human patients. Animal model studies are excellent tools for testing a hypothesis on the role of a cellular mechanism, or of a specific molecular signal in the pathophysiology of disease. To achieve these goals, animal model investigations are designed to minimize variability by using standardized protocols that control the impact of comorbid conditions, genetic differences or environmental conditions. These studies provide valuable information on cell biological mechanisms and have potential implications for organ function, but are of much more limited value in predicting the outcome of a similar intervention in the clinical context. In complex multifactorial human diseases, patient populations exhibit remarkable pathophysiologic heterogeneity. Moreover, differences in age, gender, genetic substrate, the presence or absence of concomitant diseases, treatment with other agents, environmental conditions, may directly affect cellular responses, affecting clinical outcomes. No animal model can recapitulate the pathophysiologic heterogeneity of human disease. Thus, animal model investigations should optimally be used for cell biological dissection, and not for the prediction of therapeutic outcomes. Moreover, in the clinical context, stratification of patients with complex clinical syndromes (such as heart failure, or chronic renal insufficiency) to pathophysiologically distinct subpopulations with well-defined molecular perturbations may improve the chances for successful translation.