Animal Models of Heart Failure: the Forgotten Animal Model

Heart failure remains a leading cause of death and an economic burden worldwide. The research community continues to tackle this epidemic by dedicating extensive research efforts to delineate heart failure mechanisms and to develop novel therapeutics. Animal models form the cornerstone of these basic and translational research efforts; however, despite decades of extensive research, human heart failure remains poorly understood and only limited therapeutic measures are available to human patients. While animal models in species ranging from fruit flies to primates have considerably advanced our understanding of animal cardiovascular physiology and pathophysiology, research success from these models have not proportionally translated into therapeutic success for human patients. A growing body of human‐specific mechanistic and clinical data indicate that the translational discrepancy is primarily due to the species barrier: from gene expression to excitation‐contraction coupling to drug responses, animal models do not accurately replicate human heart failure causes, natural history, manifestations, complications, and responses to treatments. Immutable interspecies differences occur at every level of biological activity and are further confounded by biological variability (age, sex, and strain), and even differences in housing and husbandry practices as well as experimental conditions. Given the disappointing history of animal research translation for heart failure, the paucity of definitive treatments, and the emergence of heart failure as a dominant cause of morbidity and mortality in the U.S. and across the world, the need to move from animal models to human‐specific research seems evident. In fact, other researchers in the field are urging the heart failure community to “modify and enhance the currently dominant translational paradigm and provide new important directions of research.” Here we present evidence indicating why it is imperative for the heart failure research community to devise a plan to incorporate Homo sapiens as the quintessential animal model. We provide specific examples of how genetic, biochemical, physiological, anatomical, and technical limitations inherent in animal models can be overcome with similar studies in humans and present how an integrative human‐based research framework incorporating every level of human biological complexity – from nucleic acid to whole organism level and beyond – can serve as the primary platform from which basic science discoveries are launched and more effective therapeutics are tested. If the ultimate goal of the research community is to advance preventive and reparative approaches for human heart failure, we need to transition from the quest to generate “better” animal models to the prioritized, widespread use of human‐based, human‐relevant research strategies. Support or Funding Information Author Institution