Large Animal Models of Heart Failure: Reduced vs. Preserved Ejection Fraction

Heart failure (HF) is the final common end point of multiple metabolic and cardiovascular diseases and imposes a significant health care burden worldwide. Despite significant improvements in clinical management and outcomes, morbidity and mortality remain high and there remains an indisputable need for improved treatment options. The pathophysiology of HF is complex and covers a spectrum of clinical presentations from HF with reduced ejection fraction (HFrEF) (≤40% EF) through to HF with preserved EF (HFpEF), with HFpEF patients demonstrating a reduced ability of the heart to relax despite an EF maintained above 50%. Prior to the last decade, the majority of clinical trials and animal models addressed HFrEF. Despite growing efforts recently to understand underlying mechanisms of HFpEF and find effective therapies for its treatment, clinical trials in patients with HFpEF have failed to demonstrate improvements in mortality. A significant obstacle to therapeutic innovation in HFpEF is the absence of preclinical models including large animal models which, unlike rodents, permit detailed instrumentation and extensive imaging and sampling protocols. Although several large animal models of HFpEF have been reported, none fulfil all the features present in human disease and few demonstrate progression to frank decompensated HF. This review summarizes well-established models of HFrEF in pigs, dogs and sheep and discusses attempts to date to model HFpEF in these species.