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

SIMPLE SUMMARY: Human heart failure (HF) is a complex clinical syndrome that can be caused by a variety of diseases. While long-term high blood pressure and heart attacks are major contributing factors, there can be many diseases of the heart and circulation that contribute to the development of HF. Although there have been salutary improvements in the medical management of HF over the last 30 years, ongoing ill effects of living with the syndrome and the persistently high death rates mean there is an irrefutable need for new and improved treatment options. Well-characterized animal models have contributed, and continue to contribute, much to the advancement of clinical care. This review will summarize the main large animal models of HF developed to date. Studies utilizing these large animal models are an essential step leading to the development of novel pharmaceutical and device-based therapies before they can undergo definitive clinical trials. This review will discuss the various benefits of different large animal models of HF and highlight some key deficiencies to date. There is clearly a need for ongoing development of clinically relevant large animal models of HF. ABSTRACT: 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.