Large Animal Models of Heart Failure: A Translational Bridge to Clinical Success

Abstract

Preclinical large animal models of heart failure (HF) play a critical and expanding role in translating basic science findings to the development and clinical approval of novel therapeutics and devices. The complex combination of cardiovascular events and risk factors leading to HF has proved challenging for the development of new treatments for these patients. This state-of-the-art review presents historical and recent studies in porcine, ovine, and canine models of HF and outlines existing methodologies and physiological phenotypes. The translational importance of large animal studies to clinical success is also highlighted with an overview of recent devices approved by the Food and Drug Administration, together with preclinical HF animal studies used to aid both development and safety and/or efficacy testing. Increasing the use of large animal models of HF holds significant potential for identifying the novel mechanisms underlying the clinical condition and to improving physiological and economical translation of animal research to successfully treat human HF.

Keywords: AF, atrial fibrillation; ECM, extracellular matrix; EDP, end-diastolic pressure; EF, ejection fraction; FDA, Food and Drug Administration; HF, heart failure; HFpEF; HFpEF, heart failure with preserved ejection fraction; HFrEF; HFrEF, heart failure with reduced ejection fraction; I/R, ischemia/reperfusion; IABP, intra-aortic balloon pump; LAD, left anterior descending; LCx, left circumflex; LV, left ventricular; MI, myocardial infarction; PCI, percutaneous coronary intervention; RV, right ventricular; heart failure; large animal model; preclinical.

Graphical abstract

Central Illustration

Experimental Animal Models of Heart Failure: Techniques, Considerations, and Translation

Figure 1

Representative Angiogram Illustrating Aortic Banding Technique for Pressure Overload-Induced HF Angiography from a male Yucatan mini-pig (8 months old) showing placement of the aortic band (anatomically marked by radiopaque umbilical tape) and narrowing of the ascending aorta proximal to the brachiocephalic artery (large peripheral vessels outlined by red dashed line). The systolic pressure gradient is determined by a fluid-filled guide catheter (femoral insertion) connected to a pressure transducer and measured proximally and/or distally to the banding location. HF = heart failure.

Figure 2

Proposed Translational Flow for Development and Testing of New Therapies and Devices to Clinical Trials and FDA Approval Continuous testing and evaluation of safety and/or efficacy during the preclinical phase is a proposed pathway to improving clinical success. (Intra-aortic balloon pump [IABP], Impella, and TandemHeart pictures from were originally published in Atkinson et al. [170]). FDA = Food and Drug Administration.