Creation of clinically relevant model of chronic heart failure: Application of multi-modality imaging to define physiology

Abstract

Heart failure (HF) remains a major cause of mortality and morbidity in the world. Despite significant improvement in both medical and surgical therapies for HF, the mortality rate persists in excess of 50% after 5 years. Ischemic heart disease remains a leading cause of HF, and has a complex and incompletely understood pathophysiology with acute ischemic injury evolving to progressive left ventricular (LV) dysfunction and structural remodeling. These chronic functional and structural changes are associated with compensatory neurohormonal and metabolic alterations. The complex natural progress of atherosclerosis in humans can lead to either acute or slowly progressive coronary occlusion with the initial ischemic insult not easily emulated in an animal model. Pre-clinical approaches and large animal models to mimic ischemic heart disease have included single and multi-step catheter-based and surgical interventions. Generally, these interventions are performed in normal animals without the same pathophysiological substrate that leads to atherosclerosis or modulates the repair processes in humans. Therefore, the initial injury, repair, and remodeling processes may not be completely comparable to the clinical scenario. However, robust large animal models have tried to reproduce the fundamental characteristics of the process of repair and LV remodeling, including changes in LV geometry and dilatation, eccentric hypertrophy, infarct expansion, alterations in regional and global LV systolic and diastolic performance and functional reserve under stress, alterations in LV mass, and changes in regional wall thickness. Ideally, these animal models should have a mortality rate that is comparable to the clinical scenario and be highly reproducible in order to provide proper predicative value for clinical investigations into the pathophysiological mechanisms, and evaluation of novel therapeutics and interventions. While several large animal models have been employed to model ischemic heart disease in humans (including canine, porcine, and ovine), the coronary and gross cardiac anatomy in swine is fairly equivocal to humans. Unlike canine models, that have a significant native collateral circulation, swine have less native preformed collateral circulation in the mid-myocardium and sub-endocardium. Therefore, the porcine model is frequently used to test devices and therapies in models of acute ischemic heart disease, as well as models of chronic ventricular remodeling post-ischemic injury, and HF. The size of swine also allow for the use of standardized clinical investigational tools and equipment, including advanced clinical imaging systems. Recent reviews have summarized the animal models of HF, and some have even focused specifically on porcine models. Large animal models of HF with preserved ejection fraction (HFpEF) have been more difficult to establish partly due to the incomplete pathological understanding of HFpEF. There is one proposed swine model that is thought to mimic HFpEF that involves staged banding of Reprint requests: Albert J. Sinusas, MD, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, P.O. Box 208017, New Haven, CT 06520-8017; albert.sinusas@yale.edu J Nucl Cardiol 2015;22:673–6. 1071-3581/$34.00 Copyright 2015 American Society of Nuclear Cardiology.