Large Animal Models of Ischemic Cardiomyopathy: Are They Enough to Bridge the Translational Gap?

Abstract

Heart failure is a devastating disease with high morbidity and mortality. In 2013, approximately 5.1 million people suffered from chronic heart failure in the United States. About 50% of these individuals died within 5 years of their initial diagnosis. The most common cause of heart failure is coronary artery disease. Unfortunately, treatment options remain limited. Current medical therapy, including angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists, and angiotensin and adrenergic receptor blockers, only slow disease progression. The chronic shortage of donor organs restricts the number of heart transplantations performed. Although novel approaches to cardiac regeneration, such as stemcell and gene therapy, are under investigation, proving efficacy and safety requires extensive preclinical studies before ‘‘first in man’’ studies can be performed. The success of clinical translation is highly dependent on how well animal models can recapitulate disease in humans and mimic how humans will respond to therapy. Modeling heart failure, however, can be challenging because heart failure results from a myriad of causes with distinct clinical features that need to be incorporated into animal models. Heart failure is also characterized by gradual deterioration of left ventricular (LV) function over a typical span of several years, which has been difficult to incorporate into existing animal models. Ischemic cardiomyopathy models were first developed in rats. Scientists created surgical models of myocardial infarction by either ligating or occluding the left anterior descending artery (LAD), causing left ventricular dysfunction. Rat models are generally preferable to mice because their larger size facilitates the performance of multimodality imaging, invasive hemodynamics, and histological analysis. The major advantage of mice, however, is the availability of transgenic and knockout strains and lower housing costs. With the advent of micro-imaging technology at specialized centers, the use of murine heart failure models has become more common albeit with greater expense for imaging. Importantly, the benefits of many of the heart failure therapies to date have first been observed in small animals. Using a rat model of myocardial infarction, for example, Pfeffer et al reported that ACE inhibitors reduced left ventricular (LV) dilatation, increased ejection fraction, and improved survival in rats with moderate to large infarcts. More recently, the role of calmodulin kinase II (CaMKII) in the causation and progression of cardiac hypertrophy was elucidated in mice. Subsequent studies in large animals and humans have shown that an increased expression of CAMKII in the myocardium is associated with the development of heart failure after myocardial infarction. Demonstration of efficacy and safety in small animal models alone, however, is insufficient for clinical Reprint requests: Patricia Nguyen, MD, Stanford Cardiovascular Institute, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building S140, Stanford, CA 94305-5111; pknguyen@stanford.edu; Joseph C. Wu, MD, PhD, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, 265 Campus Drive G1120B, Stanford, CA 94305-5454; joewu@stanford.edu J Nucl Cardiol 2015;22:666–72. 1071-3581/$34.00 Copyright 2015 American Society of Nuclear Cardiology.