Large Animal Models of Heart Failure

Abstract

Abstract-Congestive heart failure (HF) is a clinical syndrome, with hallmarks of fatigue and dyspnea, that continues to be highly prevalent and morbid. Because of the growing burden of HF as the population ages, the need to develop new pharmacological treatments and therapeutic interventions is of paramount importance. Key Words: myocardial infarction Ⅲ myocardial remodeling Ⅲ overload states Ⅲ rapid pacing C ongestive heart failure (HF) is a constellation of symptoms, with hallmarks of fatigue and dyspnea, which continues to be a highly prevalent and morbid clinical syndrome. Although the etiologic underpinnings of HF can be diverse, common pathophysiologic features include changes in left ventricle (LV) structure, function, and neurohormonal activation. The impact of HF will undoubtedly become even more substantial as the population ages. Accordingly, the need to develop new pharmacological treatments and therapeutic interventions for HF is of paramount importance. The journey from discovery, to understanding, to clinical application of the biological basis of HF is one that can only be traveled with the use of large animal models that recapitulate this clinical phenotype.The current pharmacological armamentarium in the treatment of HF includes angiotensin-converting enzyme inhibitors, aldosterone antagonists, and angiotensin and ␤-adrenergic receptor blockade. 1 Although inhibition of the renin-angiotensin-aldosterone and sympathetic adrenergic systems have provided clear benefit to those suffering from HF, the disease process nonetheless continues. Therefore, further research is required to find additional pathways and mechanisms to target in the battle against HF. The Need for Large Animal Models of HFSignificant insight into the molecular and cellular basis of cardiovascular biology has come from small animal models, particularly mice. However, significant differences exist with regard to cardiac characteristics such as heart rate, oxygen consumption, adrenergic receptor ratios, and response to loss of regulatory proteins, when mice are contrasted to humans. 2,3 Moreover, contractile protein expression, critical to the excitation-contraction coupling process, seems to differ between the 2 species, as evidenced by their differing predominant myosin isoforms. 2 Finally, evidence exists of significant phenotypic differences between mouse and human stem cells. 3 Consequently, extrapolation of murine systems, particularly after induction of cardiovascular stress, becomes problematic when making interpretations of human HF pathophysiology. Therefore, large animal models of HF, which more closely approximate human physiology, function, and anatomy, are essential to develop the discoveries from murine models into clinical therapies and interventions for HF.This review aims to summarize some of the more frequently used large animal models, which recapitulate the clinical HF phenotype arising from the common clinical etiologies of myocardial ischemia/infarction, ventricular overload states, and dilated cardiomyopath...

Isolation, Characterization and Differentiation Potential of Cardiac Progenitor Cells in Adult Pigs

“…DCM is defined by structural hallmarks of left ventricle dilation and increased left ventricle chamber radius-to-wall thickness ratio, resulting in increased left ventricle wall stress (Dixon and Spinale 2009 HCM is a primary myocardial disease that has variable manifestations because the interactions between the many facets of systolic and diastolic dysfunction of the heart are complex (Lin et al 2002) (Kushwaha et al 1997). …”

“…However, significant differences exist with regard to several cardiac characteristics when mice are compared with humans (Table 1) (Gandolfi et al 2011;Dixon et al 2009). An important parameter is heart rate, with an adult mouse heart beating 500-600 times per minute, compared with the 60-100 times typical of the human.…”

Patterns of arterial vascularization in swine hearts

“…Swine has also been used in the development of therapies for infarcted patients, such as pharmacological treatments, stem cell transplantation (Min et al 2012, Li et al 2013, and the use of angiogenic growth factors (Dixon & Spinale 2009). Banchi (1904) described the distribution of the coronary artery in humans and some animal species using the artery origin, which is largely responsible for the blood supply to the right posterior heart.…”

“…According to Dixon & Spinale (2009), although small animal models such as mice promote the understanding of the cellular and molecular basis of cardiovascular biology, to understand the mechanisms and biological bases of heart failure in humans, it is necessary to use large animals, which exhibit a similar clinical phenotype. Thus, swine have been widely used as a comparative model in recent years due to the anatomical and physiological similarities, both in normal and pathological conditions and in studies on acute heart failure (Santos et al 2012), atherosclerosis (Artinger et al 2009), valvular problems (Maluf et al 1993, Grehan et al 2000 and ventricular function (Hendry 1994).…”

Isolation, Characterization, and Spatial Distribution of Cardiac Progenitor Cells in the Sheep Heart

“…In order to optimize conditions under which CPC can be utilized to maximize their benefit for stem cell transplantation, cardiac progenitor cells need to be tested in large animals [18]. Several studies have been reported in pigs [19] and dogs [10], however, no studies have reported the isolation of cardiac progenitor cells from sheep or their effect on heart repair.…”