Small and large animal models in cardiac contraction research: advantages and disadvantages

Abstract

The mammalian heart is responsible for not only pumping blood throughout the body but also adjusting this pumping activity quickly depending upon sudden changes in the metabolic demands of the body. For the most part, the human heart is capable of performing its duties without complications; however, throughout many decades of use, at some point this system encounters problems. Research into the heart's activities during healthy states and during adverse impacts that occur in disease states is necessary in order to strategize novel treatment options to ultimately prolong and improve patients' lives. Animal models are an important aspect of cardiac research where a variety of cardiac processes and therapeutic targets can be studied. However, there are differences between the heart of a human being and an animal and depending on the specific animal, these differences can become more pronounced and in certain cases limiting. There is no ideal animal model available for cardiac research, the use of each animal model is accompanied with its own set of advantages and disadvantages. In this review, we will discuss these advantages and disadvantages of commonly used laboratory animals including mouse, rat, rabbit, canine, swine, and sheep. Since the goal of cardiac research is to enhance our understanding of human health and disease and help improve clinical outcomes, we will also discuss the role of human cardiac tissue in cardiac research. This review will focus on the cardiac ventricular contractile and relaxation kinetics of humans and animal models in order to illustrate these differences.

Keywords: (dF/dt(max))/F; (dF/dt(min))/F; AAV; APD; Cardiac contractility; Cardiac kinetics; Heart failure; Heart rate; LV dP/dt(max); LV dP/dt(min); LV τ; LVSP; MHC; Maximal velocity of contraction divided by developed force in cardiac trabeculae; Maximal velocity of contraction in cardiac trabeculae; Maximal velocity of relaxation divided by developed force in cardiac trabeculae; Maximal velocity of relaxation in cardiac trabeculae; NCX; RT(50); Relaxation time 50%: Time from peak force to 50% relaxation in cardiac trabeculae; SERCA; Species; TTP; action potential duration; adeno-associated virus; dF/dt(max); dF/dt(min); left ventricular isovolumic relaxation time constant; left ventricular maximal rate of pressure decline; left ventricular maximal rate of pressure rise; left ventricular systolic pressure; myosin heavy chain; sarcoplasmic-reticulum calcium ATPase; sodium calcium exchanger; time to peak: time from stimulation to peak force in cardiac trabeculae.

Figure 1

Right ventricle muscles were stimulated ex vivo near the species’ resting heart rates as indicated. For clarity purposes, only a single twitch of each species is shown. Temperature is 37 °C in all traces. Sources of tracings are as follows, mouse: C57BL/10 strain adapted from (J.A. Rafael-Fortney, et al., 2011), rat: male LBNF-1 strain adapted from (Monasky, et al., 2007), rabbit: unpublished data, male New Zealand White rabbit, canine: mixed-breed canine adapted from (Billman, et al., 2010), Human: unpublished data, donor heart with abnormal ECG, borderline concentric left ventricular hypertrophy, mitral valve regurgitation, and ejection fraction of 55%

Figure 2

In vivo and ex vivo kinetics of contraction and relaxation of large animal models are more similar to humans than small animal models while pressure generated by the left ventricle remains relatively constant across species. Data was obtained from animal/human ratios indicated in Tables 2–6. Note that no ex vivo right ventricular trabeculae data is presented for swine and sheep. LV dP/dt_max: left ventricular maximal rate of pressure rise. LV dP/dt_min: left ventricular maximal rate of pressure decline. RV (dF/dt_max)/F: maximal velocity of contraction divided by developed force in right ventricular trabeculae. RV (dF/dt_min)/F: maximal velocity of relaxation divided by developed force in right ventricular trabeculae. See Tables 2–6 for references and values.