Small animals and large animals, which is better for HF
preclinical
study?
Prior to preclinical research implementation, the following two issues
need to be settled: (1) primarily, what is the preferred species for
mimicking the pathophysiology of cardiovascular conditions in human? And
(2) secondly, which type of animal model is most suitable for HF
research.
To address the first question, it would be appropriate in the first
place to access the physiological and cardiovascular parameters across
species. As is well known, each species develops its cardiovascular
system at varying angles of orientation during evolution. Animal
physiological parameters (Table 1 ), such as body temperature
and heart rate, have been known to be essential parameters for species
survival. Some of the parameters, including blood pressure and body
temperature, are relatively constant among different species
(Table 1 ). Whereas other parameters, like heart rate and
respiratory rate, are in general inversely proportional to the animal
size. For instance, mice body size is smaller and exhibits a higher
heart rate than pigs (Table 1), one of the reasons can be attributed to
the shorter duration of diastole in mice. Mice need to match the shorter
time constant of the diastolic pressure decay, which can guarantee them
adequate coronary perfusion to maintain the balance between cardiac
metabolism and heart rate (Westerhof & Elzinga, 1993). Besides general
physiological parameters, speciation also produce differences in cardiac
function parameters among species (Table 1 ). Clinically,
echocardiography is the first-line technique for diagnostic evaluation
and prognostic stratification of patients with heart failure. The left
ventricular ejection fraction (LVEF) derived from echocardiography is
usually used to quantify cardiac dysfunction,with EF value ≥50% accept
as normal. This diagnostic criterion has been extended to animal models
of HF research. Most of the stimulus for heart failure, such as ischemia
reperfusion, aortic stenosis, chemical agents, etc., could induce
phenotype of heart failure with reduced ejection fraction (HFrEF)
(Table 2 ). Besides this, Other echocardiographic parameters are
also primary criteria for recognizing specific cardiovascular subtype of
animal model or conditions amenable to specific treatment (Table
1 ). Take Dahl salt-sensitive rat model (described in detail below) as
an example, fed them with high salt diet at different weeks of age may
produce very different clinical phenotypes of systolic versus diastolic
failure (Doi et al., 2000), which can be identified by echocardiographic
parameters of each model, including fractional shortening (FS) and peak
positive value of the first derivative of LV pressure (+dP/dtmax) (Table
1).
Summing up the above arguments, when the pathological or pharmacological
studies on HF are conducted with the rodents as the research object, due
to the main species differences between rodents and human, the above
mentioned physiological or cardiovascular parameters detected through
the experimental model of this species may not resemble the HF phenotype
observed in human. However, Small species is a more desired model in
cardiovascular research due to the advantages it imparts with respect to
experimental period and maintenance costs. Therefore, to avoid the huge
cost associated with clinical failure, it is usually necessary to verify
in an animal model (usually a large animal model) with less difference
from human species after preclinical research of rodents, such as dogs,
pigs and primates. In the state of consciousness, appropriate direct
measurement of cardiovascular function can supplement early rodent
research, and can be used as a better tool for translational research
(Y.-T. Shen, Chen, Testani, Regan, & Shannon, 2017). In addition, if
conditions permit, although the use of non-human primates in medical
research is generally very limited, accounting for only <0.3%
of the experimental animals used, the addition of non-human primate
models to preclinical studies is also a necessary choice to avoid the
risk of clinical failure. Non-human primates are considered to be
important transformation models because they have unique advantages
similar to humans in physiology, metabolism, biochemistry and heredity.