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.