Pigs in space

Abstract

Despite the common knowledge that experimental data from animal models cannot readily be translated into human disease, clinical trials are often based on translational research performed on species evolutionarily distant from humans. The troublesome task of extrapolating the findings from one species to another has haunted physiological experimentation since its early dawn, and the issue is still relevant in cardiovascular science with the common use of genetically modified mice. For instance, diabetic and ischemic changes in the myocardium are often pursued using in-vivo and in-vitro models mainly based on rodent cardiovascular physiology and cellular biology 1. The concern does not stop with only speculative reservation. Modern pharmacological studies most often test new drugs on small animals, resulting in a series of disappointments in human phase-3 trials 2,3, which has certainly cost us astronomical sums and may have even led to disease and death. The cardiac response to myocardial hypoxia should ideally be pursued in models that mimic human anatomy, biochemistry, and function in both health and disease. In this context, we suggest the porcine heart as the best model of choice in experimental cardiovascular research because of the following hallmarks: first and foremost, the coronary blood supply to the myocardium equals that of the normal human anatomy 4. In contrast, the functional end arteries do not supply the heart muscle in other mammalian species. Second, the cardiac production of natriuretic peptides, the gold standard endocrine markers of heart failure, differs markedly among mammalian hearts, wherein normal hormonal expression resides in the human and porcine atria 5,6 but is most dominant in the ventricular chambers in, for instance, rodents 7. Such intrinsic differences are likely to affect the endocrine cardiac response during the disease. Finally, porcine and human cardiac functions are similar, which facilitates direct interpretation to human medicine 8. Elucidation of several cardiovascular disease entities can be achieved using porcine models. For instance, we compared the neonate cardiovascular response of pigs in terms of cardiac natriuretic peptide gene expression and found patterns similar to those of neonate children. This opens up for the possibility of studying, for instance, the effects of gestational diabetes on neonate physiology. Moreover, cardiac congenital anomalies present in humans can easily be induced in pigs, and the devices for treating these conditions can even be tested on pigs 9. Another major disease entity for cardiovascular endocrinology is heart failure, in which natriuretic peptides have a central role in both pathobiological and clinical diagnosis. Accurate biochemical tools have been developed for this peptide system in pigs 10, which is not the case for other species, including mice. With an increasing appreciation and understanding of the porcine transcriptome 11,12, as well as genetically modified pigs already over the doorstep 13,14, cardiovascular endocrinology should consider the best choice of animal models for the studies on human cardiovascular pathophysiology. In this respect, a completely new pig model for human atherosclerosis has just been developed at our university by inducing overexpression of the gene for liver-specific proprotein convertase subtilisin/kexin type 9 (PCSK9), which causes severe hypercholesterolemia and human-like atherosclerosis 15. This model may easily prove valuable for several types of translational research on atherosclerosis and also in diabetes complications. For now, we would like to advocate that the use of pigs should be pursued more eagerly in elucidating human cardiovascular endocrinology (as pigs are only found in space in the Muppet Show) 16,17. Acknowledgements Conflicts of interest There are no conflicts of interest.