aDepartment of Clinical Biochemistry, Rigshospitalet, Copenhagen University, Copenhagen, Denmark
bDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark
Correspondence to Jens P. Goetze, MD, DMSc, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University, Blegdamsvej 9, DK-2100 Copenhagen, Denmark Tel: +45 3545 2202; fax: +45 3545 2880; e-mail: firstname.lastname@example.org
Received January 16, 2013
Accepted January 16, 2013
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.
Conflicts of interest
There are no conflicts of interest.
1. Krishnamurthy P, Rajasingh J, Lambers E, Qin G, Losordo DW, Kishore R. IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circ Res. 2009;104:e9–e18
2. Tardif JC, McMurray JJ, Klug E, Small R, Schumi J, Choi J, et al. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;24:1761–1768
3. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–2099
4. Weaver ME, Pantely GA, Bristow JD, Ladley HD. A quantitative study of the anatomy and distribution of coronary arteries in swine in comparison with other animals and man. Cardiovasc Res. 1986;20:907–917
5. Christoffersen C, Goetze JP, Bartels ED, Larsen MO, Ribel U, Rehfeld JF, et al. Chamber-dependent expression of brain natriuretic peptide and its mRNA in normal and diabetic pig heart. Hypertension. 2002;40:54–60
6. Goetze JP, Friis-Hansen L, Rehfeld JF, Nilsson B, Svendsen JH. Atrial secretion of B-type natriuretic peptide. Eur Heart J. 2006;27:1648–1650
7. Goetze JP, Georg B, Jørgensen HL, Fahrenkrug J. Chamber-dependent circadian expression of cardiac natriuretic peptides. Regul Pept. 2010;160:140–145
8. Schuleri KH, Boyle AJ, Centola M, Amado LC, Evers R, Zimmet JM, et al. The adult Göttingen minipig as a model for chronic heart failure after myocardial infarction: focus on cardiovascular imaging and regenerative therapies. Comp Med. 2008;58:568–579
9. Smith J, Goetze JP, Søndergaard L, Kjaergaard J, Iversen KK, Vejlstrup NG, et al. Myocardial hypertrophy after pulmonary regurgitation and valve implantation in pigs. Int J Cardiol. 2012;9:29–33
10. Hunter I, Rehfeld JF, Goetze JP. Measurement of the total proANP product in mammals by processing independent analysis. J Immunol Methods. 2011;370:104–110
11. Depre C, Tomlinson JE, Kudej RK, Gaussin V, Thompson E, Kim SJ, et al. Gene program for cardiac cell survival induced by transient ischemia in conscious pigs. Proc Natl Acad Sci USA. 2001;98:9336–9341
12. Tuggle CK, Wang Y, Couture O. Advances in swine transcriptomics. Int J Biol Sci. 2007;3:132–152
13. Rogers CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, et al. Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science. 2008;321:1837–1841
14. Casu A, Echeverri GJ, Bottino R, van der Windt DJ, He J, Ekser B, et al. Insulin secretion and glucose metabolism in alpha 1,3-galactosyltransferase knock-out pigs compared to wild-type pigs. Xenotransplantation. 2010;17:131–139
15. Al-Mashhadi RH, Sørensen CB, Kragh PM, Christoffersen C, Mortensen MB, Tolbod LP, et al. Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Sci Transl Med. 2013;5:166ra1 doi: 10.1126/scitranslmed.3004853
16. Munk M, Memon AA, Goetze JP, Nielsen LB, Nexo E, Sorensen BS. Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes. PLoS One. 2012;7:e40243
17. Kousholt B, Larsen JR, Hasenkam JM, Burnett JC, Goetze JP. BNP infusion in ischemia/reperfusion damage inverses the cardiac response and reduces infarction size. Cardiovasc Endocrinol. 2012;1:4–12