LETTER TO THE EDITOR
A four-year-old rabbit cannot be considered the right model for investigating cardiac senescence
Pasquale Abete, MD, PhDa,
Domenico de Santis, MDa,
Mario Condorelli, MDa,
Claudio Napoli, MD, PhDa and
Franco Rengo, MDa
a Dipartimento di Medicina Clinica e Scienze, Cardiovascolari ed Immunologiche, Cattedra di Geriatria, Università degli Studi di Napoli "Federico II", Via S. Pansini, 5, 80131 Napoli, Italy
p.abete{at}unina.it
Przyklenk et al. (1) have recently shown that cardioprotection with ischemic preconditioning (PC) is preserved in the senescent heart. The investigators found no differences in infarct size reduction by PC among adult (4 to 6 months), middle aged ( 2 years) and old (4 years) rabbits (1). Reduction of infarct size on "in vivo" rabbits may be considered an appropriate experimental model to study ischemic PC in animals. However, when considered in cardiac aging, serious concerns arise about the experimental model involved in their study. Indeed, animal models are used in aging research to overcome the limitation of studying aging in humans (e.g., the relatively long life span of humans). Because most aspects of aging in rodents are similar to human aging despite their short life span, rats and mice have been used extensively to study the pathophysiology of aging (2).
In contrast, data on the senescent rabbit are not available because of its relative long life span. In fact, the maximum life span potential (MLSP) for rabbits is 13 years (3,4); thus, if we optimistically consider MLSP for humans as 100 years, a 4-year-old rabbit cannot be considered a good model of the aging heart. A 4-year-old rabbit could be compared to a 30-year-old human and obviously a 6-month-old rabbit to 4-year-old human. Accordingly, morphologic markers of cardiovascular aging are qualitatively but not quantitatively similar to that observed in well-studied models of aging. Przyklenk et al. (1) showed that mean myocyte cross-sectional area increased from 397 ± 7 µm2 in adult to 445 ± 11 µm2 in middle aged (+12%) and to 506 ± 10 µm2 in old (+27%) rabbits. In addition, the investigators also claimed that myocardial collagen content increased from 6.2 ± 0.3% in adult versus 10.8 ± 0.5% in old rabbit heart. In both cases, these age-related modifications are significantly smaller than that found by Anversa et al. (5), who demonstrated that myocyte cell volume increases up to 60% from adult to senescent rat hearts while collagen content increases from 7% in adult to 22% in senescent rat hearts. The modifications showed by Przyklenk et al. (1) are approximately half of those expected from a validated model of the aging heart.
Conversely, reduction of ischemic PC mechanism has been well established in a 24-month-old rat model (6–9) that proportionally represents a human being of age 60 (rat MLSP = 3.5 years) (2). Moreover, Przyklenk et al. (1) also showed a slight reduction of ischemic PC efficacy in two-year and three- to five-year versus four- to six-month-old rabbit ( 15%). This is in agreement with the concept that pathophysiologic modifications that occur during aging are not "on–off" and that ischemic PC might have a progressive decline with aging. Infarct size progressively increases in the preconditioned rat heart (9) from 15% in adult animals (3 months), to 25% in middle-aged (12 months) and to 40% in old animals (20 months). Accordingly, as most of the age-related pathophysiologic modifications were observed in the senescent rat and human heart, ischemic PC was restored or preserved by antiaging interventions such as exercise training (10,11). On the basis of this evidence, ischemic PC efficacy should be significantly reduced also in 7- to 8-year-old rabbits that probably represent the 24-month-rat and 60-year-old human homologues of cardiac senescence.
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References
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1. Przyklenk K, Li G, Whittaker P. No loss in the in vivo efficacy of ischemic preconditioning in middle-aged and older rabbits. J Am Coll Cardiol. 2001;38:1741–1747[Abstract/Free Full Text]
2. Hazzard DG. Relevance of the rodent model to human aging studies. Neurobiol Aging. 1991;12:645–649[CrossRef][Medline]
3. Altman P, Dittmer P. Life span: animals. Biology Data Book. Bethesda, MD: Federation of American Societies for Experimental Biology; 1972. p. 229–235
4. Barja G, Herrero A. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J. 2000;14:312–318[Abstract/Free Full Text]
5. Anversa P, Palackal T, Sonnenblick EH, Olivetti G, Meggs LG, Capasso JM. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res. 1990;67:871–885[Abstract/Free Full Text]
6. Abete P, Ferrara N, Cioppa A, et al. Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol. 1996;27:1777–1786[Abstract]
7. Tani M, Suganuma H, Shinmura K, Hayashi Y, Guo X, Nakamura Y. Changes in ischemic tolerance and effects of ischemic preconditioning in middle-aged rat hearts. Circulation. 1997;95:2559–2566[Abstract/Free Full Text]
8. Fenton RA, Dickson EW, Meyer TE, Dobson JG Jr. Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol. 2000;32:1371–1375[CrossRef][Medline]
9. Schulman D, Latchman DS, Yellon DM. Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol (Heart Circ Physiol). 2001;281:H1630–1636[Abstract/Free Full Text]
10. Abete P, Calabrese C, Ferrara N, et al. Exercise training restores ischemic preconditioning in the aging heart. J Am Coll Cardiol. 2000;36:643–650[Abstract/Free Full Text]
11. Abete P, Ferrara N, Cacciatore F, et al. High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients. J Am Coll Cardiol. 2001;38:1357–1365[Abstract/Free Full Text]
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