LETTER TO THE EDITOR
Reply
Karin Przyklenk, PhDa and
Peter Whittaker, PhDa
a Heart Institute/Research, Good Samaritan Hospital, 1225 Wilshire Boulevard, Los Angeles, California 90017-2395, USA
karinp{at}dnamail.com
We thank Dr. Abete and colleagues for their interest in our work (1) and for their query of whether the rabbit is the "right" model to assess the efficacy of ischemic preconditioning (PC) in aging animals.
The rabbit has not been extensively utilized in aging studies. Indeed, there is even controversy as to the maximum life span of the rabbit, with values of 7 years (2,3) versus 13 years (cited by Abete et al.) having been reported. This variation in life span is not unique to the rabbit, and it underscores a crucial caveat: life span or age is, in itself, a poor predictor of the aging process (4). Thus, evaluation of established biomarkers of aging (4)—rather than attempts to equate, from maximum life spans, relative ages among species—may represent a more germane approach in addressing this question.
We observed significant myocyte hypertrophy and myocardial fibrosis—the morphologic hallmarks of cardiovascular aging—in four-year-old versus young adult rabbits (1). For example, left ventricular collagen content was 10.8 ± 0.5% (SD 1.8%) versus 6.2 ± 0.3% (SD 1.2%), respectively—a mean 1.7-fold increase (range: 1.2- to 2.5-fold, computed from the SD values) in fibrosis. Abete and colleagues contend that our results are qualitatively, but not quantitatively, similar to those observed in the  2-year-old rat, an accepted model of senescence. We find, however, that despite methodologic differences among studies, our results fall within the range of data reported for rats (5,6)—including those from Anversa et al. (5), in which collagen volume fraction was 16 ± 4% (mean ± SD) versus 8 ± 2% in 29- versus 4-month-old animals, corresponding to a twofold increase (range: 1.2- to 3.3-fold) in fibrosis. (Of note, the values of 7% and 22% cited by Abete et al. were obtained in the right, rather than the left, ventricle (5)). With regard to hypertrophy, our 1.3-fold increase in myocyte cross-sectional area compares favorably with the 1.4-fold increase seen in 23-month-old versus 7-month-old rats (6), and, interestingly, with human autopsy data (death unrelated to cardiovascular disease) showing, via regression analysis, a 1.3-fold increase in myocyte volume between 20 and 75 years of age (7). Finally, the four-year-old rabbits displayed a third, functional hallmark of cardiovascular aging—loss of responsiveness to beta-adrenergic stimulation (1).
There is an emerging consensus that, in isolated buffer-perfused rat heart, the efficacy of infarct size reduction with PC wanes with increasing age (8,9). In contrast—and contrary to the correspondents’ interpretation of our data—we found sustained, 49%, 58% and 50% reductions of infarct size in PC rabbits versus age-matched adult, two-year-old and four-year-old controls (1). Does this difference in outcome make the four-year-old rabbit, exhibiting definitive biomarkers of cardiovascular aging, the "wrong" model? We believe this disparity is not a question of "right" versus "wrong" models. Indeed, recent preliminary evidence from isolated human myocardial samples—arguably a "right" model—revealed persistent PC-induced protection even in cohorts aged 70 to 90 years old (10). Rather, this may reflect underlying mechanistic difference(s) among models/species that warrant resolution.
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References
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- Przyklenk K, Li G, Whittaker P. No loss in the in vivo efficacy of ischemic preconditioning in middle-aged and old rabbits. J Am Coll Cardiol. 2001;38:1741–1747[Abstract/Free Full Text]
- Rivard A, Fabre JE, Silver M, et al. Age-dependent impairment of angiogenesis. Circulation. 1999;99:111–120[Abstract/Free Full Text]
- Weisbroth SH, Flatt HE, Kraus AL. The Histology of the Laboratory Rabbit. New York, NY: Academic Press; 1974. p. 331
- Crawford D. Discussion 1: Is life-span the best measure of aging? : Science SAGE-KE; 2001. http://sageke.sciencemag.org/cgi/forum?section=Discussions
- Anversa P, Palackal T, Sonnenblick EH, et al. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res. 1990;67:871–885[Abstract/Free Full Text]
- Raya TE, Gaballa M, Anderson P, Goldman S. Left ventricular function and remodeling after myocardial infarction in aging rats. Am J Physiol. 1997;273:H2652–2658
- Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart: myocyte loss and reactive cellular hypertrophy. Circ Res. 1991;68:1560–1568[Abstract/Free Full Text]
- 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]
- 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. 2001;281:H1630–1636
- Loubani M, Ghosh S, Galinanes M. Does age really affect the tolerance to ischemia and protection of ischemic preconditioning of the human myocardium? (abstr)Circulation. 2001;104(Suppl II):II44
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