Increased apoptosis and myocyte enlargement with decreased cardiac mass; distinctive features of the aging male, but not female, monkey heart

Abstract

We studied gender-specific changes in aging cardiomyopathy in a primate model, Macaca fascicularis, free of the major human diseases, complicating the interpretation of data specific to aging in humans. Left ventricular (LV) weight/body weight decreased, p<0.05, in old males but did not change in old females. However, despite the decrease in LV weight, mean myocyte cross-sectional area in the old males increased by 51%. This increase in myocyte size was not uniform in old males, i.e., it was manifest in only 20-30% of all the myocytes from old males. In old males there was a 4-fold increase in frequency of myocyte apoptosis without any increase in proliferation-capable myocytes assessed by Ki-67 expression. Apoptosis was unchanged in old female monkey hearts, whereas the frequency of myocytes expressing Ki-67 declined 90%. These results, opposite to findings from rodent studies, indicate distinct differences in which male and female monkeys maintain functional heart mass during aging. The old male hearts demonstrated increased apoptosis, which more than offset the myocyte hypertrophy. Interestingly, the hypertrophy was not uniform and there was no significant increase in myocyte proliferation.

Figure 1

Normalized histograms and density traces for cross-sectional areas of myocytes from young (black bars) and old (grey bars) males (top) and females (bottom). At least 750 areas were measured for each histogram. The small fraction of hypertrophied myocytes is shown by the distributions at the right, without corresponding values for young animals.

Figure 2

(Top panel) Effects of age and gender on mean cardiac myocyte cross-sectional area in monkeys (YM, n=12; OM, n=9; YF, n=7; OF, n= 6). Note the significant increase in cross-sectional area in old male monkeys,*p<0.001 vs. other groups; the frequency of apoptotic myocytes (middle panel) (YM, n=10; OM, n=9; YF, n=9; OF, n= 11) and Ki-67 positive cells (bottom panel) (YM, n=6; OM, n=11; YF, n=7; OF, n= 11) are compared among the 4 groups. *p<0.05 vs. all other groups.