Abstract 300: Ischemia and Reperfusion Injury Following Cardioplegic Arrest is Attenuated by Age and Testosterone Deficiency in Male but Not Female Mice

Abstract

Cardiovascular disease increases with age in both sexes and treatment can require cardiac surgery, where the heart is pre-treated with a protective cardioplegic solution before exposure to ischemia and reperfusion (I/R). While endogenous estrogen is thought to be beneficial in I/R, the role of testosterone in cardioprotection is not well understood and whether age modifies responses to I/R is unclear. We investigated sex- and age-specific differences in I/R injury in hearts pre-treated with a clinically relevant cardioplegic solution. Hearts were isolated from adult (6-9 mos) and old (22-28 mos) C57BL/6 mice of both sexes (n=27). They were Langendorff-perfused with Krebs-Henseleit buffer (15 min; 37°C), followed by St. Thomas’2 cardioplegia (6 min; 6-7°C). This was followed by 90 min of global ischemia (room temperature) and 30 min of reperfusion (37°C). Hearts were then perfused with triphenyltetrazolium chloride to quantify infarct area. The role of testosterone was investigated in gonadectomized (GDX; 6-9 mos) male mice and serum testosterone was measured with an ELISA. Functional recovery in reperfusion was significantly better in old males than in adult males. Left ventricular developed pressure (LVDP) recovered to 67.3 ± 7.4% in old compared to 31.6 ± 12.3% in adult male hearts (p<0.05). Similar results were seen for rates of pressure development (+dP/dt; p<0.05) and decay (-dP/dt; p<0.05). Also, infarct areas were markedly smaller in old male hearts (15.5 ± 1.8%) than in younger hearts (48.1 ± 7.7%; p<0.05). By contrast, hearts from adult and old females exhibited a similar degree of post-ischemic functional recovery and showed no age-dependent difference in infarct size. Serum testosterone levels declined with age in males but were low regardless of age in females, which suggested a potential benefit of low testosterone. In support of this, hearts from GDX males exhibited much better recovery of LVDP in reperfusion when compared to hearts from intact males (values were 64.8 ± 7.7% vs. 29.9 ± 12.3%; p<0.05). GDX hearts also had smaller infarcts than hearts from intact males (p<0.05). These results suggest that low testosterone levels may be protective against I/R injury following cardioplegic arrest in the setting of aging, especially in old males.