Demographic studies have shown that the mean age of patients requiring coronary artery bypass surgery (CABG) is 68 years with approximately 44% of these patients being female. Women have been shown to have a significantly greater operative risk and to have worse outcomes after cardiac surgery compared with men, which can not be explained by illness severity, pre-surgery health status, or other patient characteristics. Women also have higher mortality rates than equally matched men in low-risk and medium-risk groups and significant differences in in-hospital mortality for women persist despite the fact that women have better cardiac function pre-operatively and fewer bypass grafts constructed as compared to men. The etiologies for these differences are speculative and include surgical technical issues associated with anatomic size differences, differences in body mass and associated fat deposition, hormonal differences. However;after adjusting for all co-morbidities including body surface area, female gender is an independent predictor of increased mortality following CABG, with a risk adjusted operative mortality of 3.81% for women as compared to 2.43% for men. These data indicate that aged women may be more susceptible to ischemia/reperfusion injury and that current clinical myoprotective procedures may be inadequate to prevent this discrepancy. The present paradigm to alleviate surgically induced ischemia/reperfusion injury requires the use of cardioplegia. In a series of studies we have demonstrated that cardioplegia significantly enhances post-ischemic functional recovery and significantly decreases infarct size and that this cardioprotection is afforded through RNA and protein synthesis. Recently we have shown that the cardioprotection afforded by cardioplegia is significantly decreased with age and is significantly decreased in the aged female. We and others have shown that RNA transcription and translation are significantly decreased in the aged as compared to the mature heart. It has also been shown that estrogen modulates genes associated with cardioprotection and that cardioprotection is lost in both aged women and in pre-menopausal women who have undergone previous oophorectomy. We hypothesize that the mechanisms modulating cardioprotection afforded by cardioplegia involve RNA and protein synthesis and that these mechanisms directly contribute to increased operative morbidity and mortality in the aged female. To test this hypothesis we have created microarrays and have initiated high throughput proteomic analysis to identify functionally related gene groups and protein biomarkers associated with the cardioprotection afforded by cardioplegia in the aged female. It is expected that the integration of the genomics and proteomics data will enhance biochemical understanding in terms of signaling pathways, biological processes, and compartmentalization and allow for the development of protocols leading to enhanced cardioprotection in the aged female through directed modulation of cardioprotection.
Women have been shown to have a significantly greater operative risk and to have worse outcomes after cardiac surgery compared with men. We hypothesize that the mechanism for this difference is related to alterations in the levels of cardioprotective RNA and protein synthesis in the aged female and that these mechanisms directly contribute to increased morbidity and mortality in the aged female. We propose to identify these biomarkers to allow for the specific modification and development of cardioplegia solutions to enhance cardioprotection and reduce surgical morbidity and mortality in the aged female.
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