Mechanisms of Acute Hyperglycemic Exacerbation of Myocardial Infarction

Coronary artery disease (CAD) and myocardial infarction (MI) remain the most significant causes of morbidity and mortality in the United States. MI is complicated by acute hyperglycemia in up to 30% of patients, and initial blood glucose concentration is strongly associated with 30-day mortality in these patients. Acute hyperglycemia is known to be associated with increased oxidative stress. In the mouse model of reperfused MI, induced acute hyperglycemia leads to larger infarcts compared to euglycemic controls. However, the mechanisms responsible for acute hyperglycemic exacerbation of MI have not been characterized. Furthermore, the French lab has previously shown that CD4+ lymphocytes are important mediators of cardiac ischemia-reperfusion injury. Other researchers at UVA recently demonstrated that natural killer T (NKT) cells are the subset of CD4+ lymphocytes that initiate the inflammatory cascade following ischemia-reperfusion injury to the liver and kidney. Our hypothesis for these studies was that hyperglycemia increases oxidative stress, which is at least partially mediated by the action of CD4+ lymphocytes or NKT cells through the elaboration of pro-inflammatory cytokines or chemokines. An additional possibility is that hyperglycemia generates a pro-inflammatory signal and oxidative stress through activation of the receptor for advanced glycolation endproducts (RAGE). The increased oxidative stress could lead to larger infarct size either directly through increased myocardial damage or through increased endothelial dysfunction and microvascular occlusion.
The specific aims of this research were: 1) Characterize the early mRNA expression changes during myocardial infarction complicated by acute hyperglycemia, and then use network analysis of the transcriptome to evaluate the role of T cells and to look for novel pathways which may be dysregulated in this disease process, and 2) Test the hypothesis that stress hyperglycemic exacerbation of myocardial infarction is mediated by the receptor for advanced glycolation endproducts (RAGE) and/or mediated through natural killer T cell (NKT cell) activity by use of RAGE or NKT cell knock out mice.
The major findings of this research include: 1) Circulating leukocytes demonstrated differential gene expression due to hyperglycemia only in the setting of MI, but not due to MI or hyperglycemia alone; effect of MI is to amplify differences in circulating leukocyte gene expression that result from acute hyperglycemia; network analysis of leukocyte gene differential regulation indicates changes to T cell activation and T cell differentiation; 2) Acute hyperglycemia causes an increase in infarct size regardless of presence of RAGE or NKT cells, which implies that neither RAGE nor NKT cells mediate the pathological effects of acute hyperglycemia; this study is the first to demonstrate that NKT cell deficient mice have smaller infarct size in the reperfused MI model.