Hyperglycaemia and insulin therapy : their role in acute myocardial infarction

Diabetes mellitus represents a state of insulin insufficiency with elevated glucose levels. Previous studies have shown that patients with diabetes not only have an increased risk for cardiovascular disease, but they are also more likely to suffer adverse outcomes following acute myocardial infarction (AMI). Even in people without known diabetes, stress-induced hyperglycaemia at the time of AMI has been associated with poor outcomes. It is uncertain if hyperglycaemia causes direct myocardial injury following acute ischaemia and reperfusion, and if short term insulin therapy protects the ischaemic myocardium. A number of clinical trials, however, suggest that insulin therapy is beneficial. In this thesis, through a number of experimental studies, the effets of glucose and insulin on the myocardium were assessed. After studying these effects in animal models, the impact of an insulin-dextrose infusion regimen aimed at maintaining norrnoglycaemia during the peri-infarct period was also evaluated in a clinical trial. In the first part of the thesis, a retrospective review of patients admitted to Westmead Hospital with AMI over a 12-month period was conducted. Clinical, historical and biochemical parameters were correlated against adverse cardiac outcomes (mortality, cardiac failure, re-infarction etc). From multi-variate logistic regression analysis, admission glucose level was a consistent predictor of mortality and morbidity in all AMIpatients as well as in those who received reperfusion therapy for up to 6 months following index AMI admission. The study confirmed that hyperglycaemia remains a significant predictor of cardiac mortality and morbidity in the reperfusion era. To evaluate whether elevated glucose levels have a direct pathological role on the ischaemic myocardium, an adult rat cardiomyocyte culture model was adopted to assess the impact of glucose and insulin on cardiomyocyte viability. Rat cardiomyocytes from primary culture were incubated in media containing different levels of glucose as well as insulin under a normoxic environment. Exposure of cardiomyocytes to higher concentration of glucose (without insulin) resulted in significantly greater cytotoxicity, while cells incubated in media containing the highest insulin concentration (at normal glucose levels) had the lowest cytotoxicity. When the high glucose media was supplemented with insulin, the cytotoxic effect of high glucose was negated. To study the effects of glucose and insulin on the ischaemic myocardium, an isolated rabbit heart model of regional ischaemia and reperfusion was also developed. The hearts were perfused with buffers containing varying levels of glucose and insulin, and the infarct size for each heart was assessed. In the high-glucose protocol, the infarct size was significantly greater than that when hearts were exposed to normal glucose levels. On the other hand, insulin, when given just before reperfusion, reduced infarct size in a dose­dependent manner. Furthermore, insulin attenuated the extent of infarction in hearts that were exposed to high glucose levels. Therefore, from these 2 different animal models, elevated glucose levels were found to be harmful to the myocardium by increasingcardiomyocyte death (in the culture model) and inducing greater infarct size (in the ischaemic model). Conversely, insulin preserved cardiomyocyte viability and reduced infarct size following an ischaemic insult. The cellular mechanism for the action of insulin on the myocardium was beyond the scope of this thesis, and it is difficult to speculate whether insulin confers protection through insulin receptor or other pathways such as the insulin-like growth factor receptor. Extending these findings to clinical practice, a randomized controlled trial was conducted to evaluate the effects of maintaining normoglycaemia by an insulin infusion regimen at the time of AMI. Patients presenting with AMI who either had known diabetes or were hyperglycemic on admission were recruited into the Hyperglycemia: Intensive Insulin Infusion !n !nfarction (HI-5) Study. Subjects were randomized to receive either intensive therapy (insulin/dextrose infusion for 24 hours to keep glucose level 4 - lOmmol/1) or conventional therapy. Intensive insulin therapy did not confer survival advantage for patients following AMI up to 6 months following admission, but it resulted in a lower incidence of in-hospital cardiac failure. Insulin therapy also reduced the incidence of composite endpoints for subjects with antero-lateral AMI or those who received reperfusion therapy. Patients with pre-existing diabetes did not derive clinical benefit from insulin therapy, but as a group, they did not have greater adverse outcomes compared to those without diabetes. Unfortunately, due to the suboptimal patient recruitment as well as the better than expected overall survival for AMI patients, the power of the study was substantially reduced. Elevated inflammatory markers have been associated with worse outcomes in myocardial infarction. In the HI-5 Study, insulin therapy reduced free fatty acid (FFA) levels and attenuated the rise of C-reactive protein (CRP) levels. Day 2 CRP levels also correlated with the mean glucose levels of subjects during the first 24 hours of treatment. Suppression of FFA and the attenuation of the rise of CRP may have theoretical benefits for the preservation of ischaemic myocardium, but it has not translated into improved clinical outcomes in the HI-5 study. In summary, from experimental studies conducted in this thesis, elevated glucose levels were found to be detrimental to the myocardium during normoxia or following ischaemia, while insulin confers cardio-protection in both conditions. However, despite the reduction of FFA levels and markers of inflammation, clinical benefits were not clearly evident in the HI-5 study. The findings of other very recent clinical studies also did not support the use of insulin-based therapy following AMI, but it is possible that a higher dose of insulin maintaining tighter glycaemic control may still improve outcomes for patients following AMI. For the time being, in the absence of consistent clinical trial evidence, one cannot justify the routine use of intensive insulin-based treatment to control glucose levels during AMI. However, optimization of the management of coronary artery disease for patients with hyperglycaemia remains an important research priority of this era