Hyperglycemia and adverse outcomes in acute coronary syndromes: is serum glucose the provocateur or innocent bystander?

Abstract

Hyperglycemia at the time of hospital admission predicts increased mortality in patients with acute coronary syndromes (ACS), including ST-segment elevation myocardial infarction (STEMI) (1–6), revascularization procedures such as thrombolysis or percutaneous coronary intervention (PCI) (7–10), and other critical illnesses (11–13). The relationship between blood glucose and mortality appears linear with escalating risk associated with increasing blood glucose levels and is independent of a diagnosis of diabetes (14). However, there is ongoing debate as to whether hyperglycemia directly contributes to the adverse outcomes or whether it is simply a marker of higher risk. There are three main hypotheses as to why hyperglycemia portends higher mortality in acutely ill patients (overview shown in Fig. 1). First, elevated blood glucose can be a physiologic response to hormones, such as epinephrine or cortisol, that are released under high systemic stress and, hence, may indicate greater overall illness severity (15). For example, those subjects with larger areas of myocardial ischemia and more impaired left ventricular function may have stronger sympathetic activation, leading to higher glucose levels. Second, hyperglycemia may be an indicator of systemic and organ-specific metabolic dysregulation, especially impaired insulin signaling. In this regard, insulin resistance causes not only hyperglycemia but also may lead to a reduction in energy production in the heart and other organs, producing a lower tolerance to hypoperfusion. In a similar vein, reduced insulin signaling may increase vulnerability to ischemic injury because downstream molecules in the insulin-signaling cascade have well-established cytoprotective effects and these are lost when insulin-signaling pathways are disrupted (16,17). Third, acute hyperglycemia is implicated in the activation of other pathologic processes that could contribute to cellular and tissue injury, such as increasing free radial formation and oxidative stress, inducing of a prothrombotic state, and worsening endothelial function (18– …