Coronary microvascular dysfunction in diabetes mellitus: A review

Abstract

The exploration of coronary microcirculatory dysfunction in diabetes has accelerated in recent years. Cardiac function is compromised in diabetes. Diabetic patients manifest accelerated atherosclerosis in coronary arteries. These data are confirmed in diabetic animal models, where lesions of small coronary arteries have been described. These concepts are epitomized in the classic microvascular complications of diabetes, i.e. blindness, kidney failure and distal dry gangrene. Most importantly, accumulating data indicate that insights gained from the link between inflammation and diabetes can yield predictive and prognostic information of considerable clinical utility. This review summarizes the evidence for the predisposing factors and the mechanisms involved in diabetes, and assesses the current state of knowledge regarding the triggers for inflammation in this disease. We evaluate the roles of hyperglycemia, oxidative stress, polyol pathway, protein kinase C, advanced glycation end products, insulin resistance, peroxisome proliferator-activated receptor-γ, inflammation, and diabetic cardiomyopathy as a "stem cell disease". Furthermore, we discuss the mechanisms responsible for impaired coronary arteriole function. Finally, we consider how new insights in diabetes may provide innovative therapeutic strategies.

Keywords: Coronary artery; Diabetes; Endothelial dysfunction; Hyperglycemia; Inflammation; Insulin; Microcirculation; Nitric oxide; Oxidative stress.

Figure 1

Etiology of mechanisms involved in coronary vascular dysfunction in diabetes. Increased oxidative stress is the unifying element common to all pathways through which the various mechanisms described interact to cause endothelial dysfunction and cardiomyopathy in diabetes. Hyperglycemia acts directly through the glycation of the scavenger enzyme superoxide dismutase (SOD) and other antioxidant enzymes, and indirectly through the cross activation of advanced glycation end product (AGE)/advanced glycation end product receptor (RAGE) interaction and of the polyol pathway. The latter raises the NADH/NAD⁺ ratio, modifying the redox state of the cells and leading to the production of superoxide anions. Tumor necrosis factor-α (TNF-α) has been shown to affect intracellular insulin signaling, promoting insulin resistance and consequently impairing the insulin-mediated endothelial function in coronary arterioles. The insulin-resistance mediated endothelial dysfunction can be restored by the activation of peroxisome proliferator-activated receptor-γ by thiazolidinediones and rosiglitazone. Then, if we consider diabetes as a chronic, subclinical inflammatory disease, it acts through TNF-α and Interleukin (IL)-6, increasing the cellular oxidative stress. AGE/RAGE interaction and hyperglycemia can in turn activate the diacylglycerol (DAG)-protein kinase C (PKC) pathway, thus promoting fibrosis, myofilament desensitization, and apoptosis, and finally leads to diabetic cardiomyopathy. TnI: Troponin I; TnT: Troponin T.

Figure 2

Possible mechanisms involved in vasomotion of impaired coronary arterioles in diabetes. Several mechanisms have been postulated to be responsible for impaired vasomotion in coronary artery disease. There is strong evidence accumulating in favor of each impairment category as causal. We hypothesize that they interact in as yet unspecified ways rather than operate through separate pathways to cause diabetes. Major challenges in this field include better understanding each of these mechanisms, but the greatest opportunity for seminal breakthroughs may reside in reconciling our understanding among these mechanisms and their roles in diabetes.