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Endothelial Dysfunction: Early Detection, Better Outcomes

Vascular disease is the principal cause of death and disability in people with diabetes [1]. Damage to the endothelial cells that line all blood vessels is an early consequence of diabetes. This damage leads to atherosclerotic plaque formation in large arteries with consequent peripheral artery disease (PAD) and reduced blood flow to the limbs, especially the lower limbs and feet. In small arterioles and capillaries, endothelial dysfunction causes small vessel disease (SVD) which disrupts local control of blood flow and tissue ischemia.


Hydrogen Sulfide Biomarker of PAD/SVD



According to the American Diabetes Association, 1 out of every 3 diabetic patients over the age of 50 suffers from PAD and SVD [2]. This disease is difficult to diagnose in diabetic patients [3] due calcium build up in arteries that causes overestimates of blood flow to the legs and feet. Currently, accurate tests of leg blood flow require expensive equipment and trained technicians so that many physicians, due to the high cost, frequently do not prescribe or perform this procedure. Thus, microvascular disease frequently goes undetected until irreversible tissue damage has occurred with high risks of amputation.


PAD is a narrowing of arteries caused by plaques and inflammation in arteries. Other causes are high blood pressure, diabetes, and chronic kidney disease. On the other hand, SVD is a damage to the small vessels that control blood flow to organs. Both PAD and SVD are caused by damage to the lining of the arteries and can cause artery blockage, limb ischemia and poor muscle function. In blood vessels, hydrogen sulfide (H2S) is produced by the endothelial cells that line arteries [4] and opens the blood vessels to increase blood delivery (see Figure). In diabetic patients, the loss of H2S production by endothelial cells impairs blood flow to the legs and feet, setting the stage for the development of irreversible damage [5].


H2S has well-known vasoprotective [6] and cardioprotective roles [7]. However, rats with simulated sleep apnea have decreased levels in their arteries of the enzyme that makes H2S, cystathionine g-lyase (CSE) compared arteries from healthy rats (top & left) and lower levels of H2S in their blood (bottom right) [8]. Furthermore, in human and animal studies of type 2 diabetes, both obesity and hyperglycemia have been shown to decrease production of H2S to cause endothelial dysfunction and diabetic tissue damage [9]. Thus, H2S detection provides the means to diagnose early stage vascular disease and to monitor progression of vascular disease as well as providing a potential novel path for treatment.