Endothelial dysfunction in patients with glucose abnormalities and coronary artery disease : studies of pathogenesis and treatment

Background: Type 2 diabetes is associated with endothelial dysfunction, which is characterised by the reduced bioavailability of nitric oxide (NO). This is a result of increased oxidative stress and inflammation and the synthesis of endothelium-dependent vasoconstricting factors such as endothelin-1 (ET-1) caused by hyperglycaemia, insulin resistance and dyslipidemia. The dysfunction of the vascular endothelium is regarded as an important factor for the increased risk of cardiovascular disease seen in patients with type 2 diabetes and it is thought to play a major role in the pathogenesis of both micro- and macrovascular complications in this patient category. This thesis aims to further explore the pathogenesis and treatment options of endothelial dysfunction in patients with glucose abnormalities.

Studies I-II: The importance of the lipid-independent (pleiotropic) effects of statins was studied in 43 patients with dysglycemia and coronary artery disease. Intensive lipid lowering with either 80 mg of simvastatin or a combination of 10 mg of simvastatin together with 10 mg of ezetimibe improved macrovascular endothelial function and microvascular function (n=36) and reduced inflammation. No difference between the two treatment strategies was found, indicating that the improvements were mainly due to lipid lowering and not to the pleiotropic effects of statins.

Study III: The effect of endothelin-A-receptor blockade on nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy was studied. Intra-arterial infusions of an endothelin-A-receptor antagonist improved nutritive skin capillary circulation in patients with type 2 diabetes (n=10) but not in healthy controls (n=8). This finding suggests that ET-1 is involved in the pathogenesis of diabetic microangiopathy.

Study IV: The effect of L-arginine and tetrahydrobiopterin (BH4) infusion on ischemia/reperfusion (I/R)-induced endothelial dysfunction following 20 minutes of forearm ischemia was studied in 12 patients with type 2 diabetes and coronary artery disease. L-arginine and BH4 significantly attenuated I/R-induced endothelial dysfunction in comparison with placebo.

Conclusions: The present studies of patients with type 2 diabetes and vascular complications indicate that 1) lipid lowering is more important than the pleiotropic effects of statins for the improvement in macrovascular endothelial function and microvascular function and the reduction in inflammation; 2) targeting the ET-1 system might be of importance in the treatment of complications related to diabetic microangiopathy and 3) supplementation with L-arginine and BH4 may represent a future treatment strategy to limit the I/R injury in patients with type 2 diabetes.

List of scientific papers

I. Settergren M, Böhm F, Rydén L, Pernow J (2008). "Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease." Eur Heart J 29(14): 1753-60. Epub 2008 Apr 25.
https://doi.org/10.1093/eurheartj/ehn166

II. Settergren M, Böhm F, Rydén L, Pernow J, Kalani M (2009). "Lipid lowering versus pleiotropic effects of statins on skin microvascular function in patients with dysglycemia and coronary artery disease." [Accepted]
https://doi.org/10.1111/j.1365-2796.2009.02128.x

III. Settergren M, Pernow J, Brismar K, Jörneskog G, Kalani M (2008). "Endothelin-A receptor blockade increases nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy." J Vasc Res 45(4): 295-302. Epub 2008 Jan 22.
https://doi.org/10.1159/000113601

IV. Settergren M, Böhm F, Malmström RE, Channon KM, Pernow J (2009). "L-arginine and tetrahydrobiopterin protects against ischemia/reperfusion-induced endothelial dysfunction in patients with type 2 diabetes mellitus and coronary artery disease." Atherosclerosis 204(1): 73-8. Epub 2008 Sep 4.
https://doi.org/10.1016/j.atherosclerosis.2008.08.034