Acute myocardial infarction is one of the most common causes of death in western countries. The underlying cause of myocardial infarction is atherosclerosis of the coronary arteries. Atherosclerosis has been extensively studied and several risk factors including smoking, hypercholesterolemia, diabetes mellitus and hypertension have been identified. However, the reason for the presentation of myocardial infarction in a previously healthy subject with atherosclerosis is largely unknown.
An early event in the development of atherosclerosis is injury to the inner cell surface of the blood vessels referred to as endothelial dysfunction. Endothelial dysfunction is usually characterized by reduced bioavailability of nitric oxide (NO) but also increased expression of vasoconstrictor and pro-inflammatory substances such as endothelin-1 (ET-1). Several clinical studies indicate that endothelial function is inversely related to cardiovascular events. One line of our research activities is to evaluate the development of endothelial dysfunction and how endothelial function can be improved in patients with cardiovascular disease. The projects are focused on patients with coronary artery disease and diabetes. One central problem that we are addressing is the role of ET-1 in endothelial dysfunction. We investigate the expression of ET-1 and its receptors (ETA and ETB), the vascular tone induced by ET-1 in patients with coronary artery disease and diabetes and how administration of ET receptor antagonists improves NO bioavailability and endothelial function. Main findings in this area are that the vasoconstrictor tone induced by ET-1 is enhanced in patients with atherosclerosis and that this effect seems to be related to upregulation of ET receptors, especially vasoconstrictor ETB receptors. Administration of ET receptor antagonists increases regional blood flow and enhances endothelium-dependent vasodilatation. Current projects are also focused on effects of ET-1 on glucose uptake and insulin resistance in patients with dysglycemia. Additional projects address the underlying cause of diminished production of NO in coronary artery disease. We have recently found that the enzyme arginase may prevent production of NO and may thereby be a key factor in endothelial dysfunction. Inhibition of arginase improves endothelial function and prevents the development of myocardial infarction by increasing NO production. Based on findings obtained in experimental models of myocardial ischemia and reperfusion our group is also evaluating the effect of pharmacological intervention on ischemia/reperfusion-induced endothelial dysfunction in patients with coronary artery disease and diabetes. By enhancing NO bioavailability, endothelial dysfunction following an ischemic period can be prevented which may be of great relevance for patients with ischemic heart disease. Knowledge obtained in the experimental studies regarding protection of the heart has been translated into clinical studies in patients with acute myocardial infarction. We are currently performing a study on designed to evaluate the effect of graded reperfusion (postconditioning) on myocardial infarct size in patients with acute myocardial infarction.
The present knowledge of the pathogenesis of myocardial infarction indicates that inflammation plays a central role in this process. Further support for this comes from the fact that inflammatory markers, such as CRP and IL-6, are increased in patients with the acute coronary syndrome and that inflammatory disease such as rheumatoid arthritis increase the risk of myocardial infarction. Interestingly, we and others have shown that experimental inflammation stimulates to activation of coagulation. With the exception for quantitative analyses little is known about the role of leukocytes in the pathogenesis of myocardial infarction. Presumably, expression of proteins in white blood cells mirrors events occurring on the surface of the vessel wall. New technologies such as gene- and protein-chip analysis have made it possible to screen large amounts of gene products. The present research program aims at investigating the role of inflammation in the pathogenesis of myocardial infarction using modern molecular biology techniques.