Detecting the Vulnerable Plaque
Myocardial infarction and stroke, mainly caused by a rupture of an atherosclerotic plaque, are two of the most common causes of mortality and morbidity in the world. Previous studies have pointed out inflammation, drivenby inflammatory lipids, as the keystone in the formation of the rupture prone vulnerable plaque. The risk for a plaque rupture is greatly enhanced in the diabetic population and increased inflammation has been suggested as thecontributing factor. However, the mechanism remains unknown. One of the current greatest challenges in theatherosclerotic field is to identify subjects with plaques that are vulnerable before the occurrence of a plaque rupture.
In this thesis we provide evidence that the enzyme lipoprotein associated phospholipase A2 (LpPLA2) and the lipids lysophosphatidylcholines and sphingolipids (ceramides, lactosylceramides, glucosylceramides) contribute tothe inflammatory process and that they are associated with the vulnerable plaque. This suggests that the synthesis of these lipids may be possible therapeutic targets. We also show that the inflammatory process in the plaque is reflected in the peripheral blood, as measured by cytokines, whereas no association was found for soluble urokinase-type plasminogen activator receptor. The inflammatory cytokines MIP-1β, TNF-α and fractalkine predict the inflammatory plaque with high sensitivity and specificity, proposing that these inflammatory cytokines could be used as plasma markers for plaque inflammation. Finally, we provide novel data regarding the biology of the diabetic plaque. According to our data the inflammatory activity is not increased in the diabetic plaque tissue.
Diabetic plaques contained less stabilizing extracellular matrix proteins (collagen and elastin). Additionally the plaque levels of the inflammation regulating cytokine IL-10 and the growth factor platelet derived growth factor as well as the smooth muscle cell stimulating matrix metalloproteinase 2 were significantly decreased in diabetic plaque tissue. These findings were independent of the presence of symptoms.
In summary, this thesis shows that lipids as LysoPCs and glycosphingolipids are important inducers of plaque inflammation and may be possible therapeutic targets. In the general population the inflammatory activity is an important factor for the formation of a vulnerable plaque and this inflammatory process is reflected in blood, hinting a role for fractalkine, MIP-1β and TNF-α as future biomarkers. In the diabetic population, however, an impaired tissue repair mechanism seems to be the keystone of plaque vulnerability, rather than inflammation, emphasizing the need for new therapeutic approaches for diabetics.