Risk recognition in patients with atherosclerotic disease : associations of circulating biomarkers with plaque composition and clinical outcomes

Over the last decade, the major underlying culprit of CVD; the atherosclerotic plaque, has shown a strong stabilization over time. Vulnerable plaque features such as large lipid core, intraplaque hemorrhage, and high macrophage content strongly decreased over time. Together with drops in inflammatory biomarkers it appears that two main drivers of atherosclerotic disease, lipids and inflammation, are now somewhat silenced. In first-world countries the current decline in major manifestation of CVD such as stroke and myocardial infarction is expected to be attributable to this stabilization. Rigorous lipid and blood pressure control, government legislation such as a public smoking ban and dietary reductions of salt and trans fats are likely causing these effects. We studied if these time-dependent effect help decrease secondary cardiovascular event-rate in a cohort of patients undergoing carotid endarterectomy. We did not find the health benefits as anticipated on. Secondary event rate remained high at approximately twenty-five percent during three-year follow-up and warrants our full efforts for future reduction. A possible explanation for this lack of decline could be that in these patients atherosclerotic disease burden is already too advanced and therefore less amenable for treatment. In patients affected by iliofemoral stenosis, secondary cardiovascular event-rate decreased over time but only due to a decrease in peripheral interventions. In patients with diabetes event-rate remained high and unchanged. In order to understand this risk for secondary cardiovascular events we studied several circulating biomarkers and their link with atherosclerotic disease. We show that decreased kidney function is a strong prognostic factor for the occurrence of secondary cardiovascular events and which specific plaque features associate with decreased kidney function in CEA patients. Interestingly we could not correlate decreased kidney function with abundant inflammation in the plaque, while inflammation is the proposed mediator for kidney-vasculature interaction. However, we did find a correlation with intraplaque hemorrhage and coagulation pathways indicating that perhaps coagulation is involved in plaque vulnerability and poor outcome in patients with decreased kidney function. Moreover, we studied the role of two major sex hormones, testosterone and estradiol, and their role in male patients undergoing carotid endarterectomy. We show that although the individual levels have limited prognostic value, the testosterone to estradiol ratio (T/E2) is more promising. Patients with low T/E2 had a higher risk of major cardiovascular events after CEA and showed increased inflammation in both plaque and blood. Lastly we focused on an often reported hematological parameter, the red cell distribution width (RDW), and its prognostic role in patients undergoing major cardiovascular surgery. There we show that this marker of anisocytosis is a strong predictor for inflammatory events following cardiovascular surgery. Moreover, we provide insight in hematopoietic tissue activity and their association with the RDW. We show a strong correlation of RDW with organ activity of the spleen and bone marrow and thereby likely reflecting a state of low grade inflammation