AbstractDespite recent advances in diagnosis and therapy, atherosclerosis-related
cardiovascular disease remains a leading cause of morbidity and mortality
worldwide. An important challenge is to detect silent atherosclerosis in
asymptomatic people at risk, so that preventative strategies can be more effectively targeted. This thesis examines the pro-inflammatory/pro-atherogenic role of platelet hyperactivity and the consequent interaction of activated platelets with circulating monocytes to form monocyte-platelet aggregates (MPA), and investigates the potential usefulness of MPA measurement and/or monocyte phenotype characterization as surrogate markers of atherosclerotic disease.
Using an experimental model of inflammation, namely that induced by influenza
vaccine administration to healthy subjects, we found that MPA formation increases in the blood under pro-inflammatory conditions, and that this is accompanied by expansion of so-called CD14highCD16+ monocytes, which are distinct from “classical” CD14+CD16- cells and exhibit higher pro-inflammatory activity. In vitro experiments showed that MPA formation increases CD16 expression on CD14+CD16- monocytes.
In an animal model of atherosclerosis (ApoE-/- mice), expansion of the murine
counterpart of human CD16+ monocytes, namely Ly6Clow cells, occurred with age and their levels strongly related to the extent of atherosclerotic disease seen in the brachiocephalic artery.
Finally, in a clinical study conducted in clinically healthy patients who had one or
more underlying cardiovascular risk factors, levels of circulating CD14highCD16+ monocytes, but not of MPA, were found to increase in those patients who had carotid plaques compared to disease-free patients, and also showed a direct correlation with intima-media thickness (IMT) as evaluated by carotid ultrasonography. Unlike monocyte characterization, traditional cardiovascular risk stratification using the Framingham risk equation or the Joint British Societies 2 charts showed no relationship to IMT or to the presence of frank plaque disease.
In conclusion, our findings delineate a novel pro-atherogenic effect of platelet
activation that is easily detectable in the peripheral blood through characterization of circulating monocytes. Measurement of CD14highCD16+ monocytes, but not MPA, offers a novel diagnostic approach to identify early atherosclerosis that gives information over and above cardiovascular risk estimation using traditional population-based assessment tools.
|Date of Award
|Albert Ferro (Supervisor) & Rene Botnar (Supervisor)