The atherosclerotic plaque and cardiovascular disease progression in men and women

Abstract

Atherosclerosis, a process in which large arteries narrow progressively due to chronic accumulation of inflammatory cells and cholesterol, is the primary cause of coronary heart disease (CHD) and stroke. These are the most common forms of cardiovascular disease (CVD). Mortality due to CVD is the highest worldwide compared to other causes of death.

Because of the high global burden of CVD, it is important to identify a patient at high risk for developing this disease so they can be targeted for the right therapy. To improve risk prediction in patients with severe atherosclerosis, we used data of the Athero-Express study, that was initiated in 2002. Patients undergoing endarterectomy in carotid (CEA) and iliac/femoral arteries to remove a plaque can participate. Analysis of the plaque is combined with clinical data, including 3 years of follow-up, all of which can be used to predict secondary cardiovascular events. Moreover, these data can give us important insights into the pathogenesis of atherosclerosis.

In the first part of this thesis, we studied different aspects of carotid plaque composition. Certain plaque features are associated with clinical events and also with recurrent manifestations of disease, and are regarded unstable. Characterization of the plaque plays an important role in association studies, and needs to be reproducible to be able to draw valid conclusions from these studies. Until now, only semi-quantitative or partly quantitative methods of plaque areas have been used, which have left room for improvement. Therefore, we developed a new automated method that uses whole slide digital images. Reproducibility assessments indicated that the old methods still perform well, but the new method was most optimal with excellent reproducibility. Furthermore, the composition of the atherosclerotic carotid plaque was studied over time. Less unstable plaque characteristics were observed over the past decade, concurrent with a decrease in CVD prevalence and improved prevention.

The next part outlines sex-specific studies in patients with severe atherosclerosis. Plaque hemorrhage, which leads to plaque instability, was shown to be less prevalent in women. In addition, plaque hemorrhages were only related to secondary events in men, not in women. This may indicate that mechanisms of disease progression are different in women. Women also have relatively worse survival after iliac/femoral endarterectomy compared to men, while women survive longer than men after CEA, as in the general population.

Recurrent stenosis after CEA was the subject of part 4. Peak systolic velocity (PSV) in the carotid artery during follow-up was used as readout for restenosis. A lipid-poor plaque showed an independent association with higher PSVs in the internal carotid artery 3 months after CEA, but not after mid-term follow-up. In women, significantly higher PSVs were found after midterm follow-up, especially if they were asymptomatic. Next, we describe the results of an independent patient data meta-analysis that was aimed to pool all internationally available data regarding treatment of restenosis after prior CEA, comparing stenting and CEA. Both treatments were comparable regarding perioperative stroke and death, and restenosis during follow-up.

The final part describes that CD14, a protein derived from microvesicles, can give information on the total extent of CVD in patients with manifest atherosclerosis.