Local atherosclorotic plaque biomarkers predict systemic clinical outcome : The translational Athero-Express biobank study

Abstract

Despite changes in lifestyle and major advances in pharmacologic approaches to treat atherosclerotic disease, atherosclerosis is the main cause of mortality and morbidity in the Western world and is expected to be the prevalent cause globally within 10 years. Atherosclerotic plaque rupture is the devastating cause of acute cardiovascular events. Prospective epidemiologic studies have predominantly focused on cardiovascular or serologic risk factors in relation to acute clinical manifestations of atherosclerotic disease. However, general cardiovascular risk factors have been proven inadequate to identify the “vulnerable patient” who is at risk for atherosclerotic manifestations. From a more fundamental approach, cross-sectional post mortem studies have revealed plaque characteristics that are associated with clinical cardiovascular events. However stratification of patients at risk for systemic atherosclerotic manifestations based on plaque composition has currently not been implemented in clinical decision making, since prognostic value of the vulnerable plaque characteristics for the development of a cardiovascular event is unknown. In this thesis we followed a different concept and we consider atherosclerosis as a systemic disease. Due to presence of atherosclerotic lesions throughout the arterial system, we assumed that local atherosclerotic lesions hold cellular and molecular information that reflects the stability of atherosclerotic lesions in all other vascular territories. Therefore we performed prospective studies, including patients who underwent carotid surgery and we have investigated if local atherosclerotic plaque markers from the carotid artery are associated with systemic clinical outcome. The outcome of the studies would enable identification and stratification of patients who are at increased risk to suffer from a cardiovascular event within 3-years after carotid endarterectomy (CEA). This innovative approach would facilitate risk stratification for systemic cardiovascular events in patients following CEA. In addition, a combination of several prognostic biomarkers may improve the identification of patients at risk of cardiovascular events. Besides risk prediction plaque characteristics may additionally serve as imaging targets for diagnostic applications. In one of the studies, we show for the first time that plaque hemorrhage and increased vessel density in a local atherosclerotic lesion are associated with increased risk for cardiovascular events, which can be quantified by minimal invasive sophisticated imaging modalities. Following this concept, molecular plaque studies could be considered that reveal targets for individual risk stratification, imaging applications as well as pharmaceutical interventions to prevent acute clinical manifestations of atherosclerotic disease. Two studies reveal molecular biomarkers that are strongly related with systemic cardiovascular events, indicating that they contribute to atherosclerotic plaque progression and are causally related with clinical manifestations. These findings contribute to the development of innovative molecular imaging modalities to identify the vulnerable plaque, which is prone to rupture. Furthermore, the prognostic molecular biomarkers may serve as new pharmaceutical targets to decrease the risk of cardiovascular events, since they are suggestive as causal targets. The outcome of the prospective studies, included in the thesis, might contribute to improved “personalized medicine”, with respect to individual risk stratification and treatment in the field of cardiovascular medicine.