Circulating cells as predictors of secondary manifestations of cardiovascular disease: design of the CIRCULATING CELLS study

Abstract

Biomarkers for primary or secondary risk prediction of cardiovascular disease (CVD) are urgently needed to improve individual treatment and clinical trial design. The vast majority of biomarker discovery studies has concentrated on plasma/serum as an easily accessible source. Although numerous markers have been identified, their added predictive value on top of traditional risk factors has been limited, as the biological specimen does not specifically reflect expression profiles related with CVD progression and because the signal is often diluted by marker release from other organs. In contrast to serum markers, circulating cells serve as indicators of the actual disease state due to their active role in the pathogenesis of CVD and are responsible for the majority of secreted biomarkers. Therefore, the CIRCULATING CELLS study was initiated, focusing on the cellular effectors of atherosclerosis in the circulation. In total, 714 patients with coronary artery disease (CAD) symptoms were included. Blood cell fractions (monocytes, T-lymphocytes, platelets, granulocytes, PBMC) of all individual patients were isolated and stored for analysis. Concomitantly, extensive flow cytometric characterization of these populations was performed. From each patient, a detailed clinical profile together with extensive questionnaires about medical history and life style was obtained. Various high-throughput -omics approaches (protein, mRNA, miRNA) are currently being undertaken. Data will be integrated with advanced bioinformatics for discovery and validation of secondary risk markers for adverse events. Overall, the CIRCULATING CELLS study grants the interesting possibility that it will both identify novel biomarkers and provide useful insights into the pathophysiology of CAD in patients.

Phenotype Changes of Circulating Monocytes in a Hypercholesterolemic Swine Model of Coronary Artery Disease

“…Taken together, our preliminary data suggest the potential relevance of circulating monocyte phenotype features in predicting CAD stage and progression, assessed by histology, in a swine model of experimentally induced ATS.In agreement with human clinical trials, demonstrating the importance of the circulating immune effector characterization in predicting cardiovascular disease outcome [43], our experimental findings, albeit preliminary, support a role of the circulating monocyte functional state in coronary plaque initiation and early progression, providing the basis for a better knowledge of immune cell contribution to CAD development in humans.…”

Total calcium-sensing receptor expression in circulating monocytes is increased in rheumatoid arthritis patients with severe coronary artery calcification

“…Recently, considerable focus has been placed on circulating cells, as circulating monocytes, involved in cardiovascular disease [23] and CaSR expression has been demonstrated in circulating monocytes [25,26]. We have previously shown that CaSR expression in circulating monocytes could represent an accessible biomarker to monitor an individual’s ‘CaSR status’ under nonpathological conditions [28].…”

“…Monocytes/macrophages are known to play a crucial role in the pathogenesis of atherosclerosis and a considerable focus has been placed on their precursor, circulating monocytes as predictors of cardiovascular disease [21–23]. Intriguingly, CaSR expression has been demonstrated in human circulating monocytes and extracellular calcium has been shown to be a chemokinetic agent for human circulating monocytes [24–26].…”

Platelets as Biomarkers of Coronary Artery Disease

“…When secondary to CAD, the biomarkers are usually found in very low concentrations compared with other more abundant proteins such as albumin or immunoglobulins. 41 Although platelets cannot be stored and batched, they are abundant in the circulation and reflect both prothrombotic potential and atherosclerotic plaque composition. Circulating platelets interact with the vessel wall and the atherosclerotic plaque incorporating pathogenic material (protein, cytoplasm, and messenger ribonucleic acid [mRNA]) from the atherosclerotic plaque.…”