Background
Acute coronary syndromes (ACS) are the most frequent causes leading to myocardial infarction, heart failure, and death. The underlying problem is plaque rupture or erosion, with partial or complete occlusion of a major epicardial coronary artery. Activation of inflammatory pathways may trigger these events. Although progress has been made in prevention and treatment of ACS, its complication rate remains high. This is due to the fact that prevention is not well implemented, triggers of the disease are incompletely understood, and diagnosis is only made once myocardial necrosis has occurred. Importantly, inflammatory mechanisms are not yet incorporated into clinical management. To further improve outcome, patient education should be improved, novel and early diagnostic markers be evaluated and anti-inflammatory strategies developped.

Previous studies
Reducing cardiovascular risk and progression of atherosclerotic lesions is one of the most important topics of modern medicine. Among preventive strategies, nutritional medicine is a new blooming field. New data indicate that nutrients rich in anti-oxidants may favorably affect cardiovascular health, for instance fruits, vegetables and more recently cocoa-rich chocolate. Another major area of interest is the unstable plaque and acute coronary syndromes as well as stem-cell based repair after such an event.

Why do coronary arteries occlude?

Figure 1: Thrombus obtained from an acute coronary lesion and monocytes expressing myeloid-related protein complex 8/14 Formation of the MRP 8/14 complex was detected in monocytes/ macrophages and granulocytes (red staining) immunohistochemically by staining with a monoclonal murine antibody to human MRP 8/14 (right, Panel A and B). In the right panel C, components of recovered atherothrombotic material are visualized by trichrome stain (Masson-Goldner), rendering fibrin red, erythrocytes grey, and platelet aggregates grayish (Panel D = negative control magnification100400).

Recent knowledge in the pathophysiology of atherothrombosis and acute coronary syndromes open new frontiers in the early detection of this deleterious disease. Over the last few years clinical research focused on the analysis of blood and thrombi sampled at the site of coronary occlusion in patients with acute myocardial infarction.We showed that local inflammation plays a crucial role in coronary plaque rupture leading to coronary occlusion.

We identified a novel protein complex expressed by invading inflammatory cells that are present at the site of plaque rupture (Figure 1). Most interestingly, this protein complex is increased in peripheral blood of patients with ACS prior to necrosis markers (such as troponin, myoglobin and creatinine kinase) opening new promising strategies for early stratification of high-risk patients.

Myeloid-Related Protein 8/14 Complex: A novel, early, and sensitive marker of acute coronary syndromes

Indeed, although the use of troponin has facilitated the management of ACS as a sensitive and specific marker of myocardial necrosis, it provides only indirect information about unstable plaques. Troponin reflects myocardial necrosis due to micro-embolisation of atherothrombotic material or coronary occlusion, which is a late event in ACS. This may explain why even some patients presenting with chest pain and negative troponin do experience cardiac events within the next 30 days. Early diagnosis and risk stratification of patients with non-cardiac chest pain, stable CAD or ACS is of utmost importance.

Markers of myocardial necrosis only rise two to three hours after symptom onset. As inflammation is an initiating event of plaque instability, markers of inflammation may provide insight into cellular processes linked to plaque instability and thrombus formation before myocardial necrosis ensues.

Our study for the first time demonstrated that Myeloid-Related Protein 8 /14 Complex (MRP8/14), a heterodimeric protein complex expressed by activated monocytes and granulocytes, is elevated prior to necrosis markers in ACS at the site of coronary occlusion and the systemic circulation (Figure 1). This makes this protein a prime candidate as a novel biomarker of unstable plaques in patients with chest pain which will be tested in ongoing protocols.

References

Altwegg LA, Neidhart M, Hersberger M et al.
Myeloid-Related Protein 8/14 Complex: A novel, early, and sensitive marker of acute coronary syndromes.
European Heart Journal. 28(8):941, 2007.

Maier W, Altwegg LA, Corti R et al.
Inflammatory Markers at the Site of Ruptured Plaque in Acute Myocardial Infarction. Locally Increased Interleukin-6 and Serum Amyloid A but Decreased C-Reactive Protein.
Circulation. 111(11):1355-1361, 2005.

 

RESEARCH AIMS
The funded subprojects comprise the following research aims (Figure 1):

Figure 1: ACS RESEARCH AIMS OF THE SWISS RESEARCH NETWORK Five major research areas (subproject #) are investigated in a joint effort designed to improve diagnosis, prognosis, therapy, and prevention of patients with ACS.

Aim 1 EDUCATION – improve patient Education after ACS (P-F. Keller, F. Mach, D. Carballo, Geneva; N. Rodondi, R. Auer, Lausanne): This subproject aims to prevent recurrent ACS and its complications by increasing adherence of patients to lifestyle changes and their medications through patient.

Aim 2 BIOMARKERS – identify novel ACS biomarkers (C.M. Matter, R. Klingenberg, Zurich): This subproject will identify novel biomarkers involved in plaque rupture using analyses of systemic and local coronary blood samples, white blood cells within thrombus, and arterial tissue.

Aim 3 PROGNOSIS – test candidate markers suitable for ACS prognosis (W. Maier, L. Altwegg, Zurich): Candidate inflammatory biomarkers such as MRP 8/14 will be evaluated in patients with chest pain seen in the emergency room.

Aim 4 OCT IMAGING – virtual histology of plaques (S.Windecker, L. Raeber, Bern): High-resolution imaging of culprit lesions using optical coherence tomography (OCT) and intravascular ultrasound (IVUS) will identify the morphological features leading to acute coronary narrowing and/or occlusion and determine the role of inflammatory markers.

Aim 5 REPAIR – identify role of progenitor cells after ACS (U. Landmesser, C. Templin, Zurich): The relation between inflammatory pathways and stem/progenitor cell function in patients with ACS will be assessed ex vivo and in vivo and anti-inflammatory therapy analyzed.

EXPERIMENTAL PROTOCOLS
We plan to include over 2000 patients in the Emergency rooms of all 4 University Hospitals (Figure 2) and assess the prognostic impact of candidate biomarkers and of education of patients and caregivers. For the characterization of novel Biomarkers, plaque imaging and progenitor cell function we will recruit patients in the catheterization laboratory.

Figure 2: ORGANIZATION OF THE CONSORTIUM. We plan to include over 2000 patients in the Emergency rooms of all 4 University Hospitals for the subprojects 1 (Prevention, ELIPS) and 3 (Markers of Prognosis) with clinical check and peripheral blood sample. Subprojects 2 (Novel Biomarkers) 4 (OCT Imaging) and 5 (Repair – progenitor cells) will recruit patients in the catheterization laboratory for analyses of plaques via imaging, thrombus aspiration and local blood samples focusing on white blood cells (WBC) and endothelial progenitor cells (EPC).

INTERDISCIPLINARY AND TRANSLATIONAL ASPECTS OF THE SUBPROJECTS
This SNF-project combines experts with backgrounds in various fields of cardiovascular disease in 4 Swiss Universities (Figure 3): Coronary interventions, epidemiology, statistics, prognosis, high-throughput analyses, basic research with foci on pathways of inflammation, stem/progenitor cell biology, molecular plaque imaging. We anticipate that our consortium will foster synergies between the subprojects that will be valuable for science, society and industry.

COLLABORATIONS AT THE UNIVERSITY OF ZURICH
We are grateful for the expert support by collaborators in Zurich that include A. von Eckardstein (Institute for Clinical Chemistry, S. Gay (Center for Experimental Rheumatology), S. P. Hoerstrup (Surgical Research), H. Moch (Institute for Surgical Pathology), Gabriela Senti and G. Zünd (Clinical Trial Center)). This cooperative project is coordinated by T. F. Lüscher and C. M. Matter, Zurich.