Risk Markers in the Acute Coronary Syndromes

The main aim of this trial is to assess the long-term prognostic value of different types of Factor XIIa in an unselected, single center series of 871 chest pain patients admitted to the emergency unit, employing blood samples collected at admission.

The second purpose of this study is to assess the incremental prognostic value of B-type natriuretic peptide (BNP) and high-sensitive C-reactive protein (hsCRP).

A third purpose of this study is to evaluate the prognostic impact of the Omega-3 Index which is a measure of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to other fatty acids in the erythrocyte membrane.

BACKGROUND Cardiac troponins are sensitive markers for myocardial injury in ACS and even a minor elevation of cardiac troponins is associated with an increased risk for future adverse coronary events. However, a detectable troponin release occurs only in a part of patients admitted with ACS. The clinical outcomes and further prognosis of patients with ACS with absent TnT release vary widely, and the identification of potential high-risk patients with troponin negative ACS still remains a major problem in clinical routine. Therefore, the aim of this study is focused on identifying new biomarkers for risk stratification.

Activated Factor XII: Activated Factor XII leads to contact activation and a number of pathophysiological processes, including hypotension, inflammation, thrombosis and fibrinolysis, are affected by contact activation following the activation of XIIa. Several studies have demonstrated a relation between XIIa and coronary artery heart disease (CAD) (1,2,3,4) and that XIIa levels post MI predict recurrent coronary occlusive events and play a role as an independent risk marker in these patients (5).

However, the detailed mechanisms of XIIa's actions in CAD still remain uncertain although recent findings in animal studies using FXII deficient mice indicate that Factor XII is essential for arterial thrombus formation (6).

Recent research indicates that in-vivo XIIa exists in multiple types and that in-vivo XIIa can exist in the circulation complexed to a variety of other proteins (7). To date, no data exist on the prognostic value of specific in-vivo types of XIIa on outcome in patients with chest pain and/or ACS.

B-type natriuretic peptide: B-type natriuretic peptide (BNP) is a counter-regulatory peptide hormone predominantly synthesized in the ventricular myocardium. BNP is released into the circulation in response to ventricular dilatation and pressure overload, and reflects ventricular wall stress and tissue hypoxia rather than cell injury per se (8, 9). It is a well known marker of left ventricular dysfunction and heart failure (HF), and it provides prognostic information beyond and above left ventricular ejection fraction (LVEF) in patients with an acute coronary syndrome (ACS) (10). This marker of neurohormonal activation and inflammation plays a pivotal role across the spectrum of ACS, including patients with ST-elevation myocardial infarction (MI) and non ST-elevation ACS (NSTE-ACS). Previous studies have demonstrated that BNP measured in the first days after the onset of symptoms independently predicts mortality, HF, and new MI in this patient population. Elevated natriuretic peptides at presentation have been shown to identify patients with ACS who are at higher risk of death and HF, and it adds information to that provided by the troponins (11-13). However, in a low-risk population the association between elevated BNP and survival is attenuated when adjustment is made for echocardiographic variables (in addition to clinical covariates), as shown by Wang and colleagues. In addition, they did not find any association between baseline BNP and the risk of coronary heart disease (CHD) (14).

High-sensitive C-reactive protein (hsCRP): C-reactive protein (CRP) is an acute-phase reactant that is produced in response to acute injury, infection or other inflammation stimuli. It is a marker for underlying systemic inflammation and plays an important role in the initiation and propagation of atherosclerosis and ultimately to plaque rupture and the ensuing thrombotic complication (15) Elevated levels of CRP were first reported in patients hospitalized with NSTE-ACS in the early 1990s (16, 17). Through the use of appropriate high-sensitive assays, it has been possible to investigate the relationship between plasma CRP levels that previously were considered to be normal and cardiovascular disease (CVD). Nevertheless, it is still under debate which markers should be preferred for risk prediction (18, 19). It has been suggested that the combined evaluation of BNP and CRP may yield incremental prognostic information in the risk stratification of patients with ACS (20), and their combined use has been shown to improve long-term risk prediction of mortality in patients with stable CHD (21). To our knowledge, there are limited data available that directly compare these two markers in a prospective manner in an unselected patient population presenting to the emergency department (ED) with chest pain. In addition, their role in risk stratification in patients with ACS is still under evaluation, and therefore additional investigations are necessary.

Omega- 3 Index: The value of the Omega-3 Index as a prognostic marker in the acute coronary syndromes is still under investigation.

STUDY DESIGN This prospective single center observational non-invasive trial includes 871 men and women admitted with chest pain and potential ACS at the Stavanger University Hospital between November 2002 and October 2003. Blood samples were collected immediately following admission. Patients were stratified according to peak troponin T (TnT) release following admission; i.e. 1) patients with an admission TnT exceeding 0.05 ng/mL, and 2) patients with a peak TnT level of 0.05 ng/mL or lower.

Assessment of a history of previous MI, angina pectoris (AP), congestive heart failure (CHF), diabetes mellitus and arterial hypertension was based on hospital records and personal interview. Electrocardiographic findings at admission were classified according to the presence of ST segment changes.

Written informed consent was obtained from all patients. Survival status, date and cause of death and clinical data were obtained by telephone interview and hospital journal reports at 4 predefined time points (30 days, 6, 12 and 24 months) during the two year follow-up period. In case of incapacity to provide information, the general practitioner or nursery home were contacted for relevant data. Hospital journals were searched for confirmation of reported data.

Primary Outcome Measures:

* During follow-up
* All cause death
* Non-fatal acute myocardial infarction (MI)
* Combined endpoint of all cause death or non-fatal acute MI
* Combined endpoint of cardiovascular death or non-fatal acute MI

Secondary Outcome Measures:

* During follow-up
* Acute hospitalizations for angina
* Myocardial revascularization

STEERING COMMITTEE

* Professor Dennis WT Nilsen MD PhD, Department of Heart Disease, Stavanger University Hospital
* Heidi Grundt MD PhD Department of Medicine, Stavanger University Hospital
* Øyvind Hetland MD PhD, Department of Clinical Chemistry, Stavanger University Hospital
* Ole Kristensen MD, Department of Clinical Chemistry, Stavanger University Hospital

BIOLOGICAL SAMPLE OWNERSHIP. The biological samples are owned by Stavanger University Hospital and their use for scientific purposes is administered by the Steering Committee.

DATA OWNERSHIP AND PUBLICATION OF RESULTS. The RACS Steering Committee has the ownership of all data registered in the RACS database, and any use of these data including the preparation and publication of scientific reports must be approved by the Steering Committee. Scientific articles will be published by RACS investigators or by authors mentioned by name. The author sequence should be approved by the Steering Committee and based upon contribution. Incentives to involve articles as part of a doctoral thesis should be encouraged. All collaborators in the study will be mentioned by name in an Appendix section of the main article from the study. The results will be published in peer-reviewed scientific journals and in magazines for the general public.

Eligibility Criteria:
Inclusion Criteria:

* adults \> 18 years able to give informed consent
* a history of chest pain or other symptoms suggestive of an ACS leading to admission at the emergency unit

Exclusion Criteria:

* \< 18 years of age
* Unwillingness or incapacity to provide informed consent
* Prior admission resulting in inclusion in the present study