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Syncope is a transient loss of consciousness due to temporary global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery. Syncope represents 1-2% of emergency department (ED) visits and is coupled with a high risk for mortality, prolonged hospital admission, and immediate false diagnosis. Many patients who present to the ED with aspecific symptoms are mainly hospitalized because of diagnostic uncertainty. It is always very important to immediately distinguish syncope of cardiac and non-cardiac origins. Cardiac syncope has higher risk for mortality especially for sudden cardiac death, while non-cardiac one shows risk of repeated events of syncope with poor quality of life. Sudden cardiac death is defined as rapid and unexpected natural death due to cardiac etiology. Researchers from the GREAT Network hypothesized to evaluate some novel biomarkers in order to test acute cardiac condition that can suggest the presence of heart structural diseases, heart failure, and electrical disorders. The primary objective of this study is to test the diagnostic performance from patient history, clinical judgment, and novel biomarkers in the diagnosis of cardiac syncope in patients admitted to the ED. The trial is designed as a prospective international multicenter observational study accounting for 730 patients aged over 40 admitted to the ED with syncope within the last 12 h. A multimarker approach combining markers of different origin and mode of relapse, should add diagnostic information to correctly identify the cardiac conditions and to therefore be pertinent in the early diagnosis of cardiac syncope and in the prediction of cardiac events including sudden death. Future data should be needed to confirm the hypothesis presented here.