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Background Spontaneous coronary artery dissection (SCAD) is an unusual cause of acute myocardial ischemia that in almost 50% of cases is followed by sudden death. The increasing frequency of SCAD diagnosis may reflect the widespread use of coronary angiography and percutaneous coronary interventions in acute coronary syndromes (ACS). The incidence of SCAD is estimated between 0.1 and 0.28% of all ACS or sudden deaths evaluated by angiography or by anatomical examination, respectively. Most published data available so far deal with single case reports and probably the real incidence of this disease is underestimated. Some predisposing conditions to SCAD are well known and include Marfan syndrome, pregnancy and peripartum state, drug abuse and some anatomical abnormalities of the coronary arteries like aneurysms and severe kinking. The most appropriate therapeutic approach to SCAD is still controversial and decision making is often based on the clinical presentation, extent of dissection and amount of ischemic myocardium. Objectives and methods The purpose of this multicenter prospective registry, named DISCOVERY (DISsection of COronary arteries: Veneto and Emilia RegistrY), with a case-control group is to try to assess the role of SCAD in the pathogenesis of ACS. The primary endpoint is the occurrence of major adverse cardiovascular events related to the therapeutic strategy in the acute phase and in the mid-term follow-up. The secondary endpoints are the estimation of the prevalence of SCAD in the pathogenesis of ACS, the association or disassociation of SCAD with presumptive predisposing factors, the appreciation of the timing and extent of multivessel involvement when present, the occurrence of vascular and ocular comorbidities (i.e. carotid dissection and ocular lens abnormalities), the evaluation of the immediate success and the mid-term outcome of percutaneous coronary interventions and the definition of the role of intravascular ultrasound in diagnosis and treatment of SCAD. The enrollment of approximately 50 patients with SCAD is planned. A planned control group of patients of comparable age, sex and clinical presentation will allow us to identify potential peculiar or specific aspects of SCAD in any phase of the disease. Conclusion The DISCOVERY multicenter registry, with a case-control group, is the first large prospective study aimed at assessing the role of SCAD in the pathogenesis of ACS and at identifying the role of different therapeutic strategies in this unusual, multifaceted and probably underestimated pathologic condition.