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Recent studies have shown that systemic inflammation caused by periodontal disease (PD) can determine important changes in the coronary arteries, favoring atherosclerosis progression and the development of acute coronary syndromes (ACS). The aim of the ATHERODENT study (Protocol Record Number CM0117-ATD) is to assess the interrelation between PD, inflammation, and the progression of coronary atherosclerosis in patients with ACS. Material and methods: This case-control observational study will enroll 100 patients (group 1 – ACS and associated PD, and group 2 – ACS and no PD), in whom the following data will be collected: (1) demographic and clinical data; (2) cardiovascular risk factors; (3) full characterization of PD markers; (4) systemic inflammatory biomarkers; (5) imaging biomarkers derived from transthoracic echocardiography, computed tomography, coronary angiography, optical coherence tomography, and intravascular ultrasound; and (6) assessment of the presence of specific oral bacteria in samples of coronary plaques collected by coronary atherectomy, which will be performed during percutaneous revascularization interventions, when indicated in selected cases, in the atherectomy sub-study. The follow-up will be performed at 1, 3, 6, 12, 15, 18, and 24 months. The primary endpoint of the study will be represented by the rate of major adverse cardiovascular events (MACE) in PD vs. non-PD patients and in correlation with: (1) the level of systemic inflammation triggered by PD and/or by ACS at baseline; (2) the vulnerability degree of atheromatous plaques in the coronary tree (culprit and non-culprit lesions); and (3) the presence and burden of oral bacteria in atheromatous plaques. Secondary endpoints will be represented by: (1) the rate of progression of vulnerability degree of non-culprit coronary plaques; (2) the rate of progression of atheromatous burden and calcium scoring of the coronary tree; and (3) the rate of occurrence of left ventricular remodeling and post-infarction heart failure. The ATHERODENT study has been registered in clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03395041).