The early outcome of acute coronary syndrome (ACS) has considerably improved in the last decade; yet cardiovascular diseases still represent the main cause of morbidity and mortality worldwide, because the recurrence of ACS eventually leads to the pandemics of heart failure. This calls for a reappraisal of the mechanisms responsible for coronary instability and for innovative preventive and therapeutic strategies. Crea et al. have recently proposed a pathogenetic classification of ACS, based on Optical Coherence Tomography (OCT) findings and systemic markers of inflammation, that provides a framework for understanding the basic mechanisms responsible for coronary instability in four homogeneous groups of patients:

1. patients with plaque rupture and inflammation;
2. patients with plaque rupture without inflammation;
3. patients with intact fibrous plaque with evidence of thrombus (plaque erosion);
4. patients with a smooth plaque.

In patients presenting plaque rupture and systemic evidence of inflammation, the high frequency of aggressive T-cells and the reduced number and function of regulatory T-cells suggest that coronary instability might be related to still unknown mechanisms involving adaptive immunity. Among the triggers, an altered gut-microbiota as well as metabolic imbalance might have a role. On the other hand, in a sizeable subset of patients, acute coronary events occur without increase in high sensitive C-reactive protein (hs-CRP) levels, a non-specific but sensitive marker of inflammation.

In these patients, other mechanisms, including emotional and physical stress, probably play a pathogenic role, involving sympathetic nervous system activation and catecholamine release that, in turn, might lead to coronary vasoconstriction and favor vulnerable plaques fissure, platelet activation and hypercoagulability. The distinction of coronary artery thrombosis caused by plaque rupture into cases with or without signs of concomitant inflammation may have substantial therapeutic implications, as direct anti-inflammatory interventions for atherosclerosis emerge. Plaque erosion is reported in about one-third of patients dying of acute myocardial infarction in post-mortem histopathological studies. Neutrophil activation seems to play a pivotal role. An intense immunostaining pattern for hyaluronan and its receptor, CD44, has been reported along the plaque/thrombus interface in eroded plaque but not in fissured or stable plaque. Hyaluronan accumulation in eroded plaques may promote CD44-dependent adhesion and accumulation of circulating leukocytes, which in turn may enhance endothelial cell death and promote thrombus formation. Thus, in patients with eroded plaques mechanisms involving innate more than adaptive immunity seems to play a pathogenic role.

Recent studies proposed a model of plaque erosion in which the endothelial shear stress and the consequent activation of Toll-Like Receptors (TLRs) might promote molecular pathways leading to plaque instability. Coronary artery thrombosis caused by plaque erosion is on the rise in an era of intense lipid lowering. In about one-fifth of patients, OCT interrogation of the culprit plaque does not show neither fissure nor thrombus. Spasm of proximal or distal coronary vessels is the likely cause of ACS in this patient subset. Accordingly, the incidence of spasm in response to ergonovine administration in patients with a recent myocardial infarction was about 20%. The mechanisms responsible for coronary spasm may involve enhanced Rho kinase activity in smooth muscle cells. Emerging management strategies may likewise apply selectively to this category of ACS.

In summary, coronary thrombus is frequently, but not always, the last common pathway leading to coronary instability and it is currently the only pharmacologic target of ACS. To further improve the outcome of ACS it is strongly needed to identify new therapeutic targets. This is possible only by improving our knowledge of the multiple molecular mechanisms leading to coronary instability through the different pathways described above.

The goal of this project is to define the molecular mechanisms responsible for the four different presentations of ACS, to identify biomarkers for their noninvasive identification and potential new therapeutic targets, thus promoting precision medicine. Briefly, after the study start-up, ACS patients will be enrolled, OCT analysis of culprit stenosis and fluid dynamic reconstruction of shear stress forces will be performed, biological samples collected and partially analyzed for parameters that need to be assessed on fresh samples or stored for biomarkers and omics analyses, animal models will be developed. The last 12 months will be dedicated to patient follow-up and data analysis.

Working group:

• Luigi Marzio Biasucci - Faculty of Medicine and Surgery
• Massimo Massetti - Faculty of Medicine and Surgery
• Carlo Trani - Faculty of Medicine and Surgery

Partners:

• Università Cattolica del Sacro Cuore (Coordinator)
• Libera Università "Vita Salute S.Raffaele" Milano
• Università degli Studi di Roma "La Sapienza"
• Università degli Studi della Campania "Luigi Vanvitelli"
• Università Telematica San Raffaele Roma