Background: Coronary calcifications represent a feature of advanced plaque remodeling and contribute to plaque instability. Spotty calcifications, i.e. with a maximum arc of <90° and a length of <4mm have been recently introduced as novel feature of plaque vulnerability and can be reliably assessed by optical coherence tomography (OCT). In vitro studies suggest, plaque calcifications being associated with a distinct inflammatory response mainly driven by monocytes, macrophages and pro-inflammatory cytokines. Therefore, the aim of the present translational study was to comprehensively characterize culprit plaque calcification patterns and to analyze associated local inflammatory mechanisms as assessed by local immunophenotyping at the ACS-causing culprit site in a large cohort of patients with acute coronary syndrome (ACS).

Methods: 155 patients within the translational OPTICO-ACS-study program, presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI) were analyzed for the entire study. Both, peripheral blood from the access site (SYS) and coronary blood from the culprit site (LOC) were collected before OCT-characterization of the ACS-causing culprit lesion. Immunophenotyping including flow-cytometric analysis and cytokine bead array technique was performed. All measurements at the culprit site (LOC) were adjusted to peripheral blood levels (SYS) to determine a “culprit ratio” for detailed characterization of the local immune processes. OCT-characteristics including a comprehensive analysis of calcium patterns of the ACS-causing culprit lesion were assessed by standardized CoreLab analysis.  

Results: Spotty calcifications occurred in the culprit lesion of 75 (45.2%) patients. Patients with spotty calcium (SC) presented with an increased inflammatory activity at the culprit site as expressed by higher culprit ratios of IL-8 (2.04 vs. 1.37 vs.; p=0.048), IL-10 (1.28 vs. 1.09; p=0.002) and TNF-α (1.17 vs. 1.06; p=0.046) as compared to patients without SC. Likewise, significant higher concentrations of neutrophils (0.96 vs. 0.91; p=0.050) were observed at culprit lesions with SC, whereas monocyte ratios were not different between patients with- and without SC (0.96 vs. 0.97; p=0.651). However, subset analysis of monocytes in SC-culprits showed a significantly increased culprit ratio of intermediate monocytes (CD14++CD16+) as compared to the overall monocyte (CD14+) population (1.15 vs 0.96; p=0.046). Importantly, this intermediate monocyte subset showed enhanced surface expression of the integrin receptor CD 49d especially in culprit sites with SC (1.06 vs. 0.97; p=0.017), indicating enhanced, pro-inflammatory monocyte trafficking across the vessel wall.

Conclusion: This study - for the first time - identified a distinct inflammatory profile at ACS-causing spotty calcified culprit lesions, characterized by more pronounced inflammatory microenvironment, increased neutrophils and enhanced pro-inflammatory monocyte invasion. These findings may pave the way for individualized, anti-inflammatory secondary preventive therapeutic strategies.