MINOCA Induces a Unique Leukotriene Driven Inflammatory Response

Background: Myocardial infarction without obstructive coronary arteries (MINOCA) accounts for up to 15% of all myocardial infarctions (MI). Unlike MI which is characterized by acute occlusion of large coronary vessels, MINOCA results from heterogenous pathologies including cardiac microembolization (CME) as a major cause. The lack of early diagnostic markers and specific therapeutic targets for MINOCA leads to poor outcomes. We have recently established a novel translational porcine animal model exhibiting all relevant clinical aspects of CME-induced MINOCA, which enables novel research opportunities.

Methods: In this study, we performed a broad, molecular profiling on animals subjected to MINOCA (n = 6) and MI (n = 6). For MINOCA, autologous microthrombi (created by carotid-crush method) were injected into the left anterior descending artery (LAD). MI was modeled by a 90-minute balloon-occlusion with subsequent reperfusion of the LAD. Serum samples were collected prior to as well as 2.5 and 5 hours after infarction induction followed by MRI examination and tissue sampling. Molecular signaling pathways were analyzed combining miRNA profiling, multi-ELISA, and proteomics. Results were confirmed by ELISA and qPCR.

Results: Distinct miRNA profiles associated with ischemia-reperfusion injury were identified (p < 0.05). Systemic inflammatory cytokine concentrations with high expression of TNF-α, IL-1β, and IL-1α were detected in both groups despite significantly smaller infarction areas in MINOCA animals (infarct size: 2.3 ± 0.8% versus 19.52 ± 1.52% of LV). However, IL-10 (p < 0.05) and IFN-γ (p < 0.01) kinetics were significantly different. Proteomics revealed leukotriene signaling as a unique inflammatory pathway instigated by MINOCA with significantly augmented leukotriene-A4-hydrolase (LTA4H) levels (p < 0.01). Notably, myocardial tissue affected by CME exhibited increased levels of leukotriene B4, the enzymatic product of LTA4H in MINOCA animals, when compared with infarcted myocardial tissue in MI animals (p < 0.05). Consistently, increased expression of LTB4 was also observed in serum of MINOCA animals (p < 0.001) when compared with MI animals. Strikingly, subjecting PBMS isolated from MINOCA animals to LTB4 promoted inflammatory cytokine expression.

Conclusion: These results indicate that accelerated leukotriene signaling instigated through CME may augment the inflammatory response following MINOCA despite small infarction areas. LTB4 may not only serve as a diagnostic biomarker to discriminate MINOCA from MI but furthermore constitute a target for future therapeutic approaches.

Publikationsverlauf

Artikel online veröffentlicht:
11. Februar 2025