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.
