Molecular screening in a translational large animal trial identifies a differential inflammatory response for MINOCA.

Abstract

Myocardial infarction without obstructive coronary arteries (MINOCA) comprises up to 15% of all myocardial infarctions (MI) and could be caused by cardiac microembolization (CME) originating from plaque rupture and/or erosion. Early diagnosis remains a challenge due to limited early biomarkers, leading to high morbidity. Here, we have systematically characterized acute (up to 5 h) CME-induced MINOCA in comparison to MI using clinical markers, histology, multi-ELISAs, miRNA profiling, and proteomics in a translational porcine animal model. CME-induced MINOCA model was created by injecting autologous microthrombi, generated by carotid crush maneuver, into the coronary arteries, whereas MI was induced by LAD balloon occlusion/reperfusion. MINOCA animals exhibited low troponin (547.0 ± 489.2 ng/L) and creatine kinase (1827.8 ± 677.3 U/L) levels, as well as infarct size (2.3 ± 0.8%), necrosis (7.6 ± 3.2%), and interstitial hemorrhage (0.6 ± 0.4%). Immune cell infiltration surrounding MINOCA microthrombi sites was significantly higher (1532 ± 722 cells/mm²) in comparison to MI infarct zones (470 ± 320 cells/mm²). Furthermore, cytokine profiling showed elevated IL-1α and IL-1β in both groups, higher IL-10 in MINOCA, and higher IFN-y in MI. The MINOCA-specific pro-inflammatory miRNA, ssc-miR-802, was identified. Plasma proteomic analysis revealed leukotriene signaling as a MINOCA inflammatory pathway with augmented leukotriene-A4-hydrolase levels. Its product, leukotriene B4, was increased in MINOCA serum at 150 min (1031 ± 537.6 pg/mL) and 300 min (1309 ± 640.8 pg/mL) and in tissue (408.2 ± 92.12 pg/mL) vs. MI (428.9 ± 9.483 pg/mL in serum at 150 min, 308.76 ± 5.484 pg/mL in serum at 300 min, and 76.22 ± 31.12 pg/mL in tissue). In summary, CME-induced MINOCA elicits a distinct pro-inflammatory leukotriene response compared to MI, presenting a new acute MINOCA diagnostic and therapeutic target.