Systemic Molecular Screening Identifies Unique Inflammatory Pathways and Diagnostic Biomarkers for MINOCA

Jasper Iske (Berlin)1, P. Wolint (Zürich)2, M. Weisskopf (Zürich)2, H. Thau (Berlin)1, C. Beez (Berlin)1, M. Hierweger (Zürich)2, V. Falk (Berlin)3, M. Emmert (Berlin)1, N. Cesarovic (Berlin)4

1Deutsches Herzzentrum der Charite (DHZC) Berlin, Deutschland; 2Eidgenössische Technische Hochschule Zürich, Schweiz; 3Charité - Universitätsmedizin Berlin Klinik für kardiovaskuläre Chirurgie Berlin, Deutschland; 4Deutsches Herzzentrum der Charite (DHZC) Klinik für Herz-, Thorax- und Gefäßchirurgie Berlin, Deutschland


Background: Despite major advances in the treatment of acute myocardial infarction (MI), myocardial infarction with non-obstructive coronary arteries (MINOCA) represents a poorly defined clinical picture, accounting for up to 15% of all MI cases. In contrast to classic MI (cMI) characterized by a large occlusion in the coronary vessels, MINOCA displays a heterogenous pathology with cardiac microembolization being the major cause. Until today there is a lack of early diagnostic methods as well as adapted therapies for MINOCA, which leads to a high mortality rate of these patients. Recent evidence has suggested a distinct inflammatory response underlying MINOCA which may be utilized for both, diagnostic as well as therapeutic purposes.

Methods: In this study, we performed a broad, molecular profiling on serum samples collected from animals subjected to MINOCA (n=6) and cMI (n=6). We hereby recruited a novel, translational porcine animal model of autologous microthrombi injection into the left anterior descending artery (LAD) which mimicked all clinical aspects of MINOCA. cMI in turn was modeled by a 90-minute balloon-occlusion with subsequent reperfusion of the LAD. Serum samples were collected prior to and 2,5 as well as 5 hours after infarction induction followed by a high-resolution MRI to characterize infarcted areas. Molecular signaling pathways were analyzed combining micro-RNA (miRNA) profiling, multi-ELISA and proteomics. All results were confirmed by ELISA and qPCR.

Results: We identified distinct miRNA profiles associated with ischemia reperfusion injury and inflammation in the serum of animals undergoing cMI and MINOCA and uncovered miRNA-802 as a unique diagnostic biomarker for MINOCA (p<0.001). Notably, we detected comparable systemic inflammatory cytokine profiles with strong upregulation of TNF-α, IL-1β and IL-1α in the kinetics of 5 hours following infarction in both groups (all p<0.05) despite significantly smaller infarction areas in MINOCA animals (2,3±0,8% vs. 54±13,7% of area at risk, p<0,001). However, Il-10 (p<0.05) and IFN-γ (p<0.01) kinetics had been significantly different. Proteomic analyses then revealed leukotriene signaling as a unique inflammatory pathway underlying MINOCA with significantly augmented leukotriene-A4-hydrolase (LTA4H) levels when compared to cMI (p<0.01). Moreover, expression of leukotriene B4, the enzymatic product of LTA4H had been significantly increased serving as a novel biomarker to discriminate cMI and MINOCA (p<0.001). In contrast, animals undergoing cMI displayed higher serum levels of enzymes involved in the anaerobic glycolysis.


Conclusions: These novel results indicate unique inflammatory pathways associated with MINOCA and unveil novel biomarkers. The leukotriene pathway may furthermore serve as a specific therapeutic target to dampen accelerated inflammatory signaling following MINOCA.

Diese Seite teilen