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.