The myocardial inflammasome and heart failure with reduced ejection fraction

Background: Left ventricular (LV) injury, particularly myocardial infarction (MI), is a leading cause of heart failure with reduced ejection fraction (HFrEF). However, whether and to what degree activation of the innate immune system, such as the NOD-LRR pyrin-containing protein 3 (NLRP3) inflammasome, occurs post-MI and the development of HFrEF remains unclear. This study tested the central hypothesis that LV myocardial induction of NLRP3 occurs and causes downstream activation of proinflammatory cytokines, notably interleukin-18 (IL-18). Methods and Results Pigs (n=6, 25kg) underwent an intracoronary occlusion (90 mins) followed by reperfusion and LV function (echocardiography) and myocardial sampling performed at 28 days post-MI. Age and weight matched pigs (n=6) served as controls. All results are reported as mean ± SEM. LV ejection fraction (EF) decreased (64.2 ± 5.1 vs. 44.6 ± 3.8 %, p<0.05) and end diastolic volume (EDV) increased (49.4 ± 1.2 vs.68.5 ± 11.6 mL, p<0.05) - consistent with the HFrEF phenotype. LV myocardial NLRP3 expression (rtPCR, 1.14 ± 0.28 vs. 61.55 ± 26.55 fold change, p<0.05), protein levels (digital immunoblot, 1271 ± 646 vs. 9177 ± 2491 pixels, p<0.05), and activity (caspase-1;YVAD-FAC substrate; 147 ± 122 vs.398 ± 58 slope of the fluorescence/time relation, p<0.05) were all increased. These results identified that NLRP3 at the mRNA level yielded functional inflammasome activation, and IL-18 mRNA levels (rtPCR) increased concordantly (1.05 ± 0.17 vs. 16.65 ± 7.20 fold change, p<0.05). Conclusions: While exogenous inflammatory pathways have been identified post-MI and with HFrEF, the unique findings of this study were clear demonstration that the innate immune system, the inflammasome, is also induced with a potent downstream induction of IL-18. These findings suggest that the inflammasome, notably NLRP3, as a potential therapeutic target in the context of ischemic HFrEF. This work was supported in part by National Institutes of Health grant R01HL130972-01A1 (F.G.S.) & R01HL5949 (F.G.S.) as well as a Merit Award from the Veterans Health Administration, BX000168-10A1 (F.G.S.) & BX005320 (F.G.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.