Interleukin-18 as a Therapeutic Target in Acute Myocardial Infarction and Heart Failure

Abstract

Interleukin 18 (IL-18) is a proinflammatory cytokine in the IL-1 family that has been implicated in a number of disease states. In animal models of acute myocardial infarction (AMI), pressure overload, and LPS-induced dysfunction, IL-18 regulates cardiomyocyte hypertrophy and induces cardiac contractile dysfunction and extracellular matrix remodeling. In patients, high IL-18 levels correlate with increased risk of developing cardiovascular disease (CVD) and with a worse prognosis in patients with established CVD. Two strategies have been used to counter the effects of IL-18:IL-18 binding protein (IL-18BP), a naturally occurring protein, and a neutralizing IL-18 antibody. Recombinant human IL-18BP (r-hIL-18BP) has been investigated in animal studies and in phase I/II clinical trials for psoriasis and rheumatoid arthritis. A phase II clinical trial using a humanized monoclonal IL-18 antibody for type 2 diabetes is ongoing. Here we review the literature regarding the role of IL-18 in AMI and heart failure and the evidence and challenges of using IL-18BP and blocking IL-18 antibodies as a therapeutic strategy in patients with heart disease.

Imbalanced production of IL-18 and its antagonist in human diseases, and its implications for HIV-1 infection

“…Consistent with its ability to induce IFN-c, IL-18 induces expression of this interferon in, and increases motility of, the smooth muscle cells of the plaques [128,131]. IL-18 has also been implicated in acute myocardial infarction and heart failure (reviewed in [132]). Daily administration of the cytokine to healthy mice induces expression of atrial natriuretic peptide (ANP) and osteopontin (OPN) in the heart causing remodeling of extracellular matrix.…”

“…The resulting chronic low grade inflammation increases their risk for the non AIDS-related clinical conditions. IL-18 is lipolytic, inhibits lipogenesis and production of adiponectin from adipocytes ( [122]; reviewed in [123]). It has also been shown to induce apoptosis of adipocytes.…”

“…Furthermore, it induces death of cardiac microvascular endothelial cells and induces proliferation of cardiac myocytes. Its administration results in cardiac hypertrophy, fibrosis and failure [132]. Increasing IL-18 concentrations in the circulation are a risk factor for adverse cardiovascular events.…”

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

“…It is clear that these favorable effects are independent of the antiplatelet properties of ticagrelor, as clopidogrel had no effect on inflammation, fibrosis, and remodeling despite achieving a similar degree of platelet aggregation inhibition. TNFα, 32,33 IL-1β, 33,34 and IL-18 [34][35][36] are involved in myocardial ischemia-reperfusion injury and remodeling. Thus, the reduction of these proinflammatory mediators induced by ticagrelor may explain the favorable effects on fibrosis and remodeling.…”

Heart failure with preserved ejection fraction: Refocusing on diastole

“…Angiotensin II, aldosterone and norepinephrine promote vasoconstriction, salt retention as well as cardiomyocyte hypertrophy and cardiac fibrosis [36]. Interleukin-1 (IL-1) and Interleukin-18 (IL-18), two members of the IL-1 family, may be responsible for the hypertrophic response of the myocardium and for the upregulation of osteopontin leading to a fibrotic response in HFpEF [37,38]. Patients with chronic IL-1-related inflammatory diseases such as rheumatoid arthritis are also more likely to have LVH and diastolic dysfunction [39,40].…”