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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.

SUBMITTER: O'Brien LC

PROVIDER: S-EPMC4069269 | biostudies-other | 2014 Jun

REPOSITORIES: biostudies-other

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Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure.

O'Brien Laura C LC Mezzaroma Eleonora E Van Tassell Benjamin W BW Marchetti Carlo C Carbone Salvatore S Abbate Antonio A Toldo Stefano S

Molecular medicine (Cambridge, Mass.) 20140612

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 wit ...[more]

PMID: 24804827

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Project description:BackgroundNo data from controlled trials exists regarding the inflammatory response in patients with de novo heart failure (HF) complicating ST-elevation myocardial infarction (STEMI) and a possible role in the recovery of contractile function. We therefore explored the time course and possible associations between levels of inflammatory markers and recovery of impaired left ventricular function as well as levosimendan treatment in STEMI patients in a substudy of the LEvosimendan in Acute heart Failure following myocardial infarction (LEAF) trial.MethodsA total of 61 patients developing HF within 48 hours after a primary PCI-treated STEMI were randomised double-blind to a 25 hours infusion of levosimendan or placebo. Levels of IL-6, CRP, sIL-6R, sgp130, MCP-1, IL-8, MMP-9, sICAM-1, sVCAM-1 and TNF-α were measured at inclusion (median 22 h, interquartile range (IQR) 14, 29 after PCI), on day 1, day 2, day 5 and 6 weeks. Improvement in left ventricular function was evaluated as change in wall motion score index (WMSI) by echocardiography.ResultsOnly circulating levels of IL-8 at inclusion were associated with change in WMSI from baseline to 6 weeks, r = ÷ 0.41 (p = 0.002). No association, however, was found between IL-8 and WMSI at inclusion or peak troponin T. Furthermore, there was a significant difference in change in WMSI from inclusion to 6 weeks between patients with IL-8 levels below, compared to above median value, ÷ 0.44 (IQR ÷ 0.57, ÷ 0.19) vs. ÷ 0.07 (IQR ÷ 0.27, 0.07), respectively (p < 0.0001). Levosimendan did not affect the levels of inflammary markers compared to control.ConclusionHigh levels of IL-8 in STEMI patients complicated with HF were associated with less improvement in left ventricular function during the first 6 weeks after PCI, suggesting a possible role of IL-8 in the reperfusion-related injury of post-ischemic myocardium. Further studies are needed to confirm this hypothesis.Trial registrationClinicalTrials.gov NCT00324766.

Project description:Importance:Hospitals in the United States have been subject to mandatory public reporting of mortality rates for acute myocardial infarction (AMI) and heart failure (HF) since 2007 and to value-based payment programs for these conditions since 2011. However, whether hospitals with initially poor baseline performance have improved relative to other hospitals under these programs, and whether patterns of improvement differ by condition, is unknown. Understanding trends within public reporting and value-based payment can inform future efforts in these areas. Objective:To examine patterns in 30-day mortality from AMI and HF and determine whether they differ for baseline poor performers (worst quartile in 2009 and 2010 in public reporting, prior to value-based payment) compared with other hospitals. Design, Setting, and Participants:Retrospective cross-sectional study at US acute care hospitals from 2009 to 2015 that included 2751 and 3796 hospitals with publicly reported mortality data for AMI and HF, respectively. Exposures:Public reporting and value-based purchasing. Main Outcomes and Measures:Hospital-level risk-adjusted 30-day mortality rates. Results:We identified 422 and 600 baseline poor-performing hospitals for AMI and HF, respectively. Baseline poor performers for AMI were more often public and for-profit and less often teaching hospitals. Baseline poor performers for HF were less often large hospitals. For AMI, 30-day mortality among baseline poor performers was higher at baseline but improved more over time compared with other hospitals (18.6% in 2009 to 14.6% in 2015; -0.74% per year; P?<?.001 vs 15.7% in 2009 to 14.0% in 2015; -0.26% per year; P?<?.001; P for interaction <.001). In contrast, for HF, baseline poor performers improved over time (13.5%-13.0%; -0.12% per year; P?<?.001), but mean mortality among all other HF hospitals increased during the study period (10.9%-12.0%; 0.17% per year; P?<?.001; P for interaction, <.001). Conclusions and Relevance:Despite being subject to identical policy pressures, mortality trends for AMI and HF differed markedly between 2009 and 2015.

Dataset Information

Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure.

Publications

Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure.

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