Introduction
The IL-1 Family
Blocking IL-1-Mediated Disease
IL-1 in Heart Failure
IL-1 in Coronary Artery Disease, Myocardial Infarction, and Remodeling
IL-1 in Arrhythmias
IL-1 in Pericarditis and Inflammatory Cardiomyopathy
IL-1 in Sepsis-Induced Cardiomyopathy
Conclusions
Clinical scenario | Cellular mechanism | Possible clinical effect |
---|---|---|
Heart failure | Decreased beta-adrenergic responsiveness of L-type calcium channels [15] | Impaired systolic function |
Decreased expression of genes important to the regulation of calcium homeostasis (phospholamban, sarcoplasmic reticulum calcium ATPase) [16] | Impaired systolic function | |
Lower energy production and myocardial contractility | ||
IL-33 down-regulates apoptosis-eliciting enzymes [19] | Ischemia–reperfusion injury protection | |
Coronary artery disease | Upregulation of TGF-β stimulates vascular smooth muscle [38] | Plaque formation and rupture |
Suppression of endothelial cell proliferation [39] | Plaque formation and rupture | |
Expression of adhesion molecules by endothelial cells [40] | Plaque formation and rupture | |
Enhancement of plasminogen activator inhibitor [41] | Plaque formation and rupture | |
Expression of matrix metalloproteinases [45] | Post-myocardial infarction remodeling | |
Arrhythmias | Prolongation of action potential via calcium channels conduction changes [57] | Higher arrhythmia propensity |
Decreased potassium current and increased calcium sparks in cardiomyocytes [59] | Higher arrhythmia propensity | |
Higher arrhythmia propensity | ||
Higher arrhythmia propensity |
Study, year | Population (n) | Design | End points | Results | Notes |
---|---|---|---|---|---|
Coronary artery disease and myocardial infarction | |||||
VCU-ART, 2010 [49] | STEMI (10) | Double-blinded, randomized: anakinra 100 mg daily vs. placebo for 14 days | Primary: Change in LVESVi on cardiac MRI and echocardiography (3 months) Secondary: Change in LVEDVi on cardiac MRI and echocardiography (3 months) CRP levels (3 days) | Anakinra treatment- decreased LVESVi and LVEDVi Placebo treatment- increased LVESVi and LVEDVi Anakinra treatment: trend towards decreased CRP levels (not significant), correlated with the change in LVESVi and LVEDVi | |
VCU-ART2, 2013 [50] | STEMI (30) | Double-blind, randomized: anakinra 100 mg daily vs. placebo for 14 days | Primary: Change in LVESVi on cardiac MRI and echocardiography (3 months) Secondary: Change in LVEDVi on cardiac MRI and echocardiography, LVEF (3 months) CRP levels (3 days) | No significant change in LVESVi, LVEDVi, LVEF Anakinra treatment: blunted the increase in CRP | VCU-ART and VCU-ART2 combined showed reduction in incidence of new HF with anakinra |
VCU-ART3, 2014 | STEMI (99) | Double-blind, randomized: anakinra 100 mg daily vs. anakinra 100 mg twice daily vs. placebo for 14 days | Primary: CRP levels in 14 days Secondary: Change in LVESVi, LVEF and new-onset HF (12 months) | Study completion is estimated in February 2018 | |
Ikonomidis et al., 2014 [48] | Rheumatoid arthritis + CAD (60), rheumatoid arthritis + no CAD (20) | Double-blind, randomized crossover trial: Anakinra 100 mg (single injection) vs. placebo, baseline compared to 3 h after treatment. After 2 days, the alternate treatment was given | Multiple: Biochemical markers, FMD of brachial artery, CFR, LVEF, systemic arterial compliance, and resistance, left ventricular global longitudinal and circumferential strain, peak twisting, untwisting velocity | Anakinra treatment: improvement of FMD, CFR, arterial compliance, resistance, longitudinal strain, circumferential strain, peak twisting, untwisting velocity, LVEF, apoptotic, and oxidative markers in CAD than in non-CAD patients | |
MRC-ILA Heart Study, 2014 [52] | NSTEMI (182) | Double-blind, randomized: anakinra 100 mg daily vs. placebo for 14 days | Primary: area-under-the-curve for CRP over the first 7 days | Anakinra treatment: reduction in CRP levels | Higher incidence of MACE at 12 months with anakinra |
CANTOS, 2012 [53] | Post-myocardial infarction patients with elevated CRP (10,061) | Double-blind, randomized, multi-center, international, subcutaneous canakinumab 50, 150, or 300 mg every 3 months vs. placebo. Median follow-up of 3.8 years | Primary: A composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death Secondary: Same as the primary endpoint, in addition to hospitalization for unstable angina that led to urgent revascularization | Canakinumab treatment: The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for both endpoints Nearly all of the risk reduction was observed in nonfatal MI. There was no significant difference in stroke, cardiovascular mortality, or overall mortality | An exploratory analysis showed a marked reduction in the incidence of lung cancer, as well as lung cancer mortality and total cancer mortality The treatment was associated with a higher incidence of fatal infection than was placebo |
Heart failure | |||||
Ikonomidis et al. 2008 [28] | Rheumatoid arthritis (23) | Acute, double-blinded randomized crossover trial: anakinra 150 mg (single injection) vs. placebo, baseline compared to 3 h after treatment. After 2 days, the alternate treatment was given Chronic, nonrandomized study: anakinra (150 mg, n = 23) vs. prednisolone (+5 mg over regular dose, n = 19) for 30 days | Multiple: Biochemical markers, CFR, aortic distensibility, E/A ratio, E/E’ ratio, FMD of the brachial artery | Acute: anakinra treatment: Reduction in IL-6, malondialdehyde, nitrotyrosine, and endothelin-1 levels increased FMD, no change in nitrate-induced vasodilation, increased CFR, increased aortic distensibility, increased E/A ratio, decreased E/E’ ratio Chronic: similar results in vascular and left ventricle function | |
AIR-HF, 2012 [24] | HFrEF and elevated CRP levels (7) | Open-label, single-arm, non-randomized design. Anakinra 100 mg daily for 14 days | Change in aerobic capacity (peak VO2) and ventilatory efficiency (VE/VCO2) between baseline and 14 days | Both median peak oxygen consumption (VO2) and ventilator efficiency (VE/VCO2 slope) improved from baseline, both statistically significant | |
D-HART, 2014 [31] | HFpEF (12) | Double-blind, randomized, placebo-controlled, crossover trial: anakinra 100 mg daily vs. placebo for 14 days and an additional 14 days of the alternate treatment | Placebo-corrected interval change in peak oxygen consumption | Anakinra treatment: improvement in peak oxygen consumption and a significant reduction in plasma CRP levels | |
D-HART 2, 2014 [32] | HFpEF and elevated CRP levels (30) | 2:1 double-blind, randomized, placebo-controlled, single-center trial: anakinra 100 mg daily or placebo for 12 weeks | Primary: placebo-corrected interval changes in peak oxygen consumption and ventilator efficiency at week 12 Secondary: cardiac structure, systemic inflammation, endothelial function, quality of life, body composition, nutritional status, and clinical outcomes | Study completed in June 2017, results are awaited | |
REDHART, 2014 | HFrEF with recently decompensated heart failure (60) | Double-blind, randomized, placebo-controlled: anakinra 100 mg daily for 2 or 12 weeks or placebo for 12 weeks, follow-up of 24 weeks | Primary: Aerobic exercise capacity (peak VO2) and ventilatory efficiency at 2 weeks (follow-up = 24 weeks) Secondary: survival free of hospital admissions | Results have yet to be published | |
ADHF, 2014 [30] | HFrEF, acute decompensation and elevated CRP levels (30) | Double-blind, randomized, placebo-controlled: anakinra 100 mg twice daily for 3 days followed by 100 mg once daily for 11 more days | Area under the curve of CRP on day 3 | Anakinra treatment: CRP reduction, greater recovery in LVEF. No difference in length of hospital stay | Treatment initiated within 24 h of admission for acute decompensated HF |
Pericarditis | |||||
AIRTRIP, 2016 [76] | Recurrent pericarditis (21) | Anakinra was administered at 2 mg/kg per day up to 100 mg for the first 2 months. Then, patients who responded with resolution of pericarditis were randomized to continuing anakinra (11 patients) or changing to placebo (ten patients) for 6 months, or until a recurrent episode of pericarditis | Recurrent pericarditis | Recurrent pericarditis occurred in nine of ten patients taking placebo, compared to two of 11 patients treated anakinra over a median follow-up of 14 months |