Abstract
Interleukin-1β (IL-1β), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction < 40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve β-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.
Highlights
The NLRP3 (NACHT, leucine-rich repeat, and pyrin-domain containing protein 3) inflammasome is an intracellular macromolecular structure involved in sensing danger signals, activating caspase-1, and the pyroptotic release of pro-inflammatory cytokines that initiate the sterile inflammatory response to injury that has been identified as a central mechanism in both the response to damage and the healing process of acute myocardial infarction (MI) [1,2,3,4]
In vivo studies investigating the inhibition of IL-1β in experimental models of MI using targeted anti-inflammatory interventions have resulted in reduced adverse remodeling and progression to heart failure (HF) [8,9,10,11], which have led to human clinical trials showing promising results in patients with MI [12,13,14]
After the assessment of the screening echocardiogram, 29 mice meeting the criteria for severe adverse left ventricular remodeling were assigned to the four different groups, each with different diets, by an investigator not involved in the assessment of the endpoints: 10 mice were assigned to Group 1—OLT1177®, 3.75 g/kg diet; 9 mice were assigned to Group 2 OLT1177®, 7.50 g/kg diet; 10 mice were assigned to Group 3, standard chow diet
Summary
The NLRP3 (NACHT, leucine-rich repeat, and pyrin-domain containing protein 3) inflammasome is an intracellular macromolecular structure involved in sensing danger signals, activating caspase-1, and the pyroptotic release of pro-inflammatory cytokines that initiate the sterile inflammatory response to injury that has been identified as a central mechanism in both the response to damage and the healing process of acute myocardial infarction (MI) [1,2,3,4].Interleukin-1β (IL-1β) is a cytokine that is produced and released by the cells due to the activation of the NLRP3 inflammasome [1,2,3,4]. In vivo studies investigating the inhibition of IL-1β in experimental models of MI using targeted anti-inflammatory interventions have resulted in reduced adverse remodeling and progression to heart failure (HF) [8,9,10,11], which have led to human clinical trials showing promising results in patients with MI [12,13,14]. In a mouse model of HF due to large non-reperfused anterior MI, IL-1β blockade preserved contractile reserve and diastolic function even after the adverse remodeling of the left ventricle had ensued [8]. The benefit of IL-1β blockade in this model paved the way to clinical trials of patients with established HF, in which the IL-1 blockers appear to improve cardiorespiratory fitness, a surrogate for contractile and diastolic reserve [15,16,17,18]
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