The Annals of thoracic surgery | 2021
Interleukin 1 receptor antagonism abrogates acute pressure-overload induced murine heart failure.
Abstract
BACKGROUND\nRecent clinical trials have suggested that blockade of interleukin-1 can favorably impact patients with myocardial infarction and heart failure. However, the mechanism of how antagonism of this specific cytokine in mediating cardiac disease remains unclear. Hence, we sought to determine the influence of IL-1 blockade on acute hypertensive remodeling.\n\n\nMETHODS\nTransverse aortic constriction (TAC) was performed in C57BL mice with or without intraperitoneal administration of interleukin 1 receptor antagonism (IL-1ra). Function, structure, and molecular diagnostics were subsequently performed and analyzed.\n\n\nRESULTS\nSix weeks after TAC, a progressive decline of ejection fraction and increases in LV mass and dimensions was effectively mitigated with IL-1ra. TAC resulted in an expected profile of hypertrophic markers including myosin heavy chain, atrial natriuretic peptide, and skeletal muscle actin which were all significantly lower in IL-1ra treated mice. While trichrome staining 2-weeks post TAC demonstrated similar levels of fibrosis, IL-1ra reduced expression of collagen-1, TIMP1, and periostin. Investigating the angiogenic response to pressure overload, similar levels of VEGF were observed, but IL-1ra was associated with more SDF-1. Immune cell infiltration (macrophages and lymphocytes) was also decreased in IL-1ra treated mice. Similarly, cytokine concentrations of IL-1, IL-18, and IL-6 were all reduced in IL-1ra-treated animals.\n\n\nCONCLUSIONS\nIL-1ra prevents the progression towards heart failure associated with acute pressure overload. This functional response was associated with reductions in mediators of fibrosis, cellular infiltration, and cytokine production. These results provide mechanistic insight into recent clinical trials and could springboard future investigations in patients with pressure-overload based cardiomyopathies.