Age-Dependent Atrial Remodeling Induced by Recombinant Human Interleukin-11: Implications for Atrial Flutter/Fibrillation

Abstract

Recombinant human interleukin-11 (rhIL-11) has been used to alleviate side effects caused by chemotherapy in patients with neoplastic diseases and as an experimental anti-inflammatory agent. Its use in elderly patients has been associated with increased frequency of atrial flutter/fibrillation (AF). The mechanism of the latter phenomenon was studied in a rat model in vivo. Adult and old Fischer 344 rats fed with either normal diet or sodium-restricted diets were treated with rhIL-11 or vehicle (control) (1 mg/kg/day, i.p., 7 days); cardiac electrophysiologic parameters and atrial dimensions were determined. In adult rats, rhIL-11 was without effect, and atrial pacing did not induce AF. In contrast, in old rats, rhIL-11 shortened atrial refractoriness and increased atrial dimensions. Also, atrial pacing induced AF in old rats treated with rhIL-11 more than in controls. These effects of rhIL-11 in old rats were reversed by sodium-restricted diet. It was concluded that rhIL-11 induces age-dependent atrial remodeling manifested by atrial stretch and reduced atrial refractoriness, which favor AF. Na retention is the most likely mechanism underlying this effect of rhIL-11.

B-Type Natriuretic Peptide Exerts Broad Functional Opposition to Transforming Growth Factor-β in Primary Human Cardiac Fibroblasts

“…CTGF and PAI-1 are well-established downstream signaling genes of the TGF-␤ pathway, and IL11 has been associated with tissue remodeling and fibrosis. 29,30 Our results raise the possibility that increased IL11 expression in cardiac fibroblasts may contribute to TGF-␤-mediated fibrosis, and the suppression of this response by BNP may have a protective effect.…”

“…CTGF and PAI-1 are well-established downstream signaling genes of the TGF-␤ pathway, and IL11 has been associated with tissue remodeling and fibrosis. 29,30 Our results raise the possibility that increased IL11 expression in cardiac fibroblasts may contribute to TGF-␤-mediated fibrosis, and the suppression of this response by BNP may have a protective effect.Collectively, these effects of BNP on gene expression in TGF-␤-stimulated cells support a role for BNP in antifibrotic processes in cardiac fibroblasts. In striking contrast to TGF-␤-treated cells, BNP had no significant effects in unstimulated fibroblasts.…”

Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

“…Administration of IL-11 reproduced this effect in experiments with old rats and revealed reduced atrial refractoriness and increased atrial dimensions in treated animals [164]. This age-dependent atrial remodeling was ascribed to increased sodium retention as the effects of IL-11 could be reversed by sodium-restricted diet [164].Further effects of IL-11 on the heart remain to be elucidated, especially whether IL-11-dependent mechanisms also affect the ventricle and which intracellular signaling pathways might be involved in its effects.…”

“…Employed as an adjuvant therapy to alleviate side effects of chemotherapy, IL-11 has been associated with increased frequency of atrial flutter/fibrillation in elderly patients (Table 1) [164]. Administration of IL-11 reproduced this effect in experiments with old rats and revealed reduced atrial refractoriness and increased atrial dimensions in treated animals [164].…”

Fluid‐Retention Side‐Effects of the Chemotherapy‐Supportive Treatment Interleukin‐11: Mathematical Modelling of Putative Underlying Mechanisms

“…Since the mechanism underlying IL-11-mediated water accumulation is not clearly defined and data is limited [11,21], the current biomathematical approach to this phenomenon cannot be applied. Therefore, we replace this approach by a new method using multiple alternative models to describe BVE following IL-11 therapy.…”