Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α

Abstract Objective To determine the mechanisms of inflammation‐induced left ventricular (LV) remodeling and effects of blocking circulating tumor necrosis factor alpha (TNF‐α) in a model of systemic inflammation. Methods Seventy Sprague‐Dawley rats were divided into three groups: the control group, the collagen‐induced arthritis (CIA) group, and the anti‐TNF‐α group. Inflammation was induced in the CIA and anti‐TNF‐α groups. Following the onset of arthritis, the anti‐TNF‐α group received the TNF‐α inhibitor, etanercept, for 6 weeks. LV geometry and function were assessed with echocardiography. Circulating inflammatory markers were measured by ELISA and LV gene expression was assessed by comparative TaqMan® polymerase chain reaction. Results The LV relative gene expression of pro‐fibrotic genes, transforming growth factor β (TGFβ) (p = 0.03), collagen I (Col1) (p < 0.0001), and lysyl oxidase (LOX) (p = 0.002), was increased in the CIA group compared with controls, consistent with increased relative wall thickness (p = 0.0009). Col1 and LOX expression in the anti‐TNF‐α group were similar to controls (both, p > 0.05) and tended to be lower compared to the CIA group (p = 0.06 and p = 0.08, respectively), and may, in part, contribute to the decreased relative wall thickness in the anti‐TNF‐α group compared to the CIA group (p = 0.03). In the CIA group, the relative gene expression of matrix metalloproteinase 2 (MMP2) and MMP9 was increased compared to control (p = 0.04) and anti‐TNF‐α (p < 0.0001) groups, respectively. Conclusion Chronic systemic inflammation induces fibrosis and dysregulated LV extracellular matrix remodeling by increasing local cardiac pro‐fibrotic gene expression, which is partially mediated by TNF‐α. Inflammation‐induced LV diastolic dysfunction is likely independent of myocardial fibrosis.

Abstract licence: CC BY

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