The Impact of Inflammatory Bowel Disease on Cardiac Remodeling

Abstract

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the human gastrointestinal (GI) tract with well-documented extra-intestinal manifestations (EIMs). Recent observational studies shed light on its cardiac manifestations, with a significantly increased risk of major adverse cardiovascular events among patients with IBD. Indeed, systemic chronic inflammation associated with IBD is postulated to drive cardiac remodeling, altering the physiological, metabolic, molecular, structural, and functional state of the heart. However, this gut-heart association remains underexplored. This work aims to investigate the impact of IBD on cardiac remodeling in a chronic IBD animal model, at the clinical, histological, and molecular levels. Methods: Chronic IBD was induced in eight-week-old C57BL/6 mice (n=12; controls n=10) using five cycles of dextran sulfate sodium (DSS). Each cycle consisted of 1.5% DSS, administered in drinking water for 5 days, followed by 10 days of regular water. Animals were monitored daily, and weight loss, rectal bleeding, and stool consistency were recorded to generate the Disease Activity Index (DAI). Echocardiography was performed at baseline and endpoint. At week 18, animals were sacrificed; serum, hearts, and colon tissues were harvested for histological and molecular analyses. Routine histology was used to assess and score structural changes, mast cell infiltration, goblet cells, and fibrosis. Interleukin (IL)-6 and Transforming Growth Factor-beta (TGF-β) levels were measured using ELISA and Western blot, respectively. Results: Compared to the controls, IBD animals exhibited significantly increased DAI (mean ± SEM: 1.69 ± 0.22 vs 0.03 ± 0.01, p < 0.0001) and colon shortening (5.08 ± 0.16 cm vs. 6.80 ± 0.18 cm, p < 0.0001). Colon histology showed increase inflammation (2.56 ± 0.12 vs. 0.23 ± 0.10, p < 0.0001), mast cell count (1.27 ± 0.29 cells/high power field (HPF) vs. 0.4 ± 0.11 cells/HPF, p < 0.0001), and goblet cell depletion (1.42 ± 0.15, vs. 3.30 ± 0.15, p < 0.0001). Cardiac histology of IBD animals showed intercellular space enlargement, myocyte hypertrophy, disorganized myofibers, inflammatory cell infiltration, and cell nuclei alterations (1.92 ± 0.13 vs. 0.56 ± 0.08, p < 0.0001), with increased interstitial (12.23 ± 4.45 vs. 0.2982 ± 0.21) and perivascular fibrosis (2.24 ± 0.27 vs. 1.13 ± 0.26, p < 0.0001). Hearts of the IBD group also revealed an insignificant decrease in vascularization (3.58 ± 0.93 blood vessels/ section) compared to the normal (3.85 ± 1.37), p = 0.86. No significant echocardiographic changes were depicted in pre-or post-IBD. IL-6 levels were significantly increased in the serum (8885 ± 103 pg/mL vs. 5148 ± 1725 pg/mL, p < 0.0001), colon (118.0 ± 36.23 vs. 37.12 ± 5.73, p < 0.0001), and heart (84.61 ± 9.79 vs. 48.12 ± 9.46, p < 0.0001). TGF-β expression was increased in the colon (8.36 ± 2.90 vs. 5.25 ± 0.99, p = 0.48), with a significant increase in the heart (8.29 ± 1.01 vs. 4.22 ± 1.00, p < 0.0001). 3 Conclusion: This study reports cardiac histological and inflammatory changes following chronic IBD, shedding light on early cardiac remodeling despite the absence of echocardiographic alterations. Further molecular evaluation is needed to clarify the exact mechanisms underlying the inflammatory process driving IBD-induced cardiac remodeling.