Tenascin C promotes valvular remodeling in two large animal models of ischemic mitral regurgitation
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ORIGINAL CONTRIBUTION
Tenascin C promotes valvular remodeling in two large animal models of ischemic mitral regurgitation Ouafa Hamza1 · Attila Kiss1 · Anne‑Margarethe Kramer1 · Sandra Trojanek2 · Dietmar Abraham2 · Eylem Acar1 · Felix Nagel1,3 · Verena Eva Tretter4 · Melitta Kitzwögerer5 · Bruno K. Podesser1,3 Received: 12 October 2020 / Accepted: 25 November 2020 © The Author(s) 2020
Abstract Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) characterized by adverse remodeling both at the myocardial and valvular levels. Persistent activation of valvular endothelial cells leads to leaflet fibrosis through endothelial-to-mesenchymal transition (EMT). Tenascin C (TNC), an extracellular matrix glycoprotein involved in cardiovascular remodeling and fibrosis, was also identified in inducing epithelial-to-mesenchymal transition. In this study, we hypothesized that TNC also plays a role in the valvular remodeling observed in ischemic MR by contributing to valvular excess EMT. Moderate ischemic MR was induced by creating a posterior papillary muscle infarct (7 pigs and 7 sheep). Additional animals (7 pigs and 4 sheep) served as controls. Pigs and sheep were sacrificed after 6 weeks and 6 months, respectively. TNC expression was upregulated in the pig and sheep experiments at 6 weeks and 6 months, respectively, and correlated well with leaflet thickness (R = 0.68; p 70 kg) were collected. Ischemic MR was achieved by ethanol injection in the obtuse marginal branches (OM) of the circumflex artery responsible for the posteromedial papillary muscle (PMPM) vascularization identified by contrast echocardiography as previously described [8]. The animal experiments were approved by the local ethics committee (BMWFW66.009/0112-WF/V/3b/2017) and conform to the NIH guidelines for animal care. First, an ischemic MR model was established in 7 pigs, which were sacrificed 6 weeks later, while healthy pigs (n = 7) were used as controls. The pigs’ experiments previously reported [8] now have extensive additional analyses. We then wanted to observe the characteristics of the valvular
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Basic Research in Cardiology
(2020) 115:76
remodeling over a longer period of ischemic MR. Unfortunately, the pig presents the limitation of its rapid growth rate. This is why, we enrolled sheep in long-term follow-up experiments (6 months) and assigned to an ischemic MR group (n = 7) and a control group (n = 4). Anesthetic regiments and periprocedural therapy are described in Supplementary Table 1.
Echocardiography LV end-diastolic, end-systolic diameters (EDD and ESD) were obtained from short- and long-axis M-Mode by averaging three cycles in each view. Left ventricle ejection fraction (LVEF), and end-diastolic and end-systolic volumes were measured in two-dimensional (2D) mode using the Simpson´s method. Color Doppler was used to evaluate MR severity by measuring the jet surface, the indexed jet area to the left atrium (IJA), and the vena contracta as previously described [26]. Tenting area was measured
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