Abstract 9851: Tenascin-C Deficiency Promotes Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function in Chronic Pressure-Overload

Abstract

Background: Tenascin-C (TnC) is a matricellular protein that is generally expressed during embryogenesis and in pathological settings; however, little is known about the role of TnC in maladaptive LV remodeling in response to chronic pressure-induced hypertrophy. Methods: Aortic constriction was performed in TnC null mice and control wild type mice (all mice in C57BL6 background). The aorta between the celiac and superior mesenteric arteries was constricted by tying a silk ligature against a 28-gauge needle for to yield a~33% narrowing of the aortic luminal diameter when the needle is removed. The LV size and function was assessed by two-dimensional guided M-mode echocardiography. Aortic blood pressure proximal to the constriction site was calculated by adding the pressure gradient across the constriction (measured by pulse Doppler) to the post-constriction blood pressure measured in the tail using a special cuff. LV mass was measured after euthanizing the mice at one month and histology was used to estimate myocardial fibrosis. Results: Before aortic constriction, LV size, EF and shortening fraction were similar in TnC null and wild type control mice. One month after constriction, the LV end diastolic diameter was larger in TnC null compared to wild type control mice (4.6 ± 0.5 vs 3.7 ± 0.2; p<0.001), the LVEF was lower in TnC null compared to wild type control mice (47.3 ± 10.7 vs. 60.7 ± 3.8; p<0.001), the fractional LV shortening was lower in TnC null compared to wild type control mice (24.2 ± 5.9 vs. 31.9 ± 2.6; p<0.001), the heart weight in mg/gram of body weight was higher in TnC null compared to wild type control mice (6.9 ± 1 vs. 5.1 ± 0.1; p<0.05). Collagen staining revealed that LV fibrosis was abundant in TnC null mice whereas it was scant in wild type control mice. There were no significant differences in the calculated proximal aortic blood pressure, the pressure gradient across the constriction, or the tail blood pressure or total body weight between the two groups of mice. Conclusions: TnC gene deletion is associated with maladptive LV remodeling, reduced LV systolic function and increased LV fibrosis in response to chronic pressure overload identifying a potentially beneficial role for TnC in myocardial response to pressure overload.