Abstract 9829: Exercise-Induced CITED4 Expression is Necessary for Regional Remodeling of Cardiac Microstructural Tissue Helicity

Background: Exercise promotes cardioprotective benefits for the adult heart; however, the exercise-induced molecular and microstructural remodeling processes have yet to be fully characterized. This study sought to define the spatial interactions between molecular and microstructural remodeling that are induced by exercise and might result in cardiac protection by evaluating regional correlations of expressed cardiac CITED4, a transcriptional co-regulator previously shown to increase in hearts with exercise, and myocardial architecture mapping with diffusion tensor cardiac MRI (DT-CMR). Methods: In the first cohort, male wild-type C57BL/6J mice were housed with or without free access to a running wheel. In the second cohort, CITED4 cardiomyocyte specific knockout (KO) mice were generated along with control littermates (fl/fl mice) and the methods were repeated. After 8-weeks of voluntary wheel running, the mice were euthanized and their hearts were excised, scanned at 14.1 T MRI, and sectioned. RNA Fluorescent in situ hybridization (RNA-FISH) was used to detect CITED4 and all slides were counterstained with DAPI. All experiments were performed under approval of the IACUC of the Massachusetts General Hospital. Results: The exercised group of cohort 1 showed a significant increase in CITED4 expression and microstructural DT-CMR markers in the lateral wall of the left ventricle (p<0.05 for all). In particular, myofiber orientation, evaluated as helicity (helix angle transmurality), was significantly increased within the exercised group (p<0.05), indicating beneficial changes in the myocardial microstructure. Cohort 2 demonstrated that CITED4 was required for these changes to take place, as the CITED4 knock out exercise group did not replicate the same structural changes seen in cohort 1, while the fl/fl control mice reproduced the expected changes in tissue microstructure following exercise. Conclusion: Exercise induces a regional increase in CITED4 expression that coincides with microstructural remodeling. In addition, we have demonstrated that CITED4 is required for these beneficial exercise-induced microstructural changes to occur.