Anne-Marie Koop

242 the RV. 47 In fact, we observed increased abundance of Myh7 transcripts and lower transcript levels of Myh6 in miR-199b TG animals subjected to RV pressure overload, also suggesting that RV hypertrophic growth under these conditions is a result of reactivation of the fetal gene program and consequent change in α MHC/β MHC ratio, rather than activation of Calcineurin/NFAT signaling. Despite most attention being given to LV function, whereas RV function and disease have remained less explored, it is an established fact that there is a relationship between LV and RV function and that ventricular interaction plays an important role in the cardiac response to stress. While impairment of the RV might influence LV function, 48 RV function is one independent predictor of mortality and the development of heart failure in patientswith LVdysfunction. 49 Abnormalmotion of the interventricular septum can occur in right ventricular pressure overload and is reflected by changes in eccentricity index of left ventricular shape. 50 We observed clear changes in LV shape under RV pressure overload conditions, even though no changes were observed between the different genotypes. Other LV parameters such as LV end-diastolic and end-systolic volumes, as well as left ventricular stroke volume, were more affected in TG animals after RV pressure overload than in the wild-type animals under similar conditions, indicating greater susceptibility of the TG LV to RV stress. This is consistent with our previous findings showing that overexpression of miR-199b does not result in cardiac dysfunctional phenotypes in resting conditions but increases LV sensitivity to cardiac stress such as pressure overload induced by transverse aortic constriction (TAC). 33 Moreover, TG animals displayed increased LV fibrosis as well as increased abundance of fibrosis-related transcripts. Interestingly, RV stress showed a clear response of the LV by activation of the Calcineurin/NFAT signaling pathway, revealed by an increased RCAN1-4 mRNA and subsequent decrease in Dyrk1A levels, a previously identified target of miR-199b. 33 Although the current study does not allow us to conclude on the contribution of miR-199b to RV remodelling towards RV failure, it does show that its overexpression sensitizes both ventricles to RV stress, with a more profound effect on the LV. Furthermore, studying RV dysfunction without significant failure allows for a better understanding of the cellular and molecular mechanisms preceding clinical failure, and thus target finding for early intervention. Perhaps more important, our study adds to the evidence that the stressed RV represents a qualitatively different substrate than the stressed LV and therefore, pharmacotherapy should be tailored accordingly. Funding SL was supported by a Foundation for Science and Technology of Portugal (FCT) grant (SFRH/BD/110404/2015). RMFB and BB were supported by the Sebald fund,