Anne-Marie Koop

272 protection, conferred by depletion of Hand2, analysis of LV function by MRI, revealed a decrease in LV volumes as well as in LVmass, reduced stroke volumes and cardiac output, explained by decreased preloading of the LV due to right-sided pressure overload. Previous studies have shown that impaired cardiac function is not always accompanied by transcriptional activation of the “classical” marker genes associated either with hypertrophy or fibrosis and that it only happens once hypertrophy and/ or fibrosis start to develop. 43-44 The fact that control mice subjected to RV pressure overload developed LV cardiomyocyte hypertrophy, but Hand2 knockout hearts did not, might be explained by the absence/presence of transcriptional alterations of hypertrophic markers. In those studies, it was speculated that the absence of transcriptional deregulation and no alterations at the cellular level, such as hypertrophy and/or fibrosis, could facilitate recovery of cardiac function by specific treatments 43-45 or eventually reversing the stress. If this is the case in our study, remains to be clarified. As LV diastolic filling is diminished in patients, and animal models, with pulmonary hypertension, 46-49 this may cause a decrease in preloading of the LV and atrophy, and ultimately heart failure. In fact, reduction in LV mass was reported in disorders that are associated with chronic RV pressure overload, dysfunction and altered LV diastolic filling. 50,51 LV atrophy is characterized by less prominent transcriptional changes in hypertrophic genes. This supports our findings in the Hand2 -depleted animals subjected to PAB where we observed decreased LV mass, no hypertrophy and no dramatic changes in hypertrophic gene expression. Whether the LV under these conditions becomes atrophic remains to be investigated as we would have to look at the IVS and LV separately as well as analyses the cardiomyocyte length and width in more detail. We have previously identified differentially expressed transcripts of cardiac Hand2 target genes in pressure overloaded LVs fromHand2 F/F andMCM-Hand2 F/F animals. 19 Besides identifying several genes that had not previously been associated with cardiac hypertrophy, we also noticed a variety of genes involved in TGF β signaling as well as genes with defined functions during embryonic cardiac development. 19 Although RV remodelling due to increased pressure load is associatedwith increased expression of genes known to be involved in hypertrophy, fibrosis and angiogenesis, most of those genes were not affected by silencing of Hand2. Unbiased approached gene analysis of Hand2 KO hearts, subjected to RV pressure overload, revealed dysregulation of several other cardiac hypertrophy-associated genes, cell cycle inhibitors and cellular components related to nucleic acid binding, regulation of transcription and transcription factor activity, as well as cell adhesion genes. While in the pressure-overloaded RVs of Hand2 KO animals we observed differential