Anne-Marie Koop

7 253 INTRODUCTION Heart failure (HF), roughly described as the inability of the heart to pump blood, is a leading cause of morbidity and mortalityworldwide, currently affecting more than 26 million people. 1 Commonly, HF is classified in left (LV) and right ventricular (RV) failure, depending on which ventricle is failing. The majority of the studies are focused on LV failure, whereas RV failure has received less attention. Therefore, it is not surprising that the knowledge on LV failure is greater and more accurate than on RV failure. Likewise, most of the therapies for HF are directed to the LV and commonly also administered to patients suffering from RV failure. As RV failure remains associated with poor prognosis, 2 new RV specific therapies are urgently needed. However, our limited understanding on RV molecular pathophysiological mechanisms remains an obstacle in the development of new and more efficient drugs. The RV has not been systematically investigated on the cellular and molecular level most likely because of the widely held opinion that the conditions governing RV and LV failure are identical or very similar and, as such, most concepts of RV failure have been shaped by the studies of the LV. However, embryological and physiological differences exist between both ventricles that support the hypothesis that gene expression patterns and their consequences differ between RV and LV failure. In fact, from embryonic development to the adult organism, both ventricles are exposed to different stimuli, including different hemodynamic forces and unique patterns of gene expression. RV is characterized by thinner walls, continuous coronary flow and is classically connected to a low-resistance pulmonary circulation, rendering it more sensitive to pressure-overload than volume-overload. 3,4 The vertebrate heart forms from two populations of cardiac progenitor cells: the primary and the secondary heart field. The primary heart field gives rise to the cardiac crescent, left ventricle and atria. 5-7 The secondary heart field gives rise to the outflow tract, the right ventricle and atria. 5,8 During these embryological processes, transcription factors are locally expressed in the developing heart and while some can be found in both the primary and secondary heart fields, others show specific expression patterns in just one of them. T-box 5 ( TBX5 ) and the basic helix-loop- helix transcription factor heart and neural crest derivatives expressed-1 ( HAND1 ) are both expressed in the primary heart field, while heart and neural crest derivatives expressed-2 ( HAND2 ), islet-1 ( ISL1 ), fibroblast growth factor-8 ( FGF8 ), fibroblast growth factor-10 ( FGF10 ) and paired-like homeodomain-2 ( PITX2 ) are expressed in the secondary heart field. 9,10 In mice, loss-of-function of these transcription factors revealed their importance during development of the heart. Without expression of Hand1 , formation of the left ventricle is disrupted due to a proliferation defect, and the mutants die from extraembryonic effects. 11-13 In contrast, Hand2 mutants show right-ventricular deficient vascularization and hypoplasia. 14,15 From embryonic day