The inhibition of RTKs in the mammalian heart contributes to the development of dilated cardiomyopathies in which the heart

964 INTRODUCTION Cardiomyopathies are generally associated with a myocyte growth program that leads to an increase in the size of individual muscle cells. Individuals who have cardiac hypertrophy and cardiomyopathies are predisposed to the development of heart failure (Vasan et al., 1997). Heart failure affects 5.7 million individuals in the United States, has an annual economic health care burden in excess of US$34 billion in the United States, is associated with significant morbidity and has a 5-year mortality rate of ~50% despite current pharmacological and device-based therapies (Roger et al., 2010). Furthermore, the development of new pharmaceutical agents to treat heart failure has been disappointing despite an increased understanding of the pathophysiology of cardiomyopathies. Since the initial descriptions of cardiac hypertrophy in humans, substantial efforts have been directed towards understanding the underlying molecular mechanisms. In response to a variety of stimuli, including RTK-mediated signals, the mammalian heart undergoes morphological changes that contribute to the development of dilated or hypertrophic cardiomyopathies (Heineke and Molkentin, 2006). Dilated cardiomyopathies are characterized by enlargement of the heart chambers, thinning of the heart walls and poor contractility of the myocardium (Braunwald and Bonow, 2012). These changes are manifest as enlargements of chamber dimensions during diastole, when the heart is relaxed, and systole, when the heart is contracted, resulting in systolic dysfunction. In fact, the thinning of the heart walls can result from a process called ‘eccentric hypertrophy’ in which sarcomeres are added in series (Braunwald and Bonow, 2012). Hypertrophic cardiomyopathies are characterized by ‘a thickened but nondilated left ventricle’ (Braunwald and Bonow, 2012). The thickened heart wall in cardiac hypertrophy can occur by the addition of sarcomeres in parallel or by a process whereby the normal architecture of the myocardium becomes disarrayed. As a result, the end-diastolic chamber dimensions are normal or reduced, and systolic function is preserved until overt heart failure develops. The inhibition of RTKs in the mammalian heart contributes to the development of dilated cardiomyopathies in which the heart chamber becomes enlarged and poorly contractile (Crone et al., 2002). In fact, individuals who receive certain chemotherapy antagonists directed towards RTKs are predisposed to developing dilated cardiomyopathy and heart failure (Chen et al., 2008; Chu et al., 2007; Suter et al., 2007). Conversely, mutations that cause inappropriate activation of RTKs and downstream signaling molecules – such as the small GTP-ase Ras and the serine/threonine-specific protein kinase Raf – are associated with a variety of human syndromes, including Noonan syndrome (Gelb and Tartaglia, 2011; Pandit et al., 2007). Moreover, subsets of individuals with Noonan syndrome that have activating mutations in Raf are predisposed to hypertrophic cardiomyopathy (Pandit et al., 2007). Therefore, identifying the signals that cause cardiac hypertrophy can lead to new insights into the pathophysiology of this disease. Strategies using the fruit fly, Drosophila melanogaster, have been developed to facilitate the discovery of genes that cause cardiomyopathies. The adult fly heart is a contractile tube that is a single myocyte layer thick and is composed of pairs of Disease Models & Mechanisms 6, 964-976 (2013) doi:10.1242/dmm.011361