Unraveling the complexities of cardiac remodeling and hypertrophy — High-content screening and computational modeling

John W. Elrod, Jop H. van Berlo
2014 Journal of Molecular and Cellular Cardiology  
Heart weight directly correlates with body weight in most mammals under homeostatic conditions [1] . However, numerous stimuli and stresses have been found to elicit myocardial growth, increase heart size, and remodel ventricular shape. Physiological provocations, such as pregnancy and exercise, result in an increase in heart size accompanied by enhanced cardiac output that is completely reversible and not related to adverse events later in life. On the other hand, it has been appreciated for
more » ... me time that numerous molecular signals elicit hypertrophy and remodeling that initially could be considered a positive response to cope with an acute insult, but with persistent signaling become maladaptive. Numerous stressors have been implicated in pathological cardiac hypertrophy/remodeling including: aortic valve stenosis, severe mitral valve regurgitation, genetic mutations, hypertension and myocardial infarction, where the remote myocardium must compensate for the lost region of cardiomyocytes [2]. The signaling pathways that lead to cardiomyocyte hypertrophy and remodeling have been extensively studied, resulting in complex molecular pathways from the level of ligand/ receptor signaling through a host of second messengers, to post-translational pathways converging on transcriptional programs. Using a reductionist approach, often incorporating pharmacologic agents and gain-/loss-of-function experimental systems, countless studies have contributed to the design of a cardiac remodeling pathway tree of enormous proportions that has been the subject of recent reviews [3] [4] [5] . However, our traditionally linear experimental approaches, while expansive and redundant in scope, have largely failed to define the exact signaling patterns that distinguish physiological from pathological remodeling [6, 7] . Further, it remains unknown how physiological hypertrophy is completely
doi:10.1016/j.yjmcc.2014.03.014 pmid:24742541 pmcid:PMC4413011 fatcat:thpwtvry5zd2pdbapbk3cbvfbu