Sizing up the heart: development redux in disease

 Following gastrulation and establishment of the three embryonic germ layers, the first definitive organ to form in the embryo is the heart, whose morphogenesis, growth, and integrated function are essential to embryonic survival, even by midgestation. Abnormalities in heart development result in congenital heart disease, the most frequent form of birth defects in humans. At the opposite end of the temporal spectrum, adult cardiac disease is the most common cause of death in the industrialized world, with congestive heart failure and inadequate pump function the end result of diverse disorders intrinsic to cardiac muscle cells, cardiac valves, systemic blood pressure, and the coronary blood supply. Despite recent therapeutic advances and mechanical devices to sustain cardiac function, only a minority of heart failure patients lives longer than 5yr. Death from heart disease therefore comprises an epidemic more prevalent than all cancers combined (Ries et al. 2003). Recent studies have begun to reveal the cellular circuitry that controls cardiac growth during development and disease. Intriguingly, many of the molecules and mechanisms that regulate growth of the embryonic heart are redeployed in the adult heart in response to stress signals that provoke cardiac enlargement and heart failure. Thus, understanding the mechanisms involved in heart development promises to provide insights into the molecular basis for pathogenesis of the adult heart, as well as to reveal novel therapeutic targets. In this review, we consider three aspects of cardiac development with significant implications for adult heart disease: (1) normal growth during organogenesis, (2) a “fetal” cardiac gene program reactivated in hypertrophy, and (3) restorative growth by undifferentiated progenitor cells that have cardiogenic potential. Each of these aspects of cardiac growth could be, itself, the subject of an in-depth review. Our goal, however, is not to comprehensively review these areas, but to identify common themes in developmental biology that are reiterated in settings of abnormal growth and dysfunction of the adult heart. Although we focus on development and disease of the myocardium, many of the same principles of allometric growth and homeostasis apply to other organs whose structure and function are influenced by physiological and pathological signaling.