Recent Advances in Cardiac Development With Therapeutic Implications for Adult Cardiovascular Disease

Abstract

Congenital heart disease (CHD) is the most common birth defect in humans, occurring as often as 1 in 125 live births.1,2 Because prenatal diagnosis and both medical and surgical care of affected neonatal infants have improved dramatically in the past decades, the number of adult survivors of CHD is increasing. Thus, it has become increasingly important for all cardiologists to be familiar with the basic and clinical characteristics of CHD. At the same time, there has been an explosion in our understanding of the molecular and genetic programs regulating cardiovascular development (for reviews, see Olson,3 Srivastava and Olson,4 and Gruber and Epstein5). Genetic causes of specific forms of CHD are appearing in the literature with increasing frequency. Interestingly, mutations in genes that encode nuclear transcription factors account for many forms of CHD. Here, we review examples of transcription factor gene mutations that cause human disease, and we address the potential utility of applying developmental insights to the study of adult cardiac regenerative therapy and to the development of novel treatment strategies for adult heart disease. CHD most commonly arises from structural defects caused by errors in the morphogenetic programs regulating heart and outflow tract development. Less commonly, functional defects of cardiac muscle account for congenital cardiac disease such as occur in muscular dystrophies or storage diseases. These disorders are not discussed further here but have been reviewed by Cox and Kunkel,6 Emery,7 and Lapidos et al.8 Distinct and diverse structural abnormalities of the heart and cardiac outflow tract have been classically categorized according to phenotypic characteristics, with less attention to developmental or genetic mechanisms. This is likely to change in the near future. This review is not intended to be an exhaustive survey of the genetic basis of CHD. Rather, a few illustrative …