Fishing for the genetic basis of cardiovascular disease

Abstract

Cardiovascular disease (CVD) has recently overtaken infectious disease to become the biggest global killer. Genetic factors have emerged as being of major importance in the pathogenesis of CVD. Owing to disease heterogeneity, variable penetrance and high mortality, human genetic studies alone are not sufficient to elucidate the genetic basis of CVD. Animal models are needed to identify novel genes that are involved in cardiovascular pathology and to verify the effect of suspected disease genes on cardiovascular function. An intriguing model organism is the zebrafish danio rerio. Several features of the zebrafish, such as a closed cardiovascular system, transparency at embryonal stages, rapid and external development, and easily tractable genetics make it ideal for cardiovascular research. Moreover, zebrafish are suitable for forward genetics approaches, which allow the unbiased identification of novel and unanticipated cardiovascular genes. Zebrafish mutants with various cardiovascular phenotypes that closely correlate with human disease, such as congenital heart disease, cardiomyopathies and arrhythmias, have been isolated. The pool of zebrafish mutants, for which the causal gene mutation has been identified, is constantly growing. The human orthologues of several of these zebrafish genes have been shown to be involved in the pathogenesis of human CVD. Cardiovascular zebrafish models also provide the opportunity to develop and test novel therapeutic strategies, using innovative technologies such as high throughput in vivo small molecule screens.