Genetic modification of the heart: exploring necessity and sufficiency in the past 10 years

It has now been approximately a decade since the directed genetic manipulation of genes responsible for normal and abnormal cardiovascular function began. During the past 10 years, thousands of embryonic stem cell lines and hundreds of unique animals carrying defined mutations in genes that impact on cardiac structure and/or function have been made. Homologous recombination in the murine genome has allowed both gene ablation and directed mutations to be placed precisely, while development of powerful transcriptional cassettes that can be exquisitely controlled has allowed both gain and loss of function approaches to be used in order to study a protein’s function, determining both necessity and sufficiency. Thus we can now ablate or augment expression of a engineered protein in the heart and are able to effectively remodel the cardiac protein profile and study the consequences of a single genetic manipulation at the molecular, biochemical, cytological and physiologic levels. The ability to effectively manipulate cardiac gene expression via transgenesis or gene targeting enables the investigator to extend correlations to defined mechanisms. This review will revisit these basic technologies, outline the strengths and weaknesses of each, and discuss the advances that are on the experimental horizon.