Giving credence to controls: Avoiding the false phenotype

Cardiovascular science has undergone a revolution in the past 25 years with the application of genetic engineering to the heart and creation of relevant animal models in worms, flies, mice, rats and pigs [1]. A series of evermore-powerful tools have catalyzed the creation of hearts that can express, over-express or not express targeted genes and in some cases, control the developmental timing of the manipulation. Using animal models has allowed the cardiovascular community to establish causality, confirm proof-of-principal for therapeutic approaches, and helped us to understand the relevant pathways and their most important intersections for normal and abnormal cardiac function [1]. The mouse has been the model of choice for the largest number of investigators using these tools as the advantages of dealing with a mammalian, four chambered heart in terms of the data's application to human cardiovascular function and disease remain compelling. The definition of reagents such as the α- and β-myosin heavy chain promoters (MyHC) [2,3] that allowed investigators to drive cardiomyocyte-specific expression at various developmental times and in a chamber-specific manner, cemented the mouse as an important, genetically amenable model for cardiovascular disease. The community's ability to rigorously characterize the resultant phenotype and cardiac physiology using techniques that were first developed for larger animal models, followed quickly [4,5]. The promoters were used to drive expression of a large number of normal and mutated proteins in the heart with the use of the α-MyHC promoter predominating, as it drives cardiomyocyte-specific expression in the atria during fetal development and in all four chambers starting a couple of days before birth, as thyroid hormone production begins and activates transcription from the myc6 locus [3].