Developmentally modulated cardiac conduction failure in transgenic mice with fetal or postnatal overexpression of DNA nonbinding mutant Nkx2.5.

ABSTRACT

INTRODUCTION: Nkx2.5 is a conserved homeodomain (HD) containing transcription factor essential for early cardiac development. We generated a DNA nonbinding missense mutation, I183P in the HD, similar to the missense HD mutation found in patients. Transgenic mice expressing this mutation under beta-MHC promoter [beta-MHC(I183P)] showed a postnatal lethal phenotype with heart failure. In contrast, mice expressing the mutation under alpha-MHC promoter [alpha-MHC(I183P)] survive, with later onset heart failure. The aim of this study was to investigate the interrelationship between lethal cardiac failure and the electrophysiologic (EP) phenotypes using cardiac-specific promoters with mutant gene expression at different stages of development and maturation. METHODS AND RESULTS: In beta-MHC(I183P) and wild-type littermates, six-lead ECG and in vivo endocardial EP studies were performed at 2.5, 3, 4, and 5 weeks of age. In alpha-MHC(I183P) and their wild-type controls, ECGs were acquired at 3, 19, 31, and 64 weeks and in vivo EP studies assessed at 19 +/- 4 weeks of age. Beta-MHC(I183P) mice display AV nodal, atrial, and ventricular EP dysfunction by 3 weeks of age. Bradycardia and PR prolongation were evident on telemetered ambulatory ECG of beta-MHC(I183P) mice. In contrast, alpha-MHC(I183P) mice had no abnormalities on serial ECG through 31 weeks or EP findings at 19 weeks, except increased myocardial tissue refractoriness. However, by 64 weeks, PR intervals lengthened in alpha-MHC(I183P) mice. CONCLUSION: Both prenatal and postnatal overexpression of DNA nonbinding mutant Nkx2.5 are associated with AV conduction malfunction and heart failure; however, more profound progressive EP defects are seen when this mutation expresses during fetal and neonatal periods. These conduction abnormalities may contribute to the lethal heart failure and early mortality evident in DNA nonbinding mutant Nkx2.5 mice.