Conditional expression of diphtheria toxin A in adult mouse hearts induced cell loss, fibrosis, and a significantly higher incidence of ventricular tachycardia compared to controls.
Does conditional lineage ablation of cardiac cells in adult mice model the structural and electrophysiological abnormalities of human cardiomyopathies?
Conditional lineage ablation using DTA expression in adult mouse hearts successfully models the structural and arrhythmogenic features of human cardiomyopathies.
Absolute Event Rate: 80% vs 11.1%
p-value: p=<0.01
Cell loss contributes to the pathogenesis of many inherited and acquired human diseases. We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline-responsive promoters. As an example of this approach, we targeted expression of DTA to the hearts of adult mice to model structural abnormalities commonly observed in human cardiomyopathies. Induction of DTA expression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated-perfused transgenic hearts demonstrated a strikingly high incidence of spontaneous and inducible ventricular tachycardia. Affected mice showed marked perturbations of cardiac gap junction channel expression and localization, including a subset with disorganized epicardial activation patterns as revealed by optical action potential mapping. These studies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicability for studies of disease pathogenesis.
Lee et al. (Tue,) conducted a other in Cardiomyopathy and Arrhythmia (n=24). Conditional DTA expression (tetracycline withdrawal) vs. Nontransgenic controls was evaluated on Spontaneous or inducible ventricular tachycardia in isolated-perfused hearts (p=<0.01). Conditional expression of diphtheria toxin A in adult mouse hearts induced cell loss, fibrosis, and a significantly higher incidence of ventricular tachycardia compared to controls.