This application presents and utilizes a new electrophysiology technique, the anthropomorphizing dynamic clamp (ADC) that increases the utility of genetically engineered mice in studies of inherited cardiac arrhythmias. Inherited channelopathies, such as the Long QT syndrome, are known causes of syncope, cardiac arrest, and sudden cardiac death. In the past decade, great progress has been made in identifying disease-causing mutations in patients. Several mouse models of these mutations have been produced;however, extrapolation of a mouse mutant phenotype to human disease is difficult because of the major differences between mouse and human cardiac electrophysiology dynamics. The technique proposed in this application uses a hybrid computational biology-electrophysiology method in order to examine isolated mouse myocytes in the context of a human action potential waveform. The ADC is a dynamic whole-cell patch clamp technique that couples an isolated murine cardiac myocyte to computational models. These models calculate a compensatory current which will allow a mouse myocyte to undergo a free-running human membrane potential. This will permit investigation of arrhythmogenic events, such as early after depolarizations, which are normally masked in the context of the short mouse action potential. Preliminary modeling studies have demonstrated that the ADC can be used to study the effects of a mutation introduced into a mouse myocyte on the human action potential. The ADC could be applied to a wide-range of mouse models of inherited channelopathies. Also, it is directly relevant to the NHLBI strategic plan, which specifically calls for the development of computational and experimental techniques that can help uncover the pathophysiologic mechanisms of cardiac diseases. Lay Summary: Disturbances in the normal rhythm of the heart (arrhythmias) can lead to serious health consequences, including death. Some people have inherited mutations which increase the likelihood of arrhythmias. Genetically engineered mice have been made in order to study these mutations;however, major differences exist between mouse and human heart rhythms. The new technique proposed in this application will convert the behavior of mouse heart cells to a more human-like state. Studies of mice using this technique should yield new insights into the mechanisms of heart rhythm diseases.
|Ahrens-Nicklas, Rebecca C; Christini, David J (2009) Anthropomorphizing the mouse cardiac action potential via a novel dynamic clamp method. Biophys J 97:2684-92|
|Ahrens-Nicklas, Rebecca C; Clancy, Colleen E; Christini, David J (2009) Re-evaluating the efficacy of beta-adrenergic agonists and antagonists in long QT-3 syndrome through computational modelling. Cardiovasc Res 82:439-47|