Heart failure (HF) is associated with a significant incidence of lethal cardiac arrhythmias. The molecular mechanisms accounting for these arrhythmias are incompletely defined and will be the basis of study for this new, four-year application. The slower and larger late sodium current (INaL) was originally described by our laboratory in normal and failing hearts and has been recognized as an important contributor to arrhythmia generation. The molecular origin and regulatory mechanisms of INaL, particularly in diseased myocardium, remain largely unknown and will serve as the focus of this proposal.
The specific aims of this proposal will test the following hypotheses: 1) the main a-subunit of the cardiac Na+ channel isoform operates in distinct gating modes and is responsible for INaL in normal and failing myocardium, 2) INaL can be regulated by the membrane micro-environment of the channel, namely by the cytoskeleton and auxiliary beta-subunits, and 3) INaL can be modulated by intracellular signaling pathways involving the Ca2+-sensing protein, calmodulin. Ventricular canine cardiomyocytes isolated from normal hearts and hearts from dogs with chronic HF produced by sequential coronary microembolizations will be used to execute the specific aims. Whole-cell and single-channel voltage clamp techniques will be employed to study the activity of the late Na+ channels in cultured cardiomyocytes with knocked-down genes and/or altered cell-signaling pathways. Knowledge derived from the present proposal may reveal novel targets for the treatment of life-threatening arrhythmias associated with chronic HF.
